Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH2:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(N)=CC=1.C(=O)(O)[O-].[Na+].[CH3:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:44]([C:43]3[C:42]([CH3:41])=[N:50][CH:49]=[CH:48][CH:47]=3)=[O:45])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1
Reactant: Cc1ncccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccc(N)cc1
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3cccnc3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (0.26 g, 0.71 mmol) (prepared following the general procedure in Scheme 3, substituting 4-amino-piperidine-1-carboxylic acid ethyl ester for p-anisidine) in CH2Cl2 (10 mL) and aqueous saturated sodium bicarbonate solution (4 mL) was added 2-methyl nicotinic chloride (0.16 g, 1.07 mmol) and the resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over sodium sulfate and concentrated. Purification of the residue by column chromatography (2-5% MeOH/CH2Cl2) provided the B-24 (0.09 g, 26%). 1H NMR (300 MHz, CDCl3) δ 8.61-8.66 (m, 2H), 8.34 (s, 1H), 8.19-8.28 (m, 1H), 7.94 (d, 2H), 7.60-7.70 (m, 2H), 7.28-7.31 (m, 1H), 4.91 (d, 1H), 4.03 (q, 2H), 3.85 (d, 2H), 3.20-3.32 (m, 1H), 2.80 (s, 2H), 2.63-2.74 (m, 2H), 1.67 (br s, 4H), 1.16-1.21 (m, 5H). LC/MS m/z 497 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].C[C:19]([CH3:22])([O-])[CH3:20].[K+].Br[CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH:19]([O:1][C:2]1[C:6]([O:7][CH:25]([CH3:27])[CH3:26])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)Br
Reactant: COC(=O)c1oc(-c2ccccc2)c(O)c1O
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1oc(-c2ccccc2)c(OC(C)C)c1OC(C)C

Procedure:
Following the procedure described in Example 119, methyl 3,4-dihydroxy-5-phenyl-2-furancarboxylate (4.80 g, 21.6 mmol is treated with potassium tert-butoxide (5.85 g, 52.3 mmol, 1.21 equiv) and 2-bromopropane (21.0 g, 170.4 mmol, 3.94 equiv) in dimethyl sulfoxide (70 mL) at room temperature for 6.5 hours to give 5.62 g of crude methyl 3,4-diisopropoxy-5-phenyl-2-furancarboxylate as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([O:19][CH2:48][CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: OCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCCN5CCOCC5)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 124 mg, 0.65 mmol) in 10 ml of anhydrous tetrahydrofuran were added N-(3-hydroxypropyl)morpholine (125 mg, 0.86 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 90 mg, 35%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].O>CC(C)=O>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 33.6 %

Procedure:
5.6 g (0.04 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 50 ml of acetone, and 4 g of sodium bicarbonate was suspended thereinto. To the suspension was added dropwise 3.7 g of valeryl chloride with stirring. After completion of the dropwise addition, the mixture was further allowed to react at 40° C. for 3 hours. Water was added to the reaction mixture, from which the reaction product was extracted with methylene chloride, followed by the concentration of methylene chloride solution. Thereafter, hexane was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water and benzene to obtain 2.3 g of 5-t-butyl-3-valerylaminopyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[Cl-].[Ca+2].[Cl-].[Br:13]Br>S(=O)(=O)(O)O>[Br:13][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1cccnc1C
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a stirred solution of 2,3-dimethyl-pyridine (6.79 mL, 60 mmol) in fuming sulfuric acid (80 mL) held at 150° C. in a round bottom flask fitted with a water cooled reflux condenser and a calcium chloride filled drying tube, was added, dropwise, bromine (3.1 mL, 60 mmol) over 2 hr. The resulting dark red solution was stirred for 16 hr then cooled to room temperature and allowed to stand overnight. This mixture was poured into approximately 400 g of ice. This mixture was brought to pH 12 with cooling in an ice bath. The resulting mixture was extracted with ether and the ether extract washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography (50 g silica, eluted with 2-20% ethyl acetate in hexanes) to give the title compound (8.3 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12

Procedure:
A suspension of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 2.18 g of potassium carbonate in 20 ml of acetone was admixed with 3.2 ml of 1,3-dibromopropane and the mixture was refluxed for 90 minutes and was filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1 to obtain 2.37 g of N-[2-[3-bromopropoxyl]phenyl]-1H-indole-4-carboxamide melting at 145° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:26]([Mg]Br)[CH3:27].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3sccc23)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(-c2cc3sccc3c(N3CCN(CC)CC3)n2)cc1

Procedure:
To a solution of 4-(4-ethylpiperazin-1-yl)-6-(4-formylphenyl)thieno[3,2-c]pyridine (0.20 g) in tetrahydrofuran (20 ml) was added 3M ethylmagnesium bromide/diethyl ether solution (0.5 ml), and the mixture was reacted at room temperature for 30 min. To the resulting reaction solution was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried. The resulting product was filtered through NH silica gel and washed with ethyl acetate. The filtrate was concentrated, to give 0.17 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N=O.[O-]Cl.[Na+]>>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: N=O
Agent: [Na+]
Agent: [O-]Cl
Product: CCCCCCC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a flask 125 μl (0.8 mmol) of the 2-octanol, 3.2 mg (8 μmol) of the product from example 1 and 2.86 ml NaOCl-solution (0.35M; 1.0 mmol; pH 9.1 with KHCO3) were added; the mixture was maintained at room temperature under vigorously stirring. After one hour the crude organic layer was analyzed using GC: 100% of 2-octanone was obtained as desired product. The catalyst was recovered by filtration of the crude reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
6-Chloropyridin-3-ol (30.00 g, 231.6 mmol), 1-(bromomethyl)benzene (43.57 g, 254.7 mmol), and potassium carbonate (80.01 g, 579.0 mmol) were added to DMF (500 mL) and stirred at ambient temperature overnight. Water was added and extracted with ether. The organic phase was washed with 1M NaOH, dried, filtered, and concentrated to provide the title compound (50.8 g, 99.86% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:25]1([CH2:28]O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[C:13]([O:20][CH2:28][CH:25]2[CH2:27][CH2:26]2)=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Reactant: OCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(OCC2CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g, 8.38 mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous THF (32 mL) was added diethyl azodicarboxylate (40 wt % solution in toluene, 3.98 g, 9.14 mmol) dropwise. The reaction mixture was stirred at room temperature for two days and then concentrated under reduced pressure. The residue was triturated with THF/hexane (1:5, 3×15 mL). The combined extracts were concentrated under reduced pressure to give a yellow solid, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (60:1 and then 10:1) to give 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.89 g, 61%) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m, 2H), 3.79 (d, 2H, J=7.2 Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz), 0.86 (m, 6H), 0.56 (d, 2H, J=6.6 Hz), 0.27 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.49, 149.98, 144.40, 135.55, 130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q, J=272 Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14, 10.66, 3.39.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:19])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:33][N:34]1[C:38]([CH:39]=O)=[N:37][CH:36]=[N:35]1.[CH3:41][CH2:42][O-:43].[Na+]>C(OCC)(=O)CC>[F:18][C:16]1[CH:15]=[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:19])[C:41]2[C:42](=[O:43])[CH:39]([C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][C:9]=2[CH:17]=1
Reactant: Cn1ncnc1C=O
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cc(F)cc21
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Temperature: 40 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
To a solution of (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (1.25 g, 4.9 mmol), anhydrous Na2SO3 (1.24 g, 9.82 mmol), anhydrous Na2SO4 (2 g, 14.7 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (900 mg, 8.1 mmol) in ethyl propionate (50 mL) was added EtONa [(sodium 316 mg, 13.8 mmol) in 25 mL ethanol] at 40° C., then the mixture was stirred at 40° C. for 3 hr. The resulting mixture was evaporated under reduced pressure, extracted with ethyl acetate (100 mL×4) and concentrated to dryness. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=200:1 to 50:1) to obtain the title compound as a green solid (190 mg, yield 10%). LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]#[N:14].[C-:15]#[N:16].[Na+]>CN(C)C=O>[NH2:14][CH:13]([CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)[C:15]#[N:16]
Reactant: [C-]#N
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC(N)C#N)c2c1
Yield: 43 %

Procedure:
Using the same method starting from 5.4 millimoles (1 g) of (5-methoxy-3-indolyl)-acetonitrile and replacing of cyanising agent by 20 ml of a normal solution of sodium cyanide in dimethylformamide, there are obtained, after purification by an acid-base extraction, 0.50 g of 2-amino-3-(5-methoxy-3-indolyl)-propionitrile with a yield of 43%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[I:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Ic1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
5. To a 20 mL vial which contained a solution of the product from step 4 (200 mg, 0.4 mmol) in dioxane was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product (150 mg, 95%); LCMS; APCI+99%, Calcd: 393.3. Found m/z: 392.3 (M−1). 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.77 (m, 1H), 1.86-2.04 (m, 2H), 2.05-2.16 (m, 1H), 3.14-3.23 (m, 2H), 3.84 (s, 2H), 3.83-3.89 (m, 1H), 4.07-4.11 (m, 1H), 4.20 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([CH3:12])=[N:11][C:3]=12.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([CH3:12])[CH:9]=2)=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: Cc1cc2[nH]c(C)nc(Cl)c-2n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2[nH]c(C)nc(N3CCOCC3)c-2n1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a 5-mL Wheaton vial was added 4-chloro-2,6-dimethylpyrrolo[3,2-d]pyrimidine (Example 46(d)) (0.10 g, 0.55 mmol) and morpholine (Aldrich Chemical Company) (0.24 mL, 2.7 mmol). A solution. of K2CO3 (0.35 g, 2.5 mmol) in water (2.5 mL) was added and the reaction mixture heated in the capped vial at reflux for 3.5 h. The reaction mixture was cooled to room temperature and the solution was filtered. The resulting precipitate was washed with H2O and hexanes and dried in a 60° C. vacuum oven to give 0.083 g (65%) of the title compound as an off-white solid. Mp: 242-243° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.39 (s, 6), 3.60 (s, 4), 3.74 (s, 4), 6.07 (s, 1), 10.90 (s, 1). MS m/z: 233 (M+1). Anal. Calcd for C12H16N4O: C, 59.73; H, 7.10; N, 23.22. Found: C, 60.01; H, 6.84; N, 23.29.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccsc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccsc3)c2c1
Yield: 95 %

Procedure:
This compound was prepared from 6b using 3-thiopheneboronic acid according to method P. Orange powder; Yield: 95%; mp>160° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.06 (t, J=8.8 Hz, 1H), 7.30–7.33 (m, 2H), 7.50 (dd, J=4.9, 1.2 Hz, 1H), 7.82 (dd, J=4.9, 3.0 Hz, 1H), 7.90–7.95 (m, 4H), 8.06 (dd, J=13.0, 2.1 Hz, 1H), 9.97 (s, 1H), 10.19 (s, 1H); MS (ESI) m/z 336 ([M−H]−), 338 ([M+H]+); Anal. Calcd for C19H12FNO2S: C: 67.64, H: 3.59, N: 4.15. Found: C: 66.81, H: 4.14, N: 3.58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Na+]>CCO.CC(O)=O.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2cccnc12
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)cc2cccnc12
Yield: 905.1 %

Procedure:
To a solution of 6-bromo-8-nitro-quinoline (4 g, 1.58 mmol) in EtOH/HOAc/H2O (50 mL/50 mL/25 mL) was added iron metal (3.18 g, 5.69 mmol). The resulting solution was heated at reflux for 3 hours. The cooled reaction mixture was neutralized with 2.5 N NaOH, filtered through celite to remove iron solids and washed with EtOAc. The eluent was extracted into EtOAc (3×200 mL), combined, dried over NASO4 and concentrated. The resulting oil was purified by column chromatography (40% EtOAc/hexanes) affording 3.19 g (91%) of a yellow solid: mp 142-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:27]([CH3:44])[NH:26][C:25]=1[CH:45]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:45]\[C:25]1[NH:26][C:27]([CH3:44])=[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol), 3,5-dimethyl-4-[3-oxo-3-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-propyl]-1H-pyrrole-2-carbaldehyde (1.7 eq.) and piperidine (1.5 eq.) in ethanol (2 mL) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:11].[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1>CO.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][CH2:21][CH2:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc2c(c1)CCCC2
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCCC3)cn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A solution of 5,6,7,8-tetrahydro-naphthalen-2-ylamine (1.132 g, 6.08 mmol, commercially available) and (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (distilled 166-175° C./2 mb, 0.985 g, 6.69 mmol, prepared as per example 1, step 1) in MeOH (10 mL) was treated with HCO2NH4 (2.301 g, 36.5 mmol) and 10% Pd/C (250 mg) and stirred at 80° C. for 1.5 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (1.333 g, 68%) as an off-white solid. MS m/e: 321.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=O.[K+].[K+].[CH:16]1[CH:21]=[CH:20][C:19]([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>O.C1(C)C(C)=CC=CC=1>[Cl-:2].[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=2)[CH:5]=1
Reactant: ClCc1cccnc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: [Cl-]
Product: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 133.5 °C
Yield: 58.9 %

Procedure:
To a stirred solution of 3-(chloromethyl)pyridine hydrochloride (5.17 g, 31.5 mmol) in water (8 mL) was added K2CO3 (4.34 g, 31.5 mmol) portionwise. The resulting mixture was extracted three times with diethyl ether. The extracts were combined and washed twice with brine, dried and concentrated. The residue (3.25 g, 25.5 mmol) was dissolved in xylene (30 mL) and Ph3P (6.70 g, 25.5 mmol) was added. The mixture was heated at 133-134° C. overnight and then cooled to ambient temperature. The solid product was filtered, washed with toluene, and dried under vacuum to give (3-pyridylmethyl)triphenylphosphonium chloride (5.86 g, 48%) as a pinkish solid.