Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:26]([O:25][C:23]([NH:30][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([NH:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:3]1)=[O:40])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 5(R,S)-amino-7-phenyl-5H-pyrimido[5,4-d][2]benzazepine (1.37 g), Boc-L-phenylalanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (HBT) (0.70 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) (0.99 g, 5.17 mmole) are combined in DMF (30 ml) and stirred at room temperature. The pH of the mixture is adjusted to 9.5 with triethylamine. After about 1/2 hour, the DMF is removed in vacuo and the residue is partitioned between methylene chloride and 10% citric acid solution. The layers are separated and the organic phase is washed with saturated NaHCO3 solution, water and brine, then dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue is chromatographed on silica gel and the combined product fractions evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.[CH:20](OCC)=[O:21]>>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:20]=[O:21])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: CCOC=O
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(CNC=O)n1

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)-6-(aminomethyl)-pyridine in 5 ml of ethyl formate was heated at reflux for 3 h. The solution was then filtered through a cartridge packed with 3 g of silica gel and this cartridge was rinsed out with ethyl acetate. The filtrate was concentrated.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15]C(OCC2C=CC=CC=2)=O)[CH2:4][N:3]1[S:27]([OH:30])(=[O:29])=[O:28].[K].[H][H].Cl>[Pd]>[NH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([NH:6][C@H:5]1[CH2:4][N:3]([S:27]([OH:30])(=[O:28])=[O:29])[C:2]1=[O:1])=[O:26]
Reactant: [H][H]
Reactant: O=C(NCc1ccccc1C(=O)N[C@H]1CN(S(=O)(=O)O)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [K]
Product: NCc1ccccc1C(=O)N[C@H]1CN(S(=O)(=O)O)C1=O

Procedure:
The deprotection of (S)-2-oxo-3-[[2-[[[(phenylmethoxy)carbonyl]amino]methyl]benzoyl]amino]-1-azetidinesulfonic acid, potassium salt (see example 167) using hydrogen gas, palladium on charcoal, and hydrochloric acid, yields the title compound, melting point 162°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
A mixture of the product from Example 86A was reacted with 3-Trifluoromethyl-phenylamine to produce 4-Fluoro-3-nitro-N-(3-trifluoromethyl-phenyl)-benzamide according to the procedure of Example 86B, which was treated sequentially using the procedures from Examples 86C and 86D to provide the title product.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:13])[C:9](=[CH:11][CH:12]=1)[OH:10])([O-:5])=[O:4].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C.O>[N+:3]([C:6]1[CH:12]=[CH:11][C:9]2[O:10][CH:16]([CH2:17][OH:18])[CH2:14][O:13][C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCC(CO)O2
Yield: 32.8 %

Procedure:
1.93 g of 60% sodium hydride was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using a EtOAc-hexanes (0-100% gradient) to give the product (2.3 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[C:36](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[C:3]([O:35][CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 78.2 %

Procedure:
348 mg (0.710 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl )-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 35 mL of acetone, 166 mg (1.20 mmol) of potassium carbonate and 0.45 mL (7.1 mmol) of iodomethane were added and the mixture was heated at reflux for 40 minutes. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with a 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 280 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methoxy-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH:32]1[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CCCCC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CCCCC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.36 g, 0.85 mmol), methyl azetidine-3-carboxylate hydrochloride (0.388 g, 2.56 mmol) according to Reference R and the general procedure for reductive amination to give methyl 1-((3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)azetidine-3-carboxylate as an oil which solidified to a white solid. MS (ESI) m/z: Calculated: 515.2; Observed: 516.1 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH:18]([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH:18]([CH3:28])[C:17]([OH:29])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: CC(Cc1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1)C(=O)O
Yield: 77.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (76 mg, 81%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19].Cl>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19]
Reactant: O[C@H]1CCNC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine (2.0 g, 22.9 mmol) in THF (40 mL) was added diisopropylethylamine (12.0 mL, 68.9 mmol) and 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (6.0 g, 25.3 mmol). The resulting solution was stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was acidified with 3N HCl and partitioned between H2O (100 mL) and Ethyl acetate (100 mL). The layers were cut and the aqueous layer was extracted with Ethyl acetate (3×100 mL) and EtOAc:THF (1:1, 2×100 mL). The combined organic cuts were washed with a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure. Silica gel chromatography (Ethyl acetate:hexanes, 4:1) afforded 6.31 g (95%) of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 108-109° C. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=2.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 4.40 (brs, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.33-3.40 (m, 3H), 3.20-3.23 (m, 1H), 1.93-2.02 (m, 1H), 1.82-1.89 (m, 1H), 1.79 (brs, 1H). Anal. Calcd. for C11H16N2O5S, C, 45.82; H, 5.59; N, 9.72; S, 11.12. Found: C, 45.92; H, 5.63; N, 9.61; S, 11.24.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:5]([O:4][C:2]([NH:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]([OH:16])=[O:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
Benzyl chloroformate (15.5 g) was added dropwise to a stirred mixture of (2S)-2-aminoadipic acid (12 g) and sodium carbonate (39.4 g) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with diethyl ether. The aqueous phase was acidified to pH1 by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give (2S)-2-benzyloxycarbonylaminoadipic acid (21.6 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:10]([C:9]4[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[C:7]([CH3:13])[CH:8]=4)=[O:11])=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A dry 25 mL flask was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl chloride (1.03 g, 5.17 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.0 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.654 g, 1.68 mmol, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ncco1
Reactant: Brc1nccs1
Solvent: CS(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3nccs3)cc2n1Cc1ncco1

Procedure:
The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210), 2-bromothiazole and DMSO with heating following General Procedure N.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](OB(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2cnc3cc(OC)ccc3c2)c1
Reaction time: 4.5 h
Yield: 76 %

Procedure:
The compound is prepared by the reaction of 3-bromo-7-methoxyquinoline (255 mg, 1.07 mmol, 1.06 eq) and 3-methoxyphenylboric acid (154 mg, 1.01 mmol, 1 eq) according to method A in 4.5 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yields the desired product in a yield of 76% (215 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH2:28].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:26]=3[F:25])=[O:20])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Product: Cc1ccc(NC(=O)c2ccc(-n3nc(-c4c(F)cccc4Cl)[nH]c3=O)cc2)c(F)c1
Yield: 44.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 2-fluoro-4-methyl aniline (0.054 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.055 g of desired product. 1H NMR (DMSO-d6): δ 2.30 (s, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (d, J=11.7 Hz, 1H), 7.39-7.48 (m, 2H), 7.51-7.58 (d, 1H), 7.65-7.72 (m, 1H), 8.07 (br s, 4H), 10.04 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 439.13 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:54])[NH:15][C@@H:16]([C:28](=[O:53])[N:29]([C@@H:31]([C:43]2[O:47][N:46]=[C:45]([C:48]([O:50]CC)=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:54])[NH:15][CH:16]([C:28](=[O:53])[N:29]([CH:31]([C:43]2[O:47][N:46]=[C:45]([C:48]([OH:50])=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)C(Cc1ccc2ccccc2c1)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1)C(Cc1ccc2ccccc2c1)c1nc(C(=O)O)no1
Yield: 54.8 %

Procedure:
4-((1R)-1-{[(1R)-1-(3-Ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 1.06 mmol) was dissolved in dioxane (5.5 ml). Water (3 ml) and solid lithium hydroxide (0.03 g) was added. After 18 h at 20° C. the reaction mixture was diluted with water (15 ml) and extracted with tert-butyl-methylether (2×10 ml). The aqueous phase was acidified with 1N aqueous sodium hydrogenphosphate (2.5 ml) and extracted with tert-butyl-methylether (3×40 ml). The collected organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on silica (60 g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.41 g of 4-(1-{[1-(3-carboxy-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)-ethylcarbamoyl)piperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
6-Chloro-N-(4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-chloro-4,6-dimethylpyrimidine in a similar manner as described above to give 6 mg (8% yield) of a pale yellow oil. 1H-NMR (CDCl3): δ 9.23 (s, 1H), 7.45 (s, 1H), 7.16 (d, 1H), 7.07 (d, 1H), 6.42 (s, 1H), 5.25 (m, 1H), 5.20 (m, 1H), 2.70 (m, 2H), 2.35 (s, 6H), 2.29 (m, 1H), 2.03-1.83 (m, 3H); MS m/z 327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccc(Cl)s2)cs1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a beige solid (29.9 mg) with purity >90%: MS (pos) m/z 405.0, 407.0; HRMS m/z 403.9278 (calc. of monoisotopic mass for C14H10Cl2N2O2S3 gives 403.9281).
Reaction SMILES: S(O[C@@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>>[N:29]([C@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OS(C)(=O)=O)[C@@H](n2cc(F)c(N)nc2=O)O1
Agent: [Li+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](N=[N+]=[N-])[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To a solution of 20 (442 mg, 1.01 mmol) in anhydrous dilmethylformamide (12 mL) was added lithium azide moistened with 10% methanol (265 mg, 4.87 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: methanol (4%) in chloroform] to give pure 21 (291 mg, 75% yield) as a white solid: mnp 147-148° C.; UV (ethanol): λmax 242 nm (ε7700), 283 nm (ε7400), λmin 226 nm (ε6600), 264 nm (ε5800); 1H NMR (DMSO-d6): δ8.05 (d, 1H, H-6, J6-F5=7.0 Hz), 7.9-7.4 (br d, 2H, NH2), 5.7 (br s, 1H, H-1′), 4.37 (d, 1H, H-2′, J2′-3′=5.5 Hz), 4.3 (m, 1H, H-4′), 4. (m, 1H, H-5′), 3.7 (m, 1H,H-5″), 2.0 (m, 1H, H-3′), 1.8 (m, 1H, H-3″), 0.88 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 1151 (3M−H)−, 767 (2M−H)−, 383 (M−H)−, 128 (B)−; [α]D20=+25 (c, 0.95 DMSO).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([C:14](=[O:15])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1(=[O:15])[C:11]2([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)[CH2:12][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC12CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-oxo-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.624 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution stirred at RT for 1 h. The crude reaction mixture was loaded onto a Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to provide 2,7-diaza-spiro[3.5]nonan-1-one as a colourless oil. To a suspension of 2,7-diaza-spiro[3.5]nonan-1-one (0.624 mmol) in dichloroethane (13 mL) were added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (130 mg, 0.458 mmol) and sodium triacetoxyborohydride (146 mg, 0.689 mmol) and the resulting suspension stirred at RT for 18 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (93 mg, 50%)