Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=2[OH:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:19][C:14]1[C:13]([OH:20])=[C:12]([S:9]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:30][CH:29]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-(aminomethyl)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (235 mg, 0.50 mmol) in a mixed solvent (10 mL of CH2Cl2 and 2 mL of i-propanol) at rt was added 4-fluorobenzaldehyde (62 mg, 0.50 mmol). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (37 mg, 1.00 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 ml of saturated aq NaHCO3. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by prep HPLC to give the title compound (164 mg, 57%) as a white solid. MS (ESI): 577.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][O:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:19]([C@H:18]([CH3:20])[C:17]([O:16][CH3:15])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: COC(=O)[C@@H](C)N
Solvent: CO
Product: COC(=O)[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol) and D-alanine methyl ester (4 g, 0.04 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (330 g of silica gel, 0-50% EtOAc/Hexane) to give a yellow solid. MS m/z 277.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[NH:26][C:25]1=[O:31]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CC3)C(=O)N2
Yield: 62.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 62.8%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[C:8]([C:7]1[C:2]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:3][C:4]([S:11][CH3:12])=[N:5][C:6]=1[CH3:10])#[N:9]
Reactant: Nc1cccc(NC(=O)N2CCCC2)c1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Product: CSc1nc(C)c(C#N)c(Nc2cccc(NC(=O)N3CCCC3)c2)n1

Procedure:
The compound was prepared from 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile and N-(3-aminophenyl)-1-pyrrolidinecarboxamide following a procedure similar to that described for Intermediate 23.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)C.O.NN>C(O)C.O.[Ni]>[C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccccc3)c2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc2ncnc(Nc3ccccc3)c2c1

Procedure:
A solution of 4-(phenylamino)-6-nitroquinazoline in ethanol/water and a polar solvent such as iso-propylalcohol is reacted at reflux temperature with hydrazine hydrate and Raney®Nickel. The reaction mixture is filtered, evaporated and purified by silica gel chromatography, to give the product, 4-(phenylamino)-6-aminoquinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28]O[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:32]O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:32][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=NS(=O)(=O)N1CCOCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: CO
Solvent: CCO
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1

Procedure:
(−)-(4S)-3-(4-Chlorophenyl)-N-methyl-N′-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. ([α25D]=−144°, c=0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)([CH2:6][CH2:7][C:8]2=[O:10])[CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:35]1[CH:36]=[CH:37][C:32]([NH:31][C:13](=[O:15])[CH2:12][CH2:11][C:5]23[CH2:6][CH2:7][C:8](=[O:10])[N:9]2[C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:33][CH:34]=1
Reactant: O=C(O)CCC12CCC(=O)N1C(=O)CC2
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC12CCC(=O)N1C(=O)CC2)Nc1ccncc1
Reaction time: 16 h

Procedure:
A suspension of 21.1 g of tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-propanoic acid, 21.7 g of dicyclohexylcarbodiimide, and 100 mg of 4-dimethylaminopyridine (catalyst) in 100 ml of methylene chloride are treated with 9.4 g of 4-aminopyridine. The mixture is stirred for 16 hours and the by-product, N,N1 -dicyclohexylurea, is removed by filtration. The product is purified by chromatography over silica gel using 40% 2-propanol-methylene chloride for elution. After recrystallization from water, the product is isolated as a white solid with a melting point of 285°-287° C.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[N:12]1([C:17]2[N:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[N:12]1([C:17]2[N:22]=[C:21]([C:2]3[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=3[CH3:11])[CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC1(C)OB(c2cccc(-n3ccnc3)n2)OC1(C)C
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2cccc(-n3ccnc3)n2)s1
Temperature: 85 °C

Procedure:
A mixture of N-(5-iodo-4-methyl-thiazol-2-yl)-acetamide (312 mg), 6-(imidazol-1-yl)pyridine-2-boronic acid pinacol ester (600 mg), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium (II) (45 mg) and sodium carbonate (594 mg) in DME (3.1 ml) and water (3.1 ml) is heated in a Emrys Optimiser personal chemistry microwave at 85° C. for 45 minutes. Water is added (5 ml) and the mixture extracted with 3×10% methanol in CH2Cl2, the combined organic layers evaporated and purified by reversed phase chromatography (Method B) collecting the 12.8 minute retention time component. Partial evaporation of the fractions, neutralization with NaHCO3, extraction with 10% methanol in CH2Cl2 (5×) and evaporation gives a white solid. Further purification of this material by normal phase chromatography on silica gel eluting with a gradient from EtOAc to 10% methanol in EtOAc gives the title compound as a white solid. Hplc/MS (Method C) RT 1.31 minutes, M+H 299.9 and M−H 298.0.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>ClCCl.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[CH2:1][CH:2]=[CH2:3])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A portion of the crude 4-(allylamino)-1-(t-butoxycarbonyl)piperidine (400 mg, 1.66 mmol) was dissolved in 10 mL of dichloromethane and treated with N,N-diisopropylethylamine (0.700 mL, 519 mg, 4.0 mmol) and 4-nitrobenzyl chloroformate (392 mg, 1.82 mmol). After stirring 3 h at rt, the mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane, to give 572 mg of the title compound as a colorless syrup.
Reaction SMILES: C(OC(OC(C)C)[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1C2C=CC=CC=2NC=1.[Li].C([O:41][C:42]([C:44]1[CH:67]=[CH:66][C:47]([O:48][C:49]2[C:54]([CH:55]3[CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56]3)=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:46][CH:45]=1)=O)C.N1C2C=CC=CC=2NC=1>C1COCC1>[NH:57]1[CH2:58][CH:55]([C:54]2[C:49]([O:48][C:47]3[CH:66]=[CH:67][C:44]([C:42]([C:7]4[NH:6][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[N:8]=4)=[O:41])=[CH:45][CH:46]=3)=[N:50][CH:51]=[CH:52][CH:53]=2)[CH2:56]1
Reactant: CCOC(=O)c1ccc(Oc2ncccc2C2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)OC(OC(C)C)n1cnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2ncccc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(diisopropoxymethyl)-1H-benzo[d]imidazole (318 mg, 1.280 mmol) in THF (5 mL) at 0° C. is added LiHMDS (0.753 mL, 0.753 mmol) over 1 min. The reaction was stirred 5 min., then 3.5 mL of the 6 mL solution (1.0 theoretical equivalent of the lithium benzoimidazole) was added to a solution of tert-butyl 3-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)azetidine-1-carboxylate (300 mg, 0.753 mmol) in THF (3 mL) at 0° C. The reaction was stirred at 0° C. 30 min. LCMS showed only 5% conversion. The remaining solution of benzoimidazole was added and the reaction stirred 1 h at 0° C. LCMS shows 2:1 ratio of starting material to desired product. The reaction was quenched with 2 N HCl (15 mL) and warmed to rt and stirred overnight. The aqueous layer was neutralized with solid Na2CO3 and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic fractions were washed with saturated NaCl, dried (MgSO4), and concentrated. The crude material was then taken up in MeOH (3 mL) and 4.0 M HCl in dioxane was added. The reaction was stirred at rt 2 h, then concentrated to give the crude amine hydrochloride, which was taken on to the next step without purification.
Reaction SMILES: C([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[Cl:17])[CH3:6])(=O)C.Cl>>[ClH:17].[NH2:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17])[CH3:6]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(Cl)c1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)cc1Cl
Yield: 240.7 %

Procedure:
Methyl (R)-4-(1-acetamidoethyl)-3-chlorobenzoate (630 mg) was added to 2N hydrochloric acid (15 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was further boiled with toluene, and dried to give 700 mg of (R)-4-(1-aminoethyl)-3-chlorobenzoic acid hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:3][CH:2]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[N:16][NH:15][C:13]([C:12]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][CH:11]=1)=[O:14]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cnc(-c2ccccn2)nc1-c1ccncc1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cnc(-c2ccccn2)nc1-c1ccncc1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid-hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.38 (s, 1H), 9.30 (s, 1H), 9.22 (s, 1H), 8.84 (m, 1H), 8.78 (d, J=6.0 Hz, 1H), 8.68 (d, J=6.0 Hz, 1H), 8.54 (m, 1H), 8.31 (s, 1H), 8.01 (m, 2H), 7.97 (s, 1H), 7.82 (m, 1H), 7.73 (m, 1H), 7.62 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[C:22]2[C:23](=[O:41])[N:24]([CH3:40])[C:25]([CH2:38][OH:39])=[C:26]([C:27]3[C:28]([CH3:37])=[C:29]4[C:34](=[CH:35][CH:36]=3)[O:33][CH2:32][CH2:31][CH2:30]4)[C:21]=2[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[C:22]2[C:23](=[O:41])[N:24]([CH3:40])[C:25]([CH:38]=[O:39])=[C:26]([C:27]3[C:28]([CH3:37])=[C:29]4[C:34](=[CH:35][CH:36]=3)[O:33][CH2:32][CH2:31][CH2:30]4)[C:21]=2[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(-c2c(CO)n(C)c(=O)c3c2ccn3Cc2ccccc2)ccc2c1CCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2c(C=O)n(C)c(=O)c3c2ccn3Cc2ccccc2)ccc2c1CCCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
A −78° C. solution of oxalyl chloride (1.816 mL, 20.75 mmol) in Dichloromethane (DCM) (40.0 mL) was treated slowly with DMSO (2.94 mL, 41.5 mmol) and the resultant was stirred at −78° C. for 15 minutes. A solution of 1-benzyl-5-(hydroxymethyl)-6-methyl-4-(5-methylchroman-6-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (5.1 g, 9.84 mmol) in Dichloromethane (DCM) (40.0 mL) was slowly added and the mixture was stirred at −78° C. for 40 minutes. Triethylamine (11.57 mL, 83 mmol) was then added and the mixture was stirred at −78° C. for 6 hours. The mixture was quenched with saturated sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to give 1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbaldehyde (1.53 g, 3.71 mmol, 35.8% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.45 (s, 1H), 7.41-7.24 (m, 5H), 7.06 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.02 (d, J=2.9 Hz, 1H), 6.00-5.93 (m, 1H), 5.88-5.78 (m, 1H), 4.21 (t, J=5.0 Hz, 2H), 3.95 (s, 3H), 2.70 (t, J=6.4 Hz, 2H), 2.18-2.07 (m, 2H), 1.98 (s, 3H); LC/MS (m/z) ES+=413 (M+1).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:42][C@H:43]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1)[C:44]([N:46]1[CH2:49][C:48]([O:57][CH2:58][CH2:59][CH2:60][CH3:61])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:47]1)=[O:45].[OH-].[Na+]>CN(C)C=O>[CH2:58]([O:57][C:48]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:49][N:46]([C:44](=[O:45])[C@H:43]([NH:42][C:10](=[O:12])[C@@H:9]([OH:8])[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:47]1)[CH2:59][CH2:60][CH3:61]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)[C@@H](O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)[C@@H](O)Cc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
0.1 ml (0.8 mmol) of triethylamine is added to a solution containing 50 mg (0.3 mmol) of (S)-2-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and 100 mg (0.3 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 hour at ambient temperature, 128 mg (0.3 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolyl-azetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydro-chloride (described in Example 6.2) are added and the mixture is stirred for 72 h at ambient temperature. A 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 17 mg of (S)—N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 13%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].CS(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: ClCCCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of 4-hydroxyindole (0.100 g, 0.75 mmol, 1.0 eq), powdered potassium hydroxide (0.042 g, 0.75 mmol, 1.0 eq), and DMSO (3 mL) was stirred at room temperature for 1 hour before 1-bromo-3-chloropropane (0.118 g, 0.75 mmol, 1.0 eq) was added. The above mixture was then stirred at room temperature for another 0.5 hour and then 15 mL of water was added to it. The resultant mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford 4-(3-chloropropoxy)-1H-indole (0.130 g, yield: 83%).
Reaction SMILES: [O:1]([C:8]([NH:10][C:11](=[S:24])[C:12](=[CH:18]N(CC)CC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32](=[O:35])[CH2:33]Br)(=[O:28])=[O:27].C(O)(C)C>O>[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([C:33]1[S:24][C:11]([NH:10][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1)=[O:35])(=[O:28])=[O:27]
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)Oc1ccccc1
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 130 g of ethyl 2-[[(phenoxycarbonyl)-amino]thioxomethyl]-3-(diethylamino)propenoate (0.37 mole), 104 g of m-fluorosulfonylphenacyl bromide (0.37 mole), and 350 ml of isopropanol was heated to reflux and held one hour. During this time, the reactants dissolved and the product precipitated. The mixture was cooled to 20°-25°, filtered, washed with isopropanol and then water to yield 133 g of white solid, ethyl 5-[3-(fluorosulfonyl)benzoyl]-2-[(phenoxycarbonyl)-amino]-3-thiophenecarboxylate, (75% yield), melting point 161°-163°. Ir: 2.88, 5.72, 5.98, 6.18, 7.12, 8.10, 8.40μ; NMR (CDCl3) δ10.75 (s,1,N-H); 8.4 (m,1); 8.2 (m,2); 7.8 (m,1); 7.7 (s,1, thiophene-proton); 4.4 (q,2); 1.4 (t,3).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.O>C(Cl)Cl>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([OH:6])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.8 %

Procedure:
A methylene chloride solution of boron tribromide (18.5 ml, 18.5 mmol) was added to a solution of 5-methoxy-1H-indazole (1.24 g, 8.40 mmol) in methylene chloride (84 ml) at 0° C. and stirred at room temperature for 10 hours. Then, water was poured into the reaction solution in an ice-water bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=96/4) to obtain 1H-indazol-5-ol (877 mg, 71%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=4)=[N:17][N:16]4[CH2:26][CH2:27][CH2:28][C:15]=34)[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[CH3:25][C:21]1[N:20]=[C:19]([C:18]2[C:14]([C:11]3[CH:12]=[C:13]4[C:8]([NH:7][CH2:6][C:5](=[O:29])[N:4]4[CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:9][CH:10]=3)=[C:15]3[CH2:28][CH2:27][CH2:26][N:16]3[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(=O)n(CCCl)c4c2)CCC3)n1
Reactant: C1CCNC1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4c(c2)N(CCN2CCCC2)C(=O)CN4)CCC3)n1
Temperature: 110 °C
Yield: 84 %

Procedure:
Combine 1-(2-chloro-ethyl)-7-[2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one (Preparation 7; 60 mg, 0.15 mmol) and pyrrolidine (0.5 ml) in dioxane (5 mL) in a pressure tube. Seal the tube and heat at 110° C. for 40 min. Dilute the reaction mixture with 1:1 chloroform/isopropyl alcohol and wash the solution with saturated sodium chloride solution. Dry the organic phase (sodium sulfate), filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (dichloromethane to 1:1 dichloromethane/methanol) to give 54 mg (84%) of the titled compound. MS ES+ m/e 441 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:31])C(=O)C1.O>COCCOC>[I:31][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of Example 10A (1.69 g, 5.3 mmol) in DME (20 mL) was treated with NIS (1.26 g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered. The filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64 g (70% yield) of the desired product. MS (ESI(+)) m/e 444.8 (M+H)+.