Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([Br:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[Br:12][C:10]1[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)=[N:14][S:13][C:9]=12
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 423.9, 426.0 (M−1).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27](OCC)=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27]([NH2:2])=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(C)c1n2Cc1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Temperature: 50 °C
Yield: 98.5 %

Procedure:
A slurry of 0.38 g of ammonium chloride in 15 ml of dry toluene was cooled in an ice bath and treated with 3.5 ml of a 2.0 M solution of trimethylaluminum in toluene. This mixture was stirred for 1 hour at room temperature, whereupon 0.762 g (2.02 mmol) of ethyl 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 10 ml of toluene and 1 ml of dichloromethane was added. The mixture was heated to 50° C. overnight, cooled and quenched with 20 ml of aqueous 5% HCl solution. Ethyl acetate extracts (3×100 ml) were washed with water and then with brine, dried over magnesium sulfate and concentrated to afford 0.693 g (98%) of the subtitle compound. ESIMS m/e 349 (M++1) NMR (300 MHz, CDCl3): δ 7.25 (m, 3H); 6.83 (d, J=7.2, 2H); 6.74 (d, J=7.8, 1H); 6.40 (d, J=7.8, 1H); 5.93 (br, 1H); 5.54 and 5.45 (ABq, J=17.7, 2H); 5.42 (br, 1H); 4.14 (br, 1H); 3.87 (s, 3H); 2.65 (dt, J=16.4, 4.1, 1H); 2.55-2.36 (m,2H); 2.45 (s, 3H); 1.97-1.86 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-6-methylpyridine (723 mg, 3.47 mmol) in N,N-dimethylformamide (11.5 ml) was added sodium hydride (mineral oil 55% dispersion) (0.18 g, 4.2 mmol) in portions under ice cooling. After stirring at room temperature for 30 minutes, tert-butyl bromoacetate (0.62 ml, 4.2 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate-10:1→5:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.14 g) substantially quantitatively as a colorless liquid.
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([O:16][Si](C(C)(C)C)(C)C)([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([C:4]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([OH:16])([CH3:14])[CH3:15])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-allyl-3-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one isomer 1 (80 mg, 0.19 mmol) in 20% TFA/DCM (2 mL) was stirred for 30 min at 0° C. The mixture was concentrated to give crude 6-allyl-3-((S)-3-hydroxy-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one isomer 1 (50 mg, 86%). LC-MS Method 2 tR=1.85 min, m/z=326, 304; 1H NMR (CDCl3) 1.07 (m, 6H), 1.18 (s, 3H), 2.15 (m, 1H), 2.25 (m, 1H), 2.58 (m, 2H), 2.90 (m, 1H), 3.08 (m, 1H), 3.20 (m, 1H), 5.02 (m, 2H), 5.68 (m, 1H), 7.22 (3H), 7.31 (2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CCCCc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of compound 77 (158 mg, 0.83 mmol), NH4Cl (666 mg, 12 mmol) and Iron Powder (463 mg, 8.3 mmol) in water (5 mL) and CH3OH (5 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 78 (100 mg, 75%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ8.04 (s, 1H), 6.90-7.00 (m, 2H), 3.53 (br s, 2H), 2.83 (t, 2H, J=7.1 Hz), 2.36 (t, 2H, J=7.1 Hz), 2.02-2.12 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=O)[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].N1CCCCC1.C(O)(=O)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:31][CH:32]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.60 g), diethyl malonate (0.69 g), piperidine (0.12 ml), benzoic acid (0.09 g), and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). Sodium borohydride (105 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml), and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (1.76 g, yield: 83%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6](C(O)=O)[NH:5][C:4]=2[CH:3]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2sc(Cl)cc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: Clc1cc2[nH]ccc2s1
Temperature: 160 °C

Procedure:
A solution of 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (4 g, prepared by following the procedure described in WO2002/20530), and 0.7 g of Cu powder in 45 mL of quinoline was vented once with nitrogen, and then heated at 160° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to r.t. and treated with 150 mL of 3N HCl and diluted with 100 mL of 1:1 EtOAc/hexane. The reaction mixture was then filtered through a pad of silica gel and the filter cake was washed with 200 mL of 1:1 EtOAc/hexanes. The organic phase was separated and washed with 200 mL of brine and dried over Na2SO4. After filtration and concentration, 3.5 g of the crude title compound was obtained as brown oil which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[NH2:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:5]2[C:6](=[O:8])[N:14]([CH:15]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:10])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)cc1
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 4.5-dichlorophthalic anhydride (0.91, 4.19 mmol) and 3-amino-3-(4'-methoxyphenyl) propionic acid in 10 mL acetic acid was stirred under nitrogen for 6 hours. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 1.20 g (61%) of 3-(4',5'-dichlorophthalimido)-3-(4'-methoxyphenyl)propionic acid as a white powder. mp 182°-185° C.; 1H NMR (DMSO-d6, 250 MHz) δ 8.19 (s, 2H), 7.34 (d, 2 H, J=8.7), 6.90 (d, 2H, J=8.7), 5.61 (t, 1H, J=7.8), 3.72 (s, 3H), 3.50-3.20 (m, 2H). 13C NMR (DMSO-d6) δ 171.6, 165.8, 158.8, 137.6, 131.0, 130.4, 128.4, 125.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14N2O7. Theoretical: pending
Reaction SMILES: Br[CH2:2][CH:3]1[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5][C:4]1([CH3:17])[CH3:16].C1(O)C=CC=CC=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH3:16][C:4]1([CH3:17])[CH:3]([CH2:2][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5]1
Reactant: CN1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1O)C(CBr)C(C)(C)O2
Solvent: CC#N
Solvent: Oc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)C(CN1CCN(C)CC1)C(C)(C)O2
Yield: 22.8 %

Procedure:
A solution of 3-bromomethyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ol (81 g, 270 mmol), phenol (26.75 g, 284 mmol) and N-methylpiperazine (28.47 g, 284 mmol) in acetonitrile (300 ml) is stirred at reflux temperature for 60 hrs. The precipitate that formed is collected, washed with acetonitrile and slurtied in 10% sodium bicarbonate solution. The product is extracted twice with ethyl acetate, and the extract is washed with water and brine, dried (sodium sulfate) and evaporated. The resulting solid is dissolved in ethanol (150 mL) and 2N hydrochloric acid (150 mL), and evaporated to near dryness. The resulting solid is recrystallized in ethanol/ethyl acetate to give after drying at 60° C. under 13 Pa and equilibration in a moist atmosphere for 24 hrs, 48.60 g (44%) of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate, mp=172°-3° C.(dec.). A second crop of 19.63 g of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol (total yield 63%) could be obtained from the filtrate after purification of the free base by column chromatography on silica gel eluting with dichloromethane/methanol 9:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6](O)=[O:7].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7]
Reactant: Nc1ccccc1
Reactant: COc1cc(C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Product: COc1cc(C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 11 %

Procedure:
The compound was prepared by reaction of 3-methoxy-5-(6-methoxynaphthalene-2-yl)benzoic acid (500 mg, 1.62 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/dichloromethane 1/1 as the eluent yielded the desired product in a yield of 11%, 68 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N([CH2:17][CH3:18])CC)C.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>ClCCl>[F:19][C:20]1[CH:21]=[CH:22][C:17]([CH3:18])=[C:24]([CH:28]=1)[C:25]([N:1]([C:25](=[O:26])[C:24]1[CH:28]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=1[CH3:29])[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[O:26]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C(=O)c2cc(F)ccc2C)C(=O)c2cc(F)ccc2C)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4.5 g of methyl 6-aminopyridine-3-carboxylate and 5.53 ml of triethylamine in 40 ml of dichloromethane (cooled in an ice bath) is added 6.38 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature under argon for 18 hours and an additional 3.4 g of 5-fluoro-2-methylbenzoyl chloride added. After stirring at room temperature for 3 hours, the mixture is filtered to give 3.0 g of methyl 6-[[bis(5-fluoro-2-methylbenzoyl)]amino]pyridine-3-carboxylate. The filtrate is concentrated to dryness and the residue triturated with hexane and ethyl acette to give an additional 9.0 g of bis acylated compound.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C.[Cl:44]CCl>>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:16]=4[Cl:15])=[CH:22][C:23]=3[Cl:44])=[O:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.472 g of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight to give the product (0.27 g) as a pale yellow glass; anal. calc'd: C, 58.7; H, 3.4; N, 11.0; Cl, 20.8 Found C, 57.3; H, 3.3; N, 9.5; Cl, 21.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>C1COCC1>[C:26]([N:29]1[CH2:34][CH2:33][C:32]([OH:35])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
Di-isopropyl amine (11.9 ml, 85 mmol) was dissolved in THF (200 ml) and cooled to 0° C. and n-butyllithium (2M, 42 ml, 85 mmol) was added over one minute. This solution was stirred at 0° C. for 15 minutes and tributyltin hydride (22.8 ml, 85 mmol) was added over one minute to give a yellow solution. After 45 minutes at 0° C. the solution was cooled to -70° C. and 1-acetyl-4-piperidone (10.2 g, 71 mmol) in THF (60 ml) was added to the solution dropwise. Upon completion of this addition, the reaction mixture had become difficult to stir and an additional 100 ml of THF was added, and stirring continued at -70° for 2.5 hours. At -70° C. the reaction was quenched by addition of sodium dihydrogen phosphate buffer, pH 6.5. The reaction was allowed to warm to 0° C. This slurry was diluted with diethylether (600 ml) and water. The organic layer was separated, washed with NaCl solution, dried over MgSO4, and evaporated to give the crude product. This was purified by flash column chromatography on silica gel using methylene chloride and 9/1 methylene chloride-ethanol. Evaporation of the appropriate fractions gave 16.4 g of the title compound, 20, which was used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:19]=[CH:18][C:14]([C:15](=[O:16])[NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)=[CH:13][CH:12]=3)[CH:6]=[CH:5]4)=[O:38])=[CH:35][CH:34]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: Nc1nccs1
Product: O=C(Nc1ccc2c(ccn2-c2ccc(C(=O)Nc3nccs3)cc2)c1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 953 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, 2-aminothiazole, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C30H27N5O3S: 538.18; found: 539.02.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][C:16]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccc(Cl)cc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 38.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 0.50 g, 3.4 mmol), 2,4-dichlorophenylboronic acid (Lancaster; 645 mg, 3.4 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,4-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (380 mg, 34%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24][NH:25][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Product: COc1ccc(C(NCc2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 95.5 %

Procedure:
Following a similar procedure to that described in Example (1a), 8.91 g of 4-methoxyphenyl 3-nitrophenyl ketone and 4.96 g of 3,4-difluorobenzylamine were reacted, to obtain 12.72 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][CH:2]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][S:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]2)(=[O:12])=[O:11]>>[ClH:9].[F:1][CH:2]1[CH2:8][N:7]([S:10]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]3)(=[O:11])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: FC1CNCCNC1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNCC(F)C3)c12
Product: Cl
Yield: 32.7 %

Procedure:
Using 0.65 g of 6-fluoro-hexahydro-1H-1,4-diazepine synthesized in accordance with J. Med. Chem., 1990, 33, 142 and 0.72 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.35 g of the objective compound (white crystals).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:9]=1.[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>CCO.C([O-])(O)=O.[Na+]>[NH:24]1[C:25]2[C:21](=[C:20]([NH:19][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:9]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1.[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:19][C:20]2[C:21]3[CH:22]=[CH:23][NH:24][C:25]=3[CH:26]=[CH:27][CH:28]=2)[CH:9]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: CC(=O)Nc1cc(-c2cnccc2Cl)nc(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cc(-c2cnccc2Nc2cccc3[nH]ccc23)nc(C)n1
Product: Cc1nc(N)cc(-c2cnccc2Nc2cccc3[nH]ccc23)n1
Temperature: 160 °C
Yield: 37 %
Yield: 35 %

Procedure:
A mixture of N-(6-(4-chloropyridin-3-yl)-2-methylpyrimidin-4-yl)acetamide (50 mg, 190 μmol) and 4-aminoindole (50 mg, 381 μmol, Alfa Aesar) in EtOH (2 mL) was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (3 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give N-(6-(4-(1H-indol-4-ylamino)pyridin-3-yl)-2-methylpyrimidin-4-yl)acetamide (24 mg, 35% yield) and N-(3-(6-amino-2-methylpyrimidin-4-yl)pyridin-4-yl)-1H-indol-4-amine (22 mg, 37% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([CH3:13])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(=O)Nc1cccc(C#N)c1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(C#N)c1C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-cyano-2-methylphenyl)acetamide (CAS #: 70946-79-1) (1.8 g, 10.33 mmol) in conc. sulfuric acid (20 mL) at −10° C., potassium nitrate (2.08 g, 20.67 mmol) in 5 mL of conc. sulfuric acid was added slowly. After addition, the reaction was stirred at −10° C. for 30 min, then at 0° C. for 3.5 hr. The reaction mixture was poured onto ice, and then the precipitate was collected by filtration. The solid was washed with water and then purified by silica gel flash column chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI−) m/z 218.0 (M−H).