Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>>[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@H:12]4[N:8]5[C:9]6[C:4](=[CH:3][CH:2]=[CH:1][C:10]=6[C@H:11]4[CH2:16]3)[CH2:5][CH2:6][CH2:7]5)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2c(CCCN3CC[C@@H]4[C@H](C3)c3cccc5c3N4CCC5)noc2c1
Yield: 31.9 %

Procedure:
The title compound (0.15 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.80-2.18 (m, 7H), 2.25 (td, J=11.5, 3.0 Hz, 1H), 2.35-2.68 (m, 4H), 2.70 (t, J=6.6 Hz, 2H), 2.75-2.88 (m, 1H), 3.01 (t, J=7.6 Hz, 2H), 3.05-3.15 (m, 1H), 3.20-3.30 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 7.06 (td, J=9.0, 2.1 Hz, 1H), 7.20-7.26 (m, 1H), 7.61 (dd, J=4.8, 8.7 Hz, 1H) ppm.
Reaction SMILES: [C:1]12([CH3:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[OH:10].[CH2:12]([OH:14])[CH3:13]>>[C:1]12([CH3:11])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2([CH2:13][CH2:12][OH:14])[OH:10]
Reactant: CCO
Reactant: CC1(C)C2CCC1(C)C(O)C2
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
combining Borneol with ethanol to produce a Borneol-ethanol mixture,
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:23]([C:24](O)=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40][C:38]=2C=1.CCN=C=NCCCN(C)C.CN.Cl.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:23]([C:24]([NH:40][CH3:38])=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (3 g, 6.4 mmol), HOBT (1.3 g, 9.6 mmol) and EDCI (2.5 g, 12.8 mmol) in DMF (50 mL) was allowed to stir at room temperature. After 30 minutes, CH3NH2.HCl (857 mg, 12.8 mmol) and Et3N (1.3 g, 12.8 mmol) were added to the mixture, and the mixture was allowed to stir overnight at room temperature. After the solvent was removed, H2O and NaHCO3 (aq.) were added and the mixture was stirred at room temperature for 1 hour. After filtration, the cake was washed with H2O and dried to give pure 5-(benzyloxy)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (3 g, yield: 97%). 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.86 (s, 1H), 7.56˜7.59 (m, 2H), 7.35˜7.44 (m, 5H), 7.16 (t, J=8.8 Hz, 2H), 5.41 (br s, 1H), 5.15 (s, 2H), 3.22 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 2.71 (s, 3H). MS (M+H)+: 483.
Reaction SMILES: C(OC(=O)[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:46])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:40][C:41]3[NH:42][CH:43]=[CH:44][N:45]=3)[CH2:34][C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CO.C(O)C.[C].[Pd]>[NH:36]1[CH:37]=[CH:38][N:39]=[C:35]1[CH2:34][N:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][NH:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:19][CH:20]=2)=[O:46])=[CH:27][CH:28]=1)[CH2:40][C:41]1[NH:45][CH:44]=[CH:43][N:42]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: O=C(Nc1ccc(CNC2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (282 mg) obtained in Example 88-1 was dissolved in methanol (14 ml). After having been cooled with ice, the solution was added with a suspension of 10% palladium-carbon (140 mg) in ethanol (3.0 ml). After having been subjected to hydrogen displacement, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the reaction solution was filtrated through Celite and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Si:34]([O:41][CH2:42][CH2:43][CH2:44]O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][S:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)(=[O:56])=[O:55])=[C:49]([CH2:67][C:68]2[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:69]=2[F:75])[CH:48]=1>O1CCCC1>[C:37]([Si:34]([CH3:35])([CH3:36])[O:41][CH2:42][CH2:43][CH2:44][N:53]([C:50]1[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][C:49]=1[CH2:67][C:68]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:69]=1[F:75])[S:54]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1)(=[O:56])=[O:55])([CH3:38])([CH3:39])[CH3:40]
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCCO[Si](C)(C)C(C)(C)C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.5 h

Procedure:
To 4.3 g of triphenylphosphine in 20 ml of tetrahydrofuran are added, at room temperature, 3.25 ml of diisopropyl azodicarboxylate. After 30 minutes, 3.5 ml of 3-[tert-butyl(dimethyl)silyloxy]propanol dissolved in 30 ml of tetrahydrofuran are introduced. The mixture is left at room temperature for 30 minutes, and 5 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are then introduced. After 48 hours at room temperature, the reaction medium is concentrated and then chromatographed on a column of silica gel to give 8.09 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O.[NH4+].[OH-]>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cccnc1N
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(-c2nc3ncccc3[nH]2)nc1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
A solution of 2,3-diaminopyridine (1.1 g, 10 mmol) and 2-picolinic acid (1.23 g, 10 mmol) in polyphosphoric acid (10 ml) was heated to 160° C. for 4 hours. The hot solution was poured into ice water and the pH adjusted to pH 9 with conc. NH4OH. The resulting precipitate was filtered and air dried. This crude product was recrystallized from EtOH to give 1.1 g (56%) of the title compound, m.p. 139°-142° C. Anal. Calcd for C11H8N4 : C, 67.34; H, 4.11; N, 28.36. Found: C, 66.88; H, 4.17; N, 8.36.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:28]([C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:27])=[CH:36][CH:35]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CN(C(=O)C(C)(C)C)c1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 89.4 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.23 g, 0.53 mmol) with a solution of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamine (0.23 g, 1.06 mmol) in anhydrous toluene/dioxane (4:1, 7 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 17:3 gradient over 30 min, 17:3 over 30 min, 17:3 to 7:3 gradient over 30 min and 7:3 over 30 min; 35 mL/min) to obtain 7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine as a yellow oil (0.235 g, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([O:14][C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[S:21][C:17]=2[CH:16]=1)[CH3:13].C(NC(C(C)C)(C(C)C)C)C.O>C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][S:22][C:20]1[S:21][C:17]2[CH:16]=[C:15]([O:14][CH2:12][CH3:13])[CH:24]=[CH:23][C:18]=2[N:19]=1
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: ClCc1nc2ccccc2s1
Agent: CCNC(C)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc2nc(SCc3nc4ccccc4s3)sc2c1
Temperature: 25 °C
Yield: 35 %

Procedure:
The compound 2-(chloromethyl)benzothiazole [15] (1 g, 5.45 mmol), dissolved in THF (50 ml), was added drop-wise to a stirred solution of 4 (1.15 g, 5.45 mmol), N-ethyldiisopropylethylamine (1.35 ml, 8.17 mmol) and 4-dimethylaminopyridine (0.08 g, 0.545 mmol) in THF (50 ml). The reaction mixture was refluxed overnight. Then, the solution was cooled to room temperature, and water (100 ml) followed by chloroform (100 ml) were added. The organic layer was separated, washed twice in water, dried over sodium sulfate, filtered and evaporated. The crude solid was purified by column chromatography using 100% dichloromethane as an eluting solvent. The compound was obtained as dark brown solid. Yield 35%, m.p. 78-82° C. 1H NMR (DMSO-d6): δ 1.31-1.33 (t, 3H, J=3.45), 4.02-4.08 (q, 2H, J=6.9), 5.08 (s, 2H), 7.02-7.06 (dd, 1H, J=2.5, 6.3), 7.42-7.50 (m, 2H), 7.59-7.60 (d, 1H, J=2.4), 7.74-7.77 (d, 1H, J=9.0), 7.95-8.06 (dd, 2H, J=8.1, 15.3). 13C NMR (DMSO-d6): δ 14.8, 35.1, 64.1, 104.8, 115.6, 121.6, 122.3, 125.3, 126.2, 141.9, 143.1, 152.6, 165.6, 173.0, 178.4. MS: MW=358.50 g/mol, MH+=359.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Si:21]([O:38][CH2:39][C:40]1[C:45]([N:46]2[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]2)=[C:44]([Cl:54])[C:43]([F:55])=[CH:42][N:41]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:56][N:57]1[CH:61]=[CH:60][N:59]=[C:58]1[CH:62]=[O:63]>C1COCC1>[Si:21]([O:38][CH2:39][C:40]1[N:41]=[C:42]([CH:62]([C:58]2[N:57]([CH3:56])[CH:61]=[CH:60][N:59]=2)[OH:63])[C:43]([F:55])=[C:44]([Cl:54])[C:45]=1[N:46]1[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]1)([C:34]([CH3:37])([CH3:35])[CH3:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: Cn1ccnc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Diisopropylamine (0.868 mL, 6.14 mmol) was added dropwise to a stirring solution of 2.5M butyllithium in hexanes (2.339 mL, 5.85 mmol) in THF (20 mL) at −78° C. The solution was warmed to 0° C. for 10 minutes and then cooled again to −78° C. Cannulation of the LDA at −78° C. into (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45, 1.5 g, 2.92 mmol) in THF (10 mL) at −78° C. Allowed dark solution to stir for 20 minutes then cannulated into a stirring solution of 1-methyl-1H-imidazole-2-carbaldehyde (0.644 g, 5.85 mmol) in THF (10 mL) at −78° C. The solution was allowed to warm to −50° C. then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and washed resulting organics with brine. After drying the organics over sodium sulfate, filtering, and evacuating the filtrate under vacuum, a crude yellow oil was obtained. The crude oil was purified on silica using 40% ethyl acetate in n-hexane to give 1.2 g (66%) of the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:11][OH:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>O>[OH:12][CH2:11][C:2]1([N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1(CO)Cc2ccccc2C1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1(CO)Cc2ccccc2C1
Temperature: 160 °C

Procedure:
A mixture of (2-aminoindan-2-yl)methanol (0.407 g, 2.50 mmol) and phthalic anhydride (0.369 g, 2.50 mmol) is heated at 160° C. for 40 minutes. The reaction mixture is poured into water and extracted with chloroform. The organic phase is dried (Na2SO4) and evaporated to afford 2-(2-hydroxymethylindan-2-yl)-isoindole-1,3-dione, MH+294.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:3]([O:5]N1C(=O)CCC1=O)=[O:4].CC(CC#CCC)C(Cl)=O.OC[C@H](NC(=O)C(C)CC#CCC)C1C=CC=CC=1>>[CH3:1][CH:2]([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: CCC#CCC(C)C(=O)ON1C(=O)CCC1=O
Agent: CCC#CCC(C)C(=O)Cl
Agent: CCC#CCC(C)C(=O)N[C@@H](CO)c1ccccc1
Product: CCC#CCC(C)C(=O)O

Procedure:
(S)-(+)-Dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared by following the sequence of reaction steps described in Scheme 7a, 7f and Scheme 8, Step A. The intermediate 2-methylhept-4-ynoic acid was prepared according to a method described in WO 2011/003058 A1. (S)-(+)-Diethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared according to the method described in the Journal of Medicinal Chemistry, 1986, 29(3), 313-315, except that 2,5-dioxopyrrolidin-1-yl 2-methylhept-4-ynoate (N-hydroxysuccinimide 2-methylhept-4-ynoate) was prepared as an activated acyl species (activated ester) instead of 2-methylhept-4-ynoyl chloride to make the intermediate diastereomeric pair N—((R)-2-hydroxy-1-phenylethyl)-2-methylhept-4-ynamide. The diastereomers were separated by silica gel chromatography and the desired diastereomer was manipulated as described to afford the title intermediate as a clear oil. The absolute stereochemistry of the title intermediate was proven by determination of its specific rotation. [α]Tλ=α/cl, [α]21.9D=+0.574/(0.025 g/1 mL×0.5)=+45.83° (c=1, CHCl3). Literature reported specific rotation from Liebigs Annalen der Chemie, 1989, 11, 1081-1083; [α]20D=+37.7° (c=1, CHCl3); chiral analytical HPLC (stationary phase: Chiralcel OJ-H normal phase 250×4.6 mm; mobile phase: 85:15 hexane/1-propanol; flow rate: 1 mL/min) retention time 6.4 min, 100% purity; TLC Rf 0.32 (solvent system: 4:1 v/v ethyl acetate-hexane); 1H-NMR (CDCl3) δ 3.76-3.80 (m, 6H), 3.11-3.29 (m, 2H), 2.86-2.95 (m, 1H), 2.36-2.44 (m, 1H), 2.26-2.33 (m, 1H), 2.09-2.16 (m, 2H), 1.16-1.20 (m, 3H), 1.06-1.11 (m, 3H); MS (ESI+) m/z 247 (M+1).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]([CH3:39])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]3[O:25][C:26]4[C:31]([CH:32]([C:33](=[CH2:38])[C:34]([O:36][CH3:37])=[O:35])[C:22]3=[CH:21][CH:20]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:15][CH:14]=1)=[O:12]>CS(C)=O>[CH3:39][N:10]([CH3:9])[C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:24]=[C:23]3[O:25][C:26]4[C:31]([CH:32]([C:33]5([C:34]([O:36][CH3:37])=[O:35])[CH2:4][CH2:38]5)[C:22]3=[CH:21][CH:20]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:17][CH:18]=1)=[O:12]
Reactant: C=C(C(=O)OC)C1c2ccccc2Oc2nc(-c3ccc(C(=O)N(C)C)cc3)ccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CC1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Sodium hydride (5.2 mg, 0.13 mmol, 60% in mineral oil) was added to a solution of trimethyl sulfoxonium iodide (28.7 mg, 0.13 mmol) in DMSO (1 mL) at room temperature. After 30 min at room temperature, the mixture was added to a solution of the product from Step 3 (45 mg, 0.109 mmol) in DMSO (1 mL). The resultant mixture was stirred at room temperature for 10 min and quenched with saturated NaHCO3 (1 mL). After addition of ethyl acetate (80 mL), the mixture was washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 50-100% ethyl acetate in hexanes) to provide methyl 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclopropanecarboxylate (12 mg, 26%). MS (ES+) m/z: 429 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:8][C@H:6]1[CH2:5][N:4]([C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=2)=[O:10])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNC(=O)Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[((2S,4R)-2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (50 mg, 0.16 mmol, prepared as described in Scheme B11) and phenylacetyl chloride (23 μL, 0.17 mmol) in CH2Cl2 (0.5 mL), was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was stirred at RT under N2 overnight. The mixture was poured into water and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. Rf, TLC (EtOAc)=0.1; MS (LC-MS): 438.1 [M+H]+, 897.2 [2M+Na]+, 393.1 [M−CONH2]−; tR (HPLC conditions f): 1.70 min.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5](=[O:6])[C:3]1=[O:4].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[Mg]Br>>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5]([C:17]2[CH:16]=[CH:15][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)([OH:6])[C:3]1=[O:4]
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Product: CN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Cl)cc(Cl)cc21
Yield: 1.5 %

Procedure:
The title compound (59.1 mg, 1.5%) was prepared from 1-methyl-4,6-dichloroisatin (250 mg) and 2-naphthyl magnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[NH:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([NH:21][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:35])[F:36])=[CH:8][CH:7]=2)=[O:20])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)N2CCc3ccccc3C2c2ccc(C(F)(F)F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCNC1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (3R)-tert-butyl 3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline-2-carboxamido)piperidine-1-carboxylate (44 mg, 87 μmol, example 20) in TFA (30% in DCM, 2 mL) was stirred at RT for 30 min. The solvents were removed and EtOAc (5 mL) and saturated NaHCO3 (3 mL) were added to the residue. The solution mixture was then stirred at RT for 10 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×2 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried under vacuum to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 404 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N+:46]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][O:54][C:55]([CH2:57][N:58]2[CH2:64][CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>C(#N)C.C(N(C(C)C)CC)(C)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:61]3[CH2:62][CH2:63][CH2:64][N:58]([CH2:57][C:55]([O:54][CH2:53][C:52]4[CH:65]=[CH:66][C:49]([N+:46]([O-:48])=[O:47])=[CH:50][CH:51]=4)=[O:56])[CH2:59][CH2:60]3)=[O:29])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CN1CCCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
3.5 g of N,N'-carbonyldiimidazole were added to a solution of 8.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 80 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 14.0 g of 1-(4-nitrobenzyloxycarbonylmethyl)homopiperazine bis(trifluoroacetate) in 80 ml of dry acetonitrile and 14.1 ml of diisopropylethylamine were added, whilst ice-cooling, to the mixture, and the resulting mixture was stirred at room temperature for 1.5 hours and then at 30° C. for a further 1.5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was diluted with ethyl acetate. The dilute solution was washed with water and with an aqueous solution of sodium chloride, in that order, and it was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art 9385), using ethyl acetate as the eluent, to give 7.6 g of the title compound as an amorphous solid.