Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
1-(3-Aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (6 g, 16 mmol) was combined with triethylamine (11.2 mL, 80 mmol) and pyridine (100 mL). Isobutyryl chloride (1.9 g, 18 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was combined with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×200 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 6.2 g of crude N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-2-methylpropionamide as a brown solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[S-:35][C:36]#[N:37].[K+]>CS(C)=O>[CH3:32][Si:31]([CH3:33])([CH3:34])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][S:35][C:36]#[N:37])[CH2:12][CH2:11]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Reactant: N#C[S-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSC#N)CC4)c3)ncnc21
Temperature: 68 °C

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL) with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction was heated at 68° C. for 4 days at which time LCMS analysis showed ˜4:1 product/starting material ratio. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+: 469, 1H NMR (CDCl3): δ 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1B1OC(C)(C)C(C)(C)O1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2C=O)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.48 g, 4.50 mmol), 2-formylfuran-3-boronic acid pinacol ester (1.00 g, 4.50 mmol), saturated aqueous sodium carbonate solution (20 ml), and tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) in ethylene glycol dimethyl ether (25 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (750 mg, 48.4%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:19][C:20]1[CH:27]=[C:24]([CH:25]=[O:26])[C:23]([OH:28])=[CH:22][CH:21]=1.Cl>C1COCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]([OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Brc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(Br)cc1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of 2-bromopyridine (5.75 g) in THF (125 ml) was added, under argon atmosphere at -78° C., a 1.6M n-butyl lithium hexane solution (40.0 ml). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 5-bromosalicylaldehyde (3.65 g) in THF (20 ml), which was stirred for 20 minutes at the same temperature, then for further 15 minutes while warming up to room temperature. The reaction mixture was poured into 3N HCl, which was washed with diethyl ether, followed by rendering the pH to alkaline side with the addition of 3N sodium hydroxide. The resultant was washed with diethyl ether, followed by being acidified to about pH 5 with 3N HCl. The weakly acodofoed reaction mixture was subjected to extraction with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and concentrated to dryness to give 5-bromo-2-hydroxy-α-(2-pyridyl)benzyl alcohol (3.50 g) (Compound D-1), whose phisical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (5.85 g) was dissolved in methanol (20 ml), 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate, and, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g).
Reaction SMILES: CN(C)CCC[OH:6].[OH-].[K+].Cl/[C:11](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12]\[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[N:16]=[C:15]2[NH:29][N:30]=[C:31]([CH3:32])[C:14]=12.B(Br)(Br)Br>CS(C)=O.O>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[N:16]=[C:15]3[NH:29][N:30]=[C:31]([CH3:32])[C:14]3=[C:13]([CH2:12][C:11](=[O:6])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[C:19]#[N:20])=[CH:26][CH:25]=1
Reactant: CN(C)CCCO
Reactant: COc1ccc(-c2nc3[nH]nc(C)c3c(/C=C(\Cl)c3ccccc3)c2C#N)cc1
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)c(C#N)c(CC(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
36 g (350 mmol) of 3-(dimethylamino)propan-1-ol and 12 g (21.4 mmol) of potassium hydroxide are added to 12 g (30 mmol) of Z-4-(2-chloro-2-phenylvinyl)-6-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dissolved in 100 ml of dimethylsulfoxide and 36 ml of water. The reaction mixture is carried at 120° C. for 3 hours. The reaction medium is cooled to room temperature and then poured over crushed ice. The product is extracted with ethyl acetate. The organic phases are dried on sodium sulfate, filtered and then concentrated. The residue is purified immediately by silica gel chromatography (eluent: 95:5 dichloromethane/methanol). The product is then dissolved in 100 ml of dichloromethane. The reaction medium is cooled in an ice bath before 36 ml (376.5 mmol) of boron tribromide is added slowly. The reaction medium is stirred at room temperature for 3 hours and then added slowly to crushed ice. The solid is filtered, rinsed with water, dried and then purified by silica gel chromatography (eluent: 5:5 cyclohexane/ethyl acetate) to yield 6 g (54%) of 6-(4-hydroxyphenyl)-3-methyl-4-(2-oxo-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:31](C#N)=[CH:30][CH:29]=[CH:28][C:27]=2C#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:36][OH:37].Cl.[CH3:39][OH:40].O>C1(C)C=CC=CC=1>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:27]([CH:36]=[O:37])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:39]=[O:40])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(C=O)c1CCCCCCCCCc1ccccc1

Procedure:
A solution of diisobutylaluminium hydride in toluene (3.1 ml, 4.6 mmol) was added dropwise to a stirred solution of 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile (0.70 g, 2.1 mmol) in dry toluene (30 ml) under nitrogen, cooled in an ice bath. After one hour at room temperature methanol (1 ml) was added cautiously, followed by methanol:water (1:1, 1 ml) and 5M hydrochloric acid (15 ml). The mixture was extracted with diethyl ether (20 ml) and the extracts dried, filtered and evaporated to a yellow oil (0.8 g). Chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3benzenedicarboxaldehyde as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([B:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]([CH3:16])[CH3:15])=[O:11])[C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(B2OC(C)(C)C(C)(C)O2)C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 2 (0.30 g) in dichloromethane (7 mL) was added triethylamine (0.11 mL) and acetyl chloride (55 uL). The reaction mixture was stirred overnight at room temperature. Evaporation gave a green-grey foam which was purified by chromatography, with chloroform:methanol (gradient, 50:1, 30:1) as the eluent, to yield the title compound (0.19 g) as a white powder; TLC: Rf =0.35, methanol:chloroform (5:95); NMR: 0.84 (d,3, J=6.7), 0.85 (d,3, J=6.8), 1.17 (s,12), 1.7-1.8 (m,1), 2.15 (s,3), 2.66 (t,1), 4.48 (s,2), 7.46-7.55 (m,5), 8.29 (d,1, J=5), 8.82 (s,1), 9.54 (s,1); MS: m/z=469(M+1). Analysis for C24H33BN4O5 : Calculated: C, 61.55; H, 7.10; N, 11.96; Found: C, 61.55; H, 7.23; N, 11.56.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[C:34]1[CH:33]=[CH:3][C:2]([C:21]2[C:20](=[O:23])[N:19]3[CH:24]=[CH:25][S:26][C:18]3=[N:17][C:16]=2/[CH:15]=[CH:14]/[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:1][CH:4]=1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC1CC1

Procedure:
The title compound was prepared from Intermediate 2 (150 mg, 31 mmol), 4-N,N-dimethylaminophenylboronic acid (61 mg, 37 mmol), Pd[(C6H5)3P]4 (61 mg, 37 mmol) and sodium carbonate (206 mg, 1.91 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 110 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 1H), 0.50 (d, J=7.8 Hz, 2H), 1.06-1.08 (m, 1H), 6.77 (d, J=8.4 Hz, 2H), 6.88-6.90 (m, 1H), 6.97-7.04 (m, 3H), 7.14 (d, J=5.1 Hz, 2H), 7.95 (d, J=5.1 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 474.19 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 113 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1) and pyridin-3-ylboronic acid to afford a white solid. HPLC (Condition 4) tR=4.68 min, UPLC-MS (Condition 7) m/z=487.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87-1.10 (m, 6H) 1.53-1.80 (m, 2H) 1.96-2.12 (m, 1H) 3.00-3.20 (m, 3H) 3.24-3.33 (m, 1H) 4.25 (s, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.46 (dd, J=7.82, 5.08 Hz, 1H) 7.74-7.89 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.55 (dd, J=4.69, 1.56 Hz, 1H) 8.61 (d, J=1.56 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:16][C:17]1([F:32])[O:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:19]=2[O:18]1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:29]([C:26]2([C:24]3[CH:23]=[CH:22][C:20]4[O:21][C:17]([F:32])([F:16])[O:18][C:19]=4[CH:25]=3)[CH2:28][CH2:27]2)=[O:30])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Nc1cccc(Br)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a solution of 6-bromopyridin-2-amine (660 mg, 3.8 mmol) and Et3N (1.1 mL, 7.7 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.0 g, 3.8 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL) and was washed with 1 N aqueous HCl (1×10 mL) and saturated aqueous NaHCO3 (1×10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-bromopyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (780 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.01-7.99 (m, 1H), 7.75-7.71 (m, 1H), 7.54 (m, 1H), 7.41-7.39 (m, 1H), 7.36-7.30 (m, 2H), 1.52-1.49 (m, 2H), 1.20-1.17 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccc(Cl)c(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 58 mmol) in acetonitrile (150 mL) was added 1-chloropyrrolidine-2,5-dione (8.1 g, 60 mmol) and the mixture was heated at 80° C. for 10 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water. The organic phase was concentrated and purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. LCMS: 208 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[PH+](C)C.[C:12]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]2[C:24](=O)[CH3:25])=[CH:16][CH:15]=1)#[N:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[C:21]([C:24]([CH3:1])=[CH2:25])[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH:23]=1)#[N:13]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2ccc(C#N)cc2c1C(C)=O
Agent: C[PH+](C)C
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1c(OC)ccc2ccc(C#N)cc12
Temperature: 100 °C
Yield: 93.7 %

Procedure:
Under nitrogen atmosphere, 0.62 g of potassium t-butoxide was suspended in 10 ml of toluene, and 2.26 g of trimethylphosphonium iodide was added to the resulting suspension at room temperature. The resulting mixture was stirred under heating at 100° C. for one hour to give a yellow suspension. Then, 0.84 g of 7′-cyano-2′-methoxy-1′-acetonaphthone was added to the yellow suspension, and the resulting mixture was further stirred at 10° C. for 30 minutes, cooled to room temperature by allowing to stand, diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.78 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1ccnc1C(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (14 mg, 0.04 mmol, 35%). LCMS: [M+H]+=335, Rt=1.44 min, 100% purity.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])(=[O:17])=[O:16].C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:19]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Temperature: 170 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-(methylsulfonyl)aniline (467 mg), N,N-diisopropylethylamine (0.48 mL) and dioxane (18 mL) was stirred in a sealed tube at 170° C. for 17 hours. After cooling, the mixture was partitioned using ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was washed with chloroform, and the solid was collected by filtration and dried to give 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (412 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in DCM (20 ml) was added TsCl (1.09 g, 5.73 mmol) and TEA (1.60 mL, 11.46 mmol), followed by DMAP (70 mg, 0.573 mmol). After stirring for 1 h at room temperature, the solution was concentrated, and the residue was partitioned between EtOAc and H2O, the organic layer was separated, washed with 1N HCl, 5% NaHCO3, dried and concentrated to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]([C:22]([O:24]CC)=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)=[O:8])[CH2:3]1.[OH-].[Li+].CO>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)=[O:8])[CH2:3]1
Reactant: CCOC(=O)c1cc(C(=O)N2CC[C@@H](O)C2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC[C@@H](O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (R)-ethyl 5-(3-hydroxypyrrolidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (1.25 g, 3.54 mmol), lithium hydroxide (0.42 g, 18 mmol), methanol (50 mL), and water (5 mL) was stirred at rt for 4 h. LC-MS indicated completion of the reaction. The volatiles were removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford a white foam. LC-MS: 326.3 [M+1]+; 1H NMR (400 MHz, CD3OD): 8.33 (m, 1H), 8.11 and 8.10 (t, 1H, J=1.6 Hz), 7.98 and 7.97 (t, 1H, J=1.6 Hz), 7.57 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=8.0 Hz), 4.51 and 4.38 (m, 1H), 3.85-3.35 (m, 4H), 2.39 (s, 3H), 2.20-1.90 (m, 2H).