Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 590.2 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:36]=[C:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:41]3[CH2:40][CH2:39][NH:38][C:37](=[O:36])[CH2:42]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Reactant: O=C1CNCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCNC(=O)C3)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole prepared in Step B (1.0 g, 2 mmol) was dissolved in DCM (10 mL). Et3N (560 uL, 4 mmol) was added, 2-oxo-piperazine (300 mg, 3 mmol) was added, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, saturated aqueous NH4Cl solution was added, and the reaction mixture was extracted with DCM. After drying, the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the title compound (825 mg, Yield 78%).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20]N>C(O)(=O)C.C(O)CCC>[F:17][C:18]([F:23])([F:22])[CH2:19][N:20]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: NNCC(F)(F)F
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1-c1ncnn1CC(F)(F)F

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide (1.0 g, 4.5 mmol) in acetic acid (25 mL) and n-butanol (15 mL) was treated with 70% aqueous 1,1,1-trifluoroethylhydrazine (1 mL, 11.3 mmol), and heated to reflux for 2 hours, at which time the volume was reduced by ˜25 mL by distillation. The remaining solvent was removed in vacuo, and the residue chromatographed on silica eluting with 3:1-1:1 hexane:ethyl acetate to afford 1-(2,2,2-trifluoroethyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced as in Example 64 to give crude 1-(2,2,2-trifluoroethyl)-5-(2-aminophenyl)-1,2,4-triazole (430 mg).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:28])[CH:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[C@H:8]2[S:7]1.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:28])[CH:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Yield: 105.4 %

Procedure:
Acetic acid (4 ml) and zinc powder (3 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate (3.2 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, ethyl acetate (100 ml) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was washed with 5% hydrochloric acid saturated with sodium chloride, and then extracted with a saturated sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After the solvent was distilled off, the crystalline residue was recrystallized from a mixture of ethyl acetate and benzene to give 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid (2.3 g), mp 162° to 166° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].C(Cl)Cl.CCN([CH2:27][CH3:28])CC>>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][C:3]([O:2][CH2:1][C:28]2[CH:27]=[CH:9][CH:10]=[CH:5][CH:6]=2)=[O:4])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
(3R,4S)-4-Amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (540 mg, synthesized according to Duan, Jingwu et al, PCT Int. Appl. (2001), WO 2001070673 A2) and WO 2002002525) was dissolved in abs. DCM and NEt3 (0.39 ml) was added.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl[C:17](OC1C=CC([N+]([O-])=O)=CC=1)=[O:18].C(N(C(C)C)CC)(C)C.[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43]([N:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)=[CH:44][CH:45]=[N:46]2)=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43]([N:49]3[CH2:54][CH2:53][N:52]([C:17]([NH:15][CH:12]4[CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]4)=[O:18])[CH2:51][CH2:50]3)=[CH:44][CH:45]=[N:46]2)=[CH:41][CH:40]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CC1

Procedure:
As described for example 78, 4-amino-N-1-Boc-azepine, p-nitrophenyl chloroformate, diisopropylethyl amine and 7-chloro-4-piperazinylquinoline are reacted to afford the title product. LC-MS: 488 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.96 (d, 1H), 7.45 (d, 1H), 6.85 (d, 1H), 4.55 (m, 1H), 4.05 (m, 1H), 3.90 (m, 1H), 3.60 (m, 4H), 3.30 (m, 1H), 3.20 (m, 4H), 3.10 (m, 2H), 2.10 (m, 1H), 1.60–1.90 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](Cc3ccccc3)(CC1)C2
Product: [Br-]
Temperature: 60 °C
Yield: 59.7 %

Procedure:
To a solution of 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) in 2CH3CN/3CHCl3 (3.5 mL) was added (bromomethyl)benzene (0.030 mL, 0.252 mmol). The solution was heated to 60° C. for 16 h. The reaction was cooled to room temperature and concentrated under vacuum. The residue was taken up in DMSO and purified by Gilson preparatory HPLC (without TFA) to give the title compound (0.0417 g, 59.6%). EI-MS m/z 451 (M+) Rt (1.20 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>CN(C)C=O.O>[CH2:16]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:17]
Reactant: CCI
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 3-aminobenzenethiol (5.0 g, 39.9 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.62 g, 47.9 mmol) and iodoethane (3.19 mL, 39.9 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-30% ethyl acetate/hexanes) to afford 3-(ethylthio)aniline (5.12 g, 84% yield). MS (m/z) 154.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: N#Cc1cccc(N)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00g, 9.01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37 mmol), then solid NaBH(OAc)3 (2.48 g, 11.7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, then dried over MgSO4, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1.58 g (54%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]benzonitrile product as a clear oil. 1H NMR (CDCl3) δ4.38 (s, 3H), 5.89 (dt, 1H), 6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40 (t, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13](Br)=[C:14]([Br:16])[N:15]=2)=[O:10])=[CH:3][CH:2]=1.C(OC([N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:51]1[O:55][N:54]=[C:53]([CH3:56])[N:52]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[NH:15][C:14]([Br:16])=[C:13]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[NH:33][C:34]([C:51]3[O:55][N:54]=[C:53]([CH3:56])[N:52]=3)=[CH:35]4)[N:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)NCc2ccncc2)nc(Br)c1Br
Reactant: Cc1noc(-c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccncc5)[nH]c4Br)ccc3[nH]2)n1
Temperature: 120 °C

Procedure:
To a solution of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid(pyridin-4-ylmethyl)-amide (280 mg, 0.57 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (243 mg, 0.57 mmol) in toluene (5.0 ml) is added aqueous Na2CO3 solution (2M, 0.63 ml, 1.26 mmol). The mixture is purged with argon for 10 minutes. (Bis(di-t-butyl(4-dimethylaminutesophenyephosphine)dichloropalladium(II) (81 mg, 0.11 mmol) is added and the reaction mixture is sealed in a sealed tube and heated to 120° C. for 14 hours. The reaction mixture is diluted with ethyl acetate (25 ml), washed with water (15 ml), brine (15 ml), dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on reversed phase HPLC. The resulting protected analog is dissolved in 50% trifluoroacetic acid in dichloromethane (10 ml). After 2 hours the solvent is evaporated in vacuo, and the product is purified by reverse phase HPLC, 25 mg, 9%, LC/MS ESI m/z (M+H)+=480.33.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:21].Cl>C(O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:4]=3[Cl:3])[C:11]=2[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Yield: 78.4 %

Procedure:
A 10% sodium hydroxide aqueous solution (3.10 g) and 10 ml of ethanol were added to 0.94 g of 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and the mixture was heat-refluxed for 1 hour. The reaction solution was adjusted to a pH of 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.68 g of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (129).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:14](=[O:16])[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=[C:2]3[C:11]=2[CH:10]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Product: COc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3d and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 3.90 (3H, s), 7.17 (1H, m), 7.27 (1H, dd, J=9.06, 2.64 Hz), 7.40 (2H, m), 7.57 (1H, d, J=3.02 Hz), 7.67 (1H, d, J=9.06 Hz), 8.20 (2H, m), 8.63 (1H, s). m/z 292.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][C:16]1[C:21]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:31].[CH3:32]OC(OC)OC>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:31]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([B:22]4[O:26][C:25]([CH3:27])([CH3:28])[C:24]([CH3:30])([CH3:29])[O:23]4)[C:16]=3[CH3:15])[CH:32]=[N:1]2)=[CH:7][CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(OC)OC
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(N)c1
Solvent: Cc1ccccc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O

Procedure:
A solution of 2-Amino-4-tert-butyl-benzoic acid (78 mg, 0.41 mmol) in 2 mL trimethylorthoformate was heated to 105° C. for 30 minutes. The resulting solution was concentrated in vacuo. 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (100 mg, 0.41 mmol) in 2 mL toluene was added. The resulting mixture was heated at reflux for 1 hour, concentrated in vacuo, and purified by flash chromatography (15% ethylacetate/hexanes) to yield 7-tert-Butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3H-quinazolin-4-one (68 mg, 0.16 mmol). MS (ESI) 419.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Oc2ccc(Br)c(C=O)c2)cc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a mixture of 6-chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (4.8 g, 16.62 mmol) and 2-bromo-5-hydroxy-benzaldehyde (4.01 g, 19.94 mmol) in DMF (30 mL) was added potassium carbonate (3.44 g, 24.93 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure and the residue was diluted with EtOAc (200 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 2-25% EtOAc/hexanes as gradient elution yielding the title compound (4.8 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 8.46 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.09 (s, 1H), 4.75-4.67 (m, 1H), 4.49-4.45 (m, 2H), 4.00-3.89 (m, 1H), 3.85-3.74 (m, 2H), 3.49-3.41 (m, 1H), 1.78-1.53 (m, 2H), 1.39-1.53 (m, 4H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([N:21]=[O:22])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCN(N=O)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 52.6 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 100 parts of acetic acid and 100 parts of water is added dropwise, during a 1.50 hours-period, a solution of 20.8 parts of sodium nitrite in 100 parts of water at a temperature between 0° and 5° C. Upon completion, stirring is continued for 30 minutes. The reaction mixture is diluted with water. The precipitated product is filtered off and crystallized from 2-propanol, yielding 22.5 parts of 1-(4-methoxyphenyl)-4-nitrosopiperazine; mp. 94.5° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[C:24]([C:27]5[CH:28]=[N:29][C:30](OC)=N[CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:35](NC(N1C2C(=C(CC3C4C(=NC=C(OC)C=4)NC=3)C=CC=2)C=C1)=O)CCC.C(NC(N1C2C(=C(CC3C4C(=NC=C(C5C=CN=CC=5)C=4)NC=3)C=CC=2)C=C1)=O)CCC>>[CH2:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[C:24]([C:27]5[CH:28]=[N:29][CH:30]=[CH:35][CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5cnc(OC)nc5)cc34)cccc21
Reactant: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(OC)cc34)cccc21
Agent: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5ccncc5)cc34)cccc21
Product: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5cccnc5)cc34)cccc21

Procedure:
The corresponding hydroxy-methyl derivative of Scheme 41 Step 2 was reacted following the protocol of Scheme 41a to prepare 4-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-indole-1-carboxylic acid butylamide P-1861, 4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylic acid butylamide P-1876, and 4-(5-Pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylic acid butylamide P-1877, with structures shown below.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl.C(OCC)C>[CH2:1]([C:8]1[CH:13]=[C:12]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc(Cc2ccccc2)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccnc(Cc3ccccc3)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyl-4-chloropyridine (0.480 q; see Example 1) and N-methylpiperazine (1.0 ml) is heated at 125° under an inert atmosphere for 17 hours. Upon cooling to room temperature, the mixture produces a crystalline mass. The crude solid is treated with saturated aqueous potassium carbonate (5 ml), water (2 ml), diethyl ether (5 ml) and dichloromethane (5 ml). The organic layer is separated, dried and concentrated to an oil. Excess N-methylpiperazine is removed by drying the oil at 45° under high vacuum (10 torr), giving the title compound as a viscous oil. Structure assignment is confirmed by nmr spectroscopy. nmr (CDCl3): δ (ppm) 2.34 (s, 3H); 2.48 (dd, 4H); 3.28 (dd, 4H); 4.07 (s, 2H); 6.5 (m, 3H); 7.26 (m, 4H); 8.22 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 40 °C
Yield: 74.5 %

Procedure:
To a stirring solution of 3-fluoro-4-hydroxybenzaldehyde (508 mg, 3.63 mmol) and CsCO3 (1.25 g, 3.84 mmol) in dry MeCN (5.6 mL) under nitrogen at ambient temperature was added benzyl chloride (0.45 mL, 3.91 mmol) and the mixture heated at 40° C. for 27 h. The mixture was then allowed to cool to rt, was quenched by the addition of aqueous NaOH (2N, 30 mL) and the product extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (80 mL) and reduced under vacuum. The residue was then purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 0:1) to afford the title compound as a colourless solid (623 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]#[N:14])=[O:10])=[CH:3][CH:2]=1.B.CSC.O.[ClH:20]>O1CCCC1>[ClH:20].[C:9]([NH:11][CH2:12][CH2:13][NH2:14])([O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:10]
Reactant: N#CCNC(=O)OCc1ccccc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Under an atmosphere of dry argon, 24.3 g (0.128 mol) of N-CBZ-aminoacetonitrile (1e) was dissolved in anhydrous tetrahydrofuran (32 ml). The solution was stirred and 64 ml of borane-methylsulfide complex (2M in tetrahydrofuran) was added via syringe. The mixture was heated to reflux and stirred overnight. The mixture was cooled with an ice bath as 5 ml of water was added slowly, with vigorous stirring. The stirring was continued for ca. 5 minutes, then 75 ml of 6M HCl was slowly added. The mixture was stirred for 1 hour, then the excess tetrahydrofuran and dimethyl sulfide was removed in vacuo . The aqueous residue was extracted with ether (2×50 ml). The ether extracts were then discarded. The pH of the aqueous residue was raised to 11 by adding concentrated NH4OH. The resulting aqueous solution was extracted with ethyl acetate (3×100 ml) and the ethyl acetate extracts were combined and washed with brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo. The resulting oil was dissolved in 30 ml of anhydrous methanol, treated with cold methanolic HCl and concentrated in vacuo to produce a solid. The solid was triturated with ether and collected by filtration to give 15.1 g (51% yield) of N-CBZ-ethylenediamine hydrochloride (1f) as a white powder. 1H NMR(D2O) δ 3.15(m, 2H), 3.46(m, 2H), 5.14(s, 2H), 7.46(bs, 5H); 13C NMR (D2O) δ 41.1, 42.6, 70.4, 131.0, 131.3, 131.7, 132.0, 139.4, 161.7.