Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[O:5][C:4](=[O:19])[CH:3]=1.C1(C)C=CC([S:26](=S)(O)=O)=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(OCC)C.C(O)C>[C:32]1([CH2:31][S:26][C:3]2[C:4](=[O:19])[O:5][C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:7][C:2]=2[OH:1])[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Reactant: Cc1ccccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(O)=S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(SCc2ccccc2-c2ccccc2)C(=O)O1
Temperature: 40 °C

Procedure:
The title compound was prepared as described in General Method 7 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.96 mmol), (2-methylbiphenyl)-p-toluenethiosulfonate (0.439 g, 1.24 mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL), NaHCO3 (0.5 g). The mixture was heated to 40° C. for 16 h then diluted with diethyl ether (100 mL), and washed with H2O. The solvent was then removed in vacuo and the residue submitted to column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to provide a solid (0.33 g, m.p. 49°-51° C.). 1H NMR (400 MHz, DMSO-d6) δ 7.425-7.153 (m, 13 H), 7.74 (dd, 1 H, J=1 Hz, J=7 Hz), 3.480 (dd, 2 H, J=12 Hz, J=17 Hz), 3.149 (dd, 2 H, J=17 Hz, J=22 Hz), 1.921-1.821 (m, 2 H), 1.402-1.336 (m, 1 H), 1.161-1.071 (m, 1 H), 0.847-0.707 (m, 7 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH:25]=[CH:24][BH:18][OH:17]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OBC=Cc1ccccn1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 1 h. To the mixture was added vinylboronic acid dibutyl ester (3.4 mL) drop wise, and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[CH2:31]([Br:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[Br-:38].[CH2:31]([N+:11]1[CH:12]=[CH:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=2)[CH:10]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccccc1-c1ccncc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Product: Cc1ccccc1-c1cc[n+](Cc2ccccc2)cc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Br-]
Yield: 78.1 %

Procedure:
To a solution of 3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-o-tolyl-pyridine (prepared as described in DE 10008042 A1; 150 mg, 0.353 mmol) and benzyl bromide (60 mg, 0.35 mmol) in 3 ml acetonitrile was heated at reflux for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography to give 163 mg (78%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C=C)[C:3]([C@@H:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[CH2:8])=[O:4]>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][N:2]1[C@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:8]=[CH:7][CH2:6][C@H:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:4].[CH3:1][N:2]1[C@@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:8]=[CH:7][CH2:6][C@H:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:4]
Reactant: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C(C=C)c1ccccc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)CC=C[C@@H]1c1ccccc1
Product: CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)CC=C[C@H]1c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of benzyl ((1S)-1-{[methyl(1-phenylprop-2-en-1-yl)amino]carbonyl}but-3-en-1-yl)carbamate (2b) (1.7 g) dissolved in Toluene (200 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (191 mg) and the reaction mixture was stirred at 80° C. for 1 h, cooled to RT and concentrated in vacuo. The crude product was directly purified via flash chromatography (gradient—5%, 10%, 15% and 20% EtOAc/hexanes) to give the title compound (2c) (811 mg) and benzyl [(3S,7R)-1-methyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (2d) (590 mg) (combined yield of 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][CH:16]([CH3:32])[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1.P(C#N)(=O)(OCC)OCC.O>ClCCCl>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH2:17][CH:16]([CH3:32])[CH3:15])[CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]1)=[O:6]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)CNC1CCCN(C(=O)OC(C)(C)C)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: ClCCCl
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-amino-4-(trifluoromethyl)benzoic acid (0.32 g) and tert-butyl 3-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.4 g) were dissolved in 1,2-dichloroethane (20 ml), diethyl phosphorocyanidate (0.31 g) was added and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-1:1) was concentrated under reduced pressure to give the object compound (0.33 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13](N=CN(C)C)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:22]>O>[OH:22][C:13]1[CH:12]=[N:11][C:10]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=2)=[N:15][CH:14]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cccc(-c2ncc(N=CN(C)C)cn2)c1
Solvent: O
Product: CC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
5.10 g of N′-[2-(3-acetylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine (19 mmol) are suspended in 65 ml of water in a 250 ml one-necked flask provided with magnetic stirrer and condenser, 8.44 ml of 95-97% sulfuric acid (152 mmol) are added, and the mixture is stirred at a bath temperature of 130° C. for 2 h. The mixture is diluted with ice-water, during which a dark-brown resin deposits. The aqueous solution is decanted off and extracted with dichloromethane. The combined dichloromethane phases are dried, filtered and evaporated to dryness, and the residue is triturated with ether, filtered off with suction and dried (═K1). The deposited dark-brown resin is extracted by stirring with tetrahydrofuran, filtered off with suction, the crystals are discarded, and the mother liquor is evaporated to dryness (═R1). The aqueous phase from the dichloromethane extraction is evaporated to dryness, the residue is extracted by stirring 2× with tetrahydrofuran, and the combined decanted-off solutions are diluted with di-chloromethane, dried, filtered and evaporated to dryness (═R2). R1 and R2 are combined, adsorbed on silica gel and purified by chromatography (silica gel/dichloromethane+0-5% of methanol). The chromatography residue is triturated with ether, filtered off with suction, washed with ether and dried (═K2).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][O:20][CH3:21])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([CH2:3][C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)([CH3:23])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)cc1
Yield: 79.1 %

Procedure:
Using the general method of Example 599, 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.60 mmol, prepared as described in Example 590) was reacted with 4-fluorobenzoyl chloride (634 mg, 4.00 mmol). The crude product was purified by IFC (silica gel eluting with a gradient of 5 to 20% CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes to provide 551 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-4-fluorobenzamide as a white solid, mp 187-189° C. MS (ESI) m/z 436 (M+H)+; Anal. Calcd for C24H26FN5O2: C, 66.19; H, 6.02; N, 16.08. Found: C, 65.92; H, 5.93; N, 15.87.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.[NH2:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1.[CH3:28][S:29]([CH3:31])=O>>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][S:29][CH3:31])=[O:26])[CH2:23][CH2:24]4)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: CS(C)=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCn1ncc2c(NCC3CCC(C(=O)OCSC)CC3)c3ccccc3nc21
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (3 g), DMSO (9 ml) and trans-4-(aminomethyl)cyclohexane carboxylic acid (4.1 g) was heated at 180° C. overnight. The reaction mixture was then partitioned between CH2Cl2 and water, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silca gel to afford an oil which was crystallized from ether/hexane and then recrystallized from ether/hexane to afford 1-ethyl-N-[[4-(methylthiomethoxycarbonyl) cyclohexyl]methyl]-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 135°-136° C.
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)[N:17]=1>CN(C)C=O>[CH2:11]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)[N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:12][CH3:13]
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccsc2C1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCBr
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)no1
Reaction time: 1 h
Yield: 49 %

Procedure:
7 ml (23 mmol)of N-ethyldiisopropylamine and 0.9 ml (9.9 mmol) of 1-bromopropane were added to a solution of 1.5 g (4.74 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 40 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 250:10:1). There were obtained 930 mg (49%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one of m.p. 128.5°-130.0°.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCC(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCC(C)C)[nH]n1
Temperature: 25 °C
Yield: 707.9 %

Procedure:
Hydrazine hydrate (1.43 mL, 2.95 mmol) was added to a stirring room temperature solution of 46 (6.3112 g, 2.95 mmol) in EtOH (29.5 mL, 1 M) under N2. The reaction was then stirred at room temperature until judged complete by HPLC (35 min): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 4.3911 g (70.9%) of 47. 1H (CDCl3, 400 MHz): δ 13.01 (1H, broad s), 6.52 (1H, s), 4.29 (2H, q, J=7.1 Hz), 2.64 (2H, t, J=7.8 Hz), 1.57-1.41 (3H, m), 1.26 (3H, t, J=7.1 Hz), 5.85 (6H, d, J=5.9 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.37, 146.26, 143.1, 105.73, 60.53, 37.88, 27.35, 23.42, 22.11, 14.06 ppm. HPLC: 10.006 min.
Reaction SMILES: CO[C:3]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:4]=1[CH:5]=O.[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[CH3:16][O:15][C:13]([CH:11]([C:8]1[CH:9]=[CH:10][CH:3]=[C:4]([CH:7]=1)[CH2:5][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:12])=[O:14]
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COC(=O)C(C)c1ccc(OC)c(C=O)c1
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COC(=O)C(C)c1cccc(CN[C@H]2CCCN[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 33 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.O1CCN([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)CC1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[C:4]=2[CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C1=C(N2CCOCC2)CCC1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(F)cc2c2c1CCC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluorophenylisocyanate (5.0 g, 36.5 mmol) in chloroform (25 ml) is mixed with 1-morpholino-1-cyclopentene (5.5 ml, 36.5 mmol) and refluxed for 15 minutes. The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 7.6 g (94%) of cyclopentanone-2-carboxylic acid-(4-fluorophenyl)amide, 1H-NMR (DSC842). The amide is stirred in concentrated sulfuric acid (30 ml) for 30 minutes at 100° C. The batch is poured onto ice water and filtered. The filter residue is recrystallized from ethanol: 2.02 g (29%) of product.
Reaction SMILES: [N+](C1C=CC(C2C=CC(C(NCCCCC3C=NC=CC=3)=O)=CC=2)=CC=1)([O-])=O.S(Cl)([Cl:31])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.[OH-].[Na+]>ClCCl>[Cl:31][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: OCCCCCc1ccccn1
Reactant: O=S(Cl)Cl
Agent: O=C(NCCCCc1cccnc1)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCCCCCc1ccccn1
Temperature: -5 °C
Reaction time: 17 h

Procedure:
A solution of 4 1 mL of thionyl chloride in 30 mL of dichloromethane was added over 10 minutes to a stirred solution of 6.65 g of 2-pyridinepentanol in 60 mL of dichloromethane maintained at -5° C. After the addition was complete. the mixture was stirred at room temperature for 17 hours, then was rechilled to 5° C. as 150 ml of 1N NaOH was added droPwise over 10 minutes. The layers were separated and the aqueous layer was extracted with 75 mL of dichloromethane. The organic layers were washed with brine, then were combined. dried (K2CO3) and evaporated to yield 7.4 g of 2-(5-chloropentyl)pyridine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([N:5]1[CH:6]=[C:2]([Br:1])[C:3]([CH3:7])=[N:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Into a 500-mL 3-neck round-bottom flask, was placed a solution of 4-bromo-3-methyl-1H-pyrazole (20.0 g, 124 mmol) in N,N-dimethylformamide (100 mL). The system was purged with nitrogen, then the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 10.0 g, 250 mmol) was carefully added portion-wise and then the resulting mixture was stirred for 30 min at room temperature. The mixture was cooled to 0° C., then benzyl bromide (22.1 mL, 186 mmol) was added drop-wise and the resulting mixture was stirred overnight at room temperature. The mixture was carefully quenched by drop-wise addition of water (40 mL), then the mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (4×100 mL), dried (Na2SO4), filleted and concentrated under reduced pressure to obtain the title compound as a yellow oil (24.9 g, 80%).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:36]2[CH2:35][CH2:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:26]([NH:25][CH:22]4[CH2:24][CH2:23]4)=[O:39])=[CH:32][CH:31]=3)[CH2:38][CH2:37]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Product: CC1Oc2c(Cc3ccccc3)cc(CN3CCN(c4ccc(C(=O)NC5CC5)cc4)CC3)cc2NC1=O

Procedure:
Using 353A and N-cyclopropyl-4-(piperazin-1-yl)benzamide 284 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.55 (m, 2H) 0.62-0.69 (m, 2H) 1.31 (d, J=6.82 Hz, 3H) 2.42-2.49 (m, 4H) 2.75-2.82 (m, 1H) 3.17-3.25 (m, 4H) 3.38 (s, 2H) 3.89 (s, 2H) 4.57 (q, J=6.74 Hz, 1H) 6.73-6.82 (m, 2 H) 6.91 (d, J=9.09 Hz, 2H) 7.14-7.19 (m, 1H) 7.19-7.24 (m, 2H) 7.24-7.30 (m, 2H) 7.69 (d, J=9.09 Hz, 2H) 8.14 (d, J=4.04 Hz, 1H) 10.60 (s, 1H). ESI-MS: m/z 511.4 (M+H)+. mp=192.3-203.2° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:29]3[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: OCc1cccc(B(O)O)c1
Agent: OBO
Product: OCc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15])(=[O:13])=[O:12].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][N:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[C:6]([OH:8])=[O:7])(=[O:13])=[O:12]
Reactant: CN(C1CCCCC1)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N(C)C2CCCCC2)CC1

Procedure:
The reaction was carried out in a manner analogous to that of Example 31, using 33 g of 4-chloro-3-(N-methylcyclohexylaminosulfonyl)-benzoic acid and 30 g of N-methylpiperazine. The moist crude product, which had been washed with water, was freed from by-products by boiling with methanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][Si:20]([CH3:29])([CH3:28])[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[CH2:25]([O:24][C:22]([O:23][Si:31]([CH3:34])([CH3:33])[CH3:32])=[C:21]([Si:20]([CH3:28])([CH3:29])[CH3:19])[CH3:27])[CH3:26]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C(C)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(O[Si](C)(C)C)=C(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 21.8 mL (0.156 mole) of diisopropylamine in 100 mL of THF at 0° was added 0.156 mole of butyl lithium/hexane. After 30 minutes, the solution was cooled to -78°, and 27.19 g of ethyl 2-trimethylsilylpropionate (vide supra) was added. After 30 minutes at -78°, 17.38 g (20.3 mL, 0.16 mole) of chlorotrimethylsilane was added. The mixture was allowed to warm to ambient temperature, filtered under argon, and the filtrate was evaporated. The residue was treated with hexane and filtered. The filtrate was concentrated and distilled in a spinning band column to give, in three fractions, 29.6 g of (82% E-) [(1-ethoxy-2-trimethylsilyl-1-propenyl)oxy]-trimethylsilane, b.p 36°/0.8 mm, -43°/0.7 mm. There were no compositional differences in the three fractions. A fraction with b.p. 45°/0.7 mm was analyzed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=S)[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1.[F:19][C:20]([F:26])([F:25])[C:21]([NH:23][NH2:24])=O.C1(O)CCCCC1.FC(F)(F)C(O)=O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[N:16]4[C:21]([C:20]([F:26])([F:25])[F:19])=[N:23][N:24]=[C:15]4[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1
Reactant: S=C1CCCc2cc(-c3cccnc3)ccc2N1
Reactant: NNC(=O)C(F)(F)F
Solvent: OC1CCCCC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2n1-c1ccc(-c3cccnc3)cc1CCC2
Temperature: 120 °C

Procedure:
A flask containing the title compound from Example 2 Step E (9.0 mg, 0.04 mmol), 2,2,2-trifluoroacetohydrazide (3.2 mg, 0.04 mmol) and cyclohexanol (0.50 mL) was heated at 120° C. overnight. The reaction was then concentrated to give a residue that was diluted with dimethylsulfoxide, acidified with trifluoroacetic acid, and passed through a syringe filter before being purified by reverse phase HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, 1 M hydrochloric acid was added, and the solution concentrated to provide the title compound: LCMS m/z 330.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (br s, 1H), 8.76 (br s, 1H), 8.26 (d, J=Hz, 1H), 7.75-7.59 (m, 4H), 3.34 (br s, 1H), 2.90-2.85 (m, 1H), 2.52-2.40 (m, 3H), 2.27 (br s, 1H).