Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]([OH:19])[CH2:11][O:10]1.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([C@H:32]([O:34][C@@H:35]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:39]([CH:47]=O)[CH2:38][CH2:37][O:36]2)[CH3:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[C:24]([C@H:32]([O:34][C@@H:35]2[C@@H:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:39]([CH2:47][N:16]3[CH2:17][CH2:18][C:13]4([CH2:9][O:10][CH2:11][CH:12]4[OH:19])[CH2:14][CH2:15]3)[CH2:38][CH2:37][O:36]2)[CH3:33])[CH:23]=[C:22]([C:21]([F:50])([F:49])[F:20])[CH:27]=1
Reactant: OC1COCC12CCNCC2
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
Triethylamine (140 μL, 1.0 mmol) was added to a suspension of 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g, 0.54 mmol) in 1,2-dichloroethane (2 ml). After 10 minutes, (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (see Example 43 in WO 00/56727; 0.24 g, 0.54 mmol) was added as a solution in 1,2-dichloroethane (3 ml). The mixture was stirred at room temperature for 30 minutes then sodium triacetoxyborohydride (0.2 g, 0.94 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound (72 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:9][C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-iodo-pyridin-3-ol (1.00 g) in N,N-dimethylformamide (10 mL) copper (I) iodide (120 mg), Pd(PPh3)2Cl2 (140 mg), and triethylamine (550 μL) are added. The mixture is stirred at room temperature for 1 h. A solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (860 mg) in N,N-dimethylformamide (3 mL) is added and the resulting mixture is stirred at 70° C. over night. After cooling to room temperature the mixture is concentrated and chromatographed on silica gel (ethyl acetate/cyclohexane 25:75) to give the title compound. Yield: 241 mg (18% of theory); LC (method 2): tR=1.41 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH:13][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2sccc2-3)cc1

Procedure:
The title compound was prepared from 4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-amine (105 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and 4-n-propylbenzenesulfonyl chloride (111 mg) as described in the synthetic METHOD A to give a white powder (18 mg) with a purity >90%: MS-ES (neg) m/z 389.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29]CC3C=CC=CC=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:37]CC2C=CC=CC=2)[N:3]=1.C(O)(=O)C>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[OH:37])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(OCc4ccccc4)cccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3O)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.2 %

Procedure:
A suspension of tert-butyl 3-{2-amino-6-[2,6-bis(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (3.46 g, 5.9 mmol) and Pd/C (10%, 600 mg) in ethyl acetate (50 mL) including acetic acid (5 mL) was stirred for 2 days at room temperature under a hydrogen atmosphere. The reaction mixture was diluted with THF (200 mL) and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate and hexane, and dried under reduced pressure to give tert-butyl 3-[2-amino-3-cyano-6-(2,6-dihydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (1.82 g, yield; 76%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+]=[N-]>CO.[Pd]>[N:11]1([C:6]2[C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: [N-]=[N+]=NCc1cccnc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: NCc1cccnc1N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To a solution of the product from Example 98A (0.62 g) in methanol (10 ml) was added Pd/C (0.06 g) under N2 atmosphere. The reaction mixture was stirred at room temperature under H2 atmosphere. After 6 hours, the reaction mixture was filtered through celite and concentrated to yield 0.42 g (78%) of product. MS (ESI+) m/z 194 (M+H)+;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51](=[O:61])[NH:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([NH2:60])[CH:54]=1)([CH3:49])([CH3:48])[CH3:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:51](=[O:61])[O:50][C:46]([CH3:47])([CH3:49])[CH3:48])=[CH:54][C:55]=1[NH:60][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (1.01 g, 5.61 mmol), HATU (1.8 g, 5.61 mmol) and DIPEA (1.953 mL, 11.21 mmol) in DMF (8 mL) was stirred for 15 min. (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl 27 (1.246 g, 5.61 mmol), DIPEA (1 eq) in DMF (8 mL) were added and stirred overnight at rt. Citric acid solution (3%) was added and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-20% EtOAc in CH2Cl2) gave tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate 28 (1.43 g, 66.4%). (m/z)=385 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](N)=[O:35])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: NC(=O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (58 mg, 51%), MS (ISP) m/z=453.4 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-(tetrahydro-pyran-4-yl)-acetamide.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH:19]([CH:20]=[CH:21][C:22](=[O:28])[CH2:23]CCCC)[CH2:18][CH2:17][C:12]21[O:16][CH2:15][CH2:14][O:13]2.C[Si](C)(C)OCCCCCCCC1C(C=CC(=O)[CH2:53][O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)CCC21OCCO2.C[Si](C)(C)OCCCCCCCC1COC2(CCCC2)O1>>[OH:28][C:22]([CH3:23])([CH2:53][O:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH:21]=[CH:20][CH:19]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:3][Si:2]([CH3:30])([CH3:29])[CH3:1]
Reactant: C[Si](C)(C)OCCCCCCCC1C(C=CC(=O)COc2ccccc2)CCC12OCCO2
Reactant: CCCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Agent: C[Si](C)(C)OCCCCCCCC1COC2(CCCC2)O1
Product: CC(O)(C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C)COc1ccccc1

Procedure:
By proceeding in a similar manner to that hereinbefore described in Example 3(iii), but replacing the 6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane used as starting material by the appropriate quantity of 6-(7-trimethylsiloxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane, there was prepared 7-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-6-(7-trimethylsiloxyheptyl-1,4-dioxaspiro[4,4]nonane.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:15][CH2:16]OCC>CCO>[CH2:15]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4]1)=[O:10])[CH3:16]
Reactant: CCOCC
Reactant: NC1CCC(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-amino-cyclohexanecarboxylic acid (G) (5 g, 35 mmol) in EtOH (175 mL) at 0° C. was added SOCl2 (12.6 mL, 174 mmol) dropwise via a syringe. The reaction mixture was warmed to room temperature and stirred for 16 h. After concentration of the reaction mixture, ether was added and the suspension was filtered to give 4-amino-cyclohexanecarboxylic acid ethyl ester (H) (mixture of cis/trans) as a white solid (4.8 g): 1H NMR (300 MHz, CDCl3) δ 8.35 (br s, 3 H), 4.18 (m, 2 H), 3.36-3.15 (m, 1 H), 2.54 (m, 1 H), 2.30-1.45 (series of m, 8 H), 1.13 (t, 3 H); mass spectrum m/z 172 [(M+H)+; calcd for C9H18NO2: 172].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4OC)[C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncc(F)s3)ccc12
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
A vial was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (67.1 mg, 0.282 mmol), perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol), and THF (938 μl). The resulting solution was cooled to 0° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. LCMS after 15 min showed incomplete conversion of SM. Additional LHMDS (400 μL, 1M in THF) was added. After 15 min, TLC showed complete conversion of PFP-sulfonate to a lower spot. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 59.0% yield) as a brown solid. m/z (ESI) 587.0 (M+H)+, 609.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 0.105 mmol) was dissolved in DCM (1053 μl, 0.105 mmol) and then TFA (40.6 μl, 0.527 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford impure product. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (1.3 mg, 2.64% yield) as off-white solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[C:44]([OH:46])=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)CC)C.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>C(#N)C>[C:57]([O:56][C:54]([N:61]1[CH2:66][CH2:65][N:64]([C:44]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][N:38]2[C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[O:46])[CH2:63][CH2:62]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: O=C(O)C1CCCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2C(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
26.6 g of BOP, 13.6 g of 1-(carbobenzyloxy)-2-piperidinecarboxylic acid and then 11.9 ml of triethylamine are added, at 0° C., to a solution of 8 g of 1-Boc-piperazine in 80 ml of acetonitrile. The medium is stirred at AT for 12 hours and then concentrated. The medium is taken up in EtOAc, and washed three times with a saturated Na2CO3 solution and then with a saturated NaCl solution. After drying over MgSO4 and evaporation, 35.45 g of reaction crude are recovered. It is taken up in DCM and then washed twice with 5M sodium hydroxide, and with a saturated NaCl solution, and then dried over MgSO4. After evaporation, the solid is triturated in TBME, filtered, rinsed with TBME, and then dried, to give 17.93 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27]C(=O)CC1C2C(=CC=C(OC)C=2)N(CC2C=CC=CN=2)C=1C)C.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH3:25][OH:27]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccn2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccn1
Agent: NN
Product: CO
Yield: 67 %

Procedure:
5-Methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide. Using the method described in Example 6, Part B, 480 mg 1.4 mmol) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid ethyl ester was reacted with 1.4 mL of hydrazine to give on crystallization from MeOH 304 mg (67% yield) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide, mp, 147-148° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]([CH3:10])([CH3:9])[CH2:6][O:7][CH3:8].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH2:4][C:5]([CH3:10])([CH3:9])[CH2:6][O:7][CH3:8])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of (S)-tert-butyl 1-hydroxy-5-methoxy-4,4-dimethylpentan-2-ylcarbamate (7.8 g, 30 mmol) in methylene chloride (150 mL) and Et3N (10.4 mL, 75 mmol) was cooled to −20° C., MsCl (6.9 g, 60 mmol) was added with fast dropwise addition maintaining the internal temperature at −20° C. The reaction mixture was stirred for 1 h in rt. The reaction was quenched with water (100 mL), extracted with CH2Cl2 (3×100 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give (S)-2-(tert-butoxycarbonylamino)-5-methoxy-4,4-dimethylpentyl methanesulfonate (10.1 g, 100%) as an oil that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:41]([OH:52])(=O)[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=O)=[CH:44][CH:43]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([CH3:10])[C:11]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[N:15]([C:46]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([N:15]3[C:16]4[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:17]=4[N:18]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][C:23]=4[CH3:32])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:10])[CH2:14]3)=[O:52])=[CH:50][CH:49]=2)=[O:48])[CH2:14]1)=[O:39])=[O:40])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of {(S)-1-[(S)-7-cyano-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 16) (90 mg, 0.166 mmol) in pyridine (1 mL) was added terephthalic acid (13.808 mg, 0.083 mmol). After 10 min the mixture was cooled to 0° C., POCl3 (0.017 mL, 0.183 mmol) was added and the cooling bath was removed. After 1 h, the mixture was concentrated, the residue was dissolved in ethyl acetate and the mixture was washed with water, NaHCO3 solution, and brine, dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase HPLC to provide tert-butyl N-[(1S)-2-[[(3S)-5-[4-[(3S)-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate as white solid (5 mg, 5.32%). LC-MS: 1213.6 (M+H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N1C=CN=C1>C(Cl)Cl.CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a stirred solution of p-bromophenol (5) (4.0 g, 23.1 mmol) in DCM (40 ml) was added triisopropylsilyl chloride (5 ml, 23.4 mmol). The reaction mixture was cooled to 0° C. and imidazole (3.94 g, 57.9 mmol) was added and the mixture was stirred at 0° C. for 30 minutes then allowed to warm to ambient temperature over 12 hours. The reaction mixture was diluted with ether and sequentially washed with 0.5 M HCl (2×), sat. aq. NaHCO3, water and brine then dried over MgSO4. The crude product was purified by bulb to bulb distillation (boiling point: 149-150° C. at 2.0 mmHg) to give 6 as a clear oil (6.23 g, 82% yield): 1H-NMR (400 MHz, chloroform-d) δ 7.30 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 1.24 (septet, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 18H); 13C-NMR (100 MHz, chloroform-d) δ 155.2, 132.2, 121.7, 113.2, 17.8, 12.6; FTIR (thin film) 2945, 2892, 2867, 1586, 1487, 1274, 909, 883, 828, 732 cm−1; HRMS (EI+) for C15H25BrOSi calcd. 328.0858 found 328.0844.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 26.5 h

Procedure:
To a solution of 18.92 g (82.6 mmol) of 4-bromo-2-t-butylphenol (Compound E) in 110 ml of dichloromethane was added dropwise 10.42 g (11.3 ml, 123.9 mmol) of 3,4-dihydro-2H-pyran (DHP). To this clear, colorless solution was added 1.86 g (7.4 mmol) of pyridinium p-toluenesulfonate (PPTS). The resulting mixture was stirred at room temperature under a blanket of argon for 26.5 hours, partitioned between 250 ml of water and 400 ml of hexane, and the layers were separated. The organic phase was washed with 2×250 ml-portions of water and with 150 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a light yellow, crystalline solid. PMR (CDCl3): d 1.39 (9H, s), 1.6-2.1 (6H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.7 Hz), 7.06 (1H, d, J=8.8 Hz), 7.24 (1H, dd, J=8.8, 2.7 Hz), 7.36 (1H, d, J=2.7 Hz).
Reaction SMILES: [C:1]1(=[N:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH2:13]>>[NH:11]1[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][C:10]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: O
Reactant: ON=C1CCCc2ccccc21
Product: O=C1CCCc2ccccc2N1
Temperature: 120 °C

Procedure:
To 3,4-dihydro-2H-naphthalen-1-one oxime (5 g, 31 mmol), PPA (50 g) was added and the mixture was heated at 120° C. for 4.5 hrs. While hot the mixture was quenced in a slurry of ice and water and vigorously stirred until a precipitate formed. The precipitate was filtered and rinsed with water to yield 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (3.1 g). MS [M+H]+: 162.0; tR=1.76 min. (method 1)