Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:45])[C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:46][O:47][C@@H:48]([C@@H:69]1[CH2:73][CH2:72][CH2:71][NH:70]1)[C@@H:49]([CH3:68])[C:50]([NH:52][C@H:53]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51].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(OCC)(=O)C.CN(C=O)C.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:45])[C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:70]3[CH2:71][CH2:72][CH2:73][C@H:69]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:68])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a stirring solution of #128 (1.67 g, 3.1 mmol, 1.0 eq.) in 20 of dichloromethane and 2 mL of DMF, #121 (2.4 g, 3.1 mmol, 1.0 eq.) was added followed by HATU (1.29 g, 3.39 mmol, 1.1 eq.) and then Hunig's base (2.2 mL, 12.3 mmol, 4.0 eq.). The reaction was allowed to stir at room temperature for -2 hours. Reaction was reduced down, diluted with ethyl acetate before being washed with 0.5 N HCl and brine. Organics where dried over sodium sulfate and then reduced down onto silica. Residue was purified by Silica Chromatography (Gradient: 0%-50% acetone in heptanes) producing #129 (1.9 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 996.3 [M+H+] retention time=2.53 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)([O-:3])=[O:2].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>FC(F)(F)CO>[N+:1]([C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: OCC(F)(F)F
Product: O=[N+]([O-])c1cccc2c3c([nH]c12)CCNC3
Temperature: 105 °C
Yield: 55.4 %

Procedure:
2-Nitrophenylhydrazine (3.7 g, 24.2 mmol) and 4-piperidone monohydrate hydrochloride (3.7 g, 24.2 mmol) were suspended in 2,2,2-trifluoroethanol (25 mL). The resultant mixture was heated at reflux for 2 h and then concentrated. Conc. HCl (35 mL) was added in one portion. The resultant mixture was then heated at 105° C. for 15 h, and allowed to cool to rt, after which it was poured onto ice. While vigorously stirring, a 50% NaOH solution was added portionwise over 10 min until pH 12, maintaining the internal temperature at <20° C. The solid was collected via filtration and dried at room temperature under vacuum for 18 h to afford 6-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.91 g, 55%). 1H NMR (300 MHz, DMSO) δ 11.65-11.60 (br s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 3.86 (s, 2H), 2.99 (br s, 2H), 2.72 (br s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH2:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a solution of 0.748 g (4.48 mmol) of the product of Example 30 in 10.0 mL of pyridine was added 0.928 g (4.48 mmol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred for 24 h at room temperature and then diluted with chloroform and washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes and the resulting solid was filtered and dried to provide 0.86 g (57%) of the desired product as a tan solid. Electrospray Mass Spec: 338.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:32]#[C:33]C4CCOC4)=[C:17]([NH:20][C:21]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:22])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(NC2C3C(=CC(C#C[C@@H:61]4[CH2:65][CH2:64][CH2:63][O:62]4)=C(N)C=3)N=CN=2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:32]#[C:33][C@@H:61]4[CH2:65][CH2:64][CH2:63][O:62]4)=[C:17]([NH:20][C:21]([CH2:23][P:24](=[O:31])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:22])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#CC1CCOC1)OCC
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#C[C@@H]1CCCO1
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#C[C@@H]1CCCO1)OCC

Procedure:
Compound 2.4 was prepared with the same procedure as the preparation of Compound 1.3, using Compound 2.3 instead of Compound 1.2. MS (ESI) m/z=562 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[C:22]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32]O)=[CH:27][CH:26]=3)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C1(P([N:55]=[N+:56]=[N-:57])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:55]([CH2:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:23]([C:22]1[C:13]([Cl:12])=[N:14][C:15]3[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:31]2)=[N+:56]=[N-:57]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN=[N+]=[N-])ccc21
Temperature: 23 °C
Reaction time: 20 h

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.400 mL, 2.69 mmol, 1.10 equiv) was added dropowise over 2 min to a solution of tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2, 1.00 g, 2.45 mmol, 1 equiv) and diphenylphosphoryl azide (0.580 mL, 2.69 mmol, 1.10 equiv) in THF (20 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 50% EtOAc in hexane) to afford tert-butyl 5-(azidomethyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-3) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ8.34 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.3 Hz), 7.88 (d, 1H, J=7.8 Hz), 7.79 (br t, 1H, J=8.1 Hz), 7.62 (br t, 1H, J=8.0 Hz), 7.58 (s, 1H), 7.36 (dd, 1H, J=8.6, 1.5 Hz), 6.68 (s, 1H ), 4.46 (s, 2H), 127 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:18]=[C:17]([NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[H-].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:18]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 5-(4-chloro-butanoylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 4.4 mmol, 1 equiv) THF (20 ml) was treated portionwise with NaH (60% dispersion in mineral oil, 180 mg, 4.5 mmol, 1.1 equiv) and the resulting mixture was stirred for 1 h and then was diluted with AcOEt (100 ml). The resulting solution was washed with 2N aqueous HCl solution (50 ml), dried over MgSO4 and concentrated in vacuo to give 5-(2-oxo-pyrrolidin-1-yl)-N,N-dipropyl-isophthalamic acid methyl ester (B80) (1.38 g, 91%) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[C:8]([CH:12]3[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][N:28](CCN(C)C)C.CCOC(C)=O.C1CCCCC1>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:27]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[C:8]([CH:12]3[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1)#[N:28]
Reactant: Cc1c(C(=O)NCc2ccc(F)cc2)c(C2CC2)nc2cc(Br)ccc12
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCc2ccc(F)cc2)c(C2CC2)nc2cc(C#N)ccc12
Temperature: 160 °C
Yield: 191.5 %

Procedure:
To a solution of 880 mg (2.13 mmol) 7-Bromo-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 28) in DMF (3 mL) were added 70 μL (0.47 mmol) TMEDA, 152 mg (1.28 mmol) Zinccyanide, 4 mg (0.007 mmol) Pd2 dba3 and 25 mg (0.040 mmol) Xantphos. The reaction solution was degasses and flushed with nitrogen three times and then heated in MW to 160° C. for 4 min. After cooling to RT the mixture was filtered through celite and it was washed with dichloromethane. The combined organic layers were concentrated in vacuo. After CC (EtOAc/cyclohexane 1:2) of the residue, 325 mg (0.90 mmol, 42%) 7-Cyano-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 38) were obtained. MS: m/z 360.1 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)=[CH:18][CH:17]=1>>[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:23]2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Reactant: c1cc(C2CCNC2)ccn1
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2ccncc2)C1

Procedure:
A procedure analogous to that described in Example 19 Step 1 was followed using 1-hydroxy-4-adamantyl chloroformate solution and 3-(4-pyridyl)pyrrolidine. The title compound was isolated as a mixture of isomers. LC-MS Method 1 tR=0.90 min, m/z=343, 1H NMR (CD3OD) [selected resonances] 4.69 (s, 0.5H), 4.78 (s, 0.5H), 8.03 (d, 2H), 8.78 (d, 2H)
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]([CH3:22])([CH2:20][OH:21])[CH2:18]O.N1C(C)=CC=CC=1C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][C@H:41]([NH2:43])[CH3:42])=[CH:32]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][C@H:41]([NH:43][CH2:18][C:17]([F:16])([CH3:22])[CH2:20][OH:21])[CH3:42])=[CH:32]1
Reactant: CC(F)(CO)CO
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Trifluoromethanesulfonic anhydride (1.151 ml, 6.80 mmol) was added to a solution of 2-fluoro-2-methylpropane-1,3-diol (0.70 g, 6.47 mmol) in DCM (17.85 ml) at 0° C., followed by 2,6-lutidine (0.908 ml, 7.77 mmol). The reaction was allowed to warm to room temperature over 30 min, then was washed with 2M HCl. The organic phase was passed through a phase separator cartridge and concentrated in vacuo. The residue was dissolved in dioxane (12 mL), then (R)-1-(1H-indol-3-yl)propan-2-amine (1.128 g, 6.47 mmol) and DIPEA (1.678 ml, 9.71 mmol) were added and the reaction was heated to 90° C. for 2 h. After cooling, the reaction was diluted with DCM and washed with water. The aqueous was extracted with DCM, then the organics were concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (0.815 g, 47.6%) as a brown gum. m/z (ES+), [M+H]+=265.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[I-]>N1C=CC=CC=1>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-diethylamino-4-phenyl-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.13 mmol) and LiI in pyridine. Pale yellow solid (30 mg, 65%). LC-MS: 355 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:32]12[O:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:36]12[O:39][CH:32]([CH2:38][CH2:37]1)[CH2:33][N:34]([CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])[CH2:35]2
Reactant: C1CC2CNCC1O2
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@@H](CN1CC2CCC(C1)O2)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) was added 48.7 mg (0.43 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane (Connolly, T.; Considine, J.; Ding, Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy, K.; Place, D.; Sharma, A.; Sutherland, K. Organic Process Research & Development. 2010, 14(2), 459-465. Note: reference is for the HCl Salt). Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed by acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O.B(Br)(Br)Br.[CH2:26](O)[CH3:27]>C(Cl)Cl>[CH2:26]([O:16][C:14]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:15])[CH3:27]
Reactant: COc1ccc(C2(C(=O)O)CCCC2)cc1
Reactant: CCO
Agent: BrB(Br)Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(O)cc2)CCCC1
Temperature: -78 °C
Yield: 79 %

Procedure:
A solution of 1-(p-methoxyphenyl)-cyclopentanecarboxylic acid 093909 (5.0 g, 22.7 mmol) in ethanol (50 mL) was treated with conc. H2SO4 (4.40 g, 44.9 mmol) and heated to reflux under N2 for 12 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to 5.93 g crude ester (100%) that was utilized without purification. The ester (5.93 g, assume 22.7 mmol) was dissolved in dry CH2Cl2 (75 mL), cooled to −78° C. and then treated dropwise with BBr3 (11.4 g, 45.6 mmol). The reaction was warmed to 0° C. for 15 minutes and then quenched with methanol then water. The reaction mixture was extracted with CH2Cl2 and water, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 6:1 hexanes:EtOAc to afford 4.34 g (79%) 1-(4-hydroxy-phenyl)-cyclopentanecarboxylic acid ethyl ester. MS (ES+) Calc'd for C14H19O3 (M+1) 235. Found m/z 235 (100%). 1H NMR.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CO>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C@H:16]([OH:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)[C@H](O)CCC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Intermediate 85 (900 g, 1.0 eq, 1.0 wt) was charged to a solution of (S)-(−)-2-methyl-CBS-oxazaborolidine (198 g, 0.3 eq, 0.22 wt) in tetrahydrofuran (3.6 L, 4 vol) at 20° C., followed by a line rinse with tetrahydrofuran (0.9 L, 1 vol). The suspension was cooled to 0° C. and chilled (0° C.) 1M borane in tetrahydrofuran solution (4.82 L, 2 eq 5.35 vol) was added over 1 hour 35 minutes at <3° C. The mixture was stirred at 0° C. for 1 hour 20 minutes when complete dissolution was observed and sampled for completion by HPLC. Reaction was complete. The mixture was added into chilled (0° C.) methanol (3.6 L, 4 vol) at <5° C. over 40 minutes, followed by a line rinse with methanol (0.9 L, 1 vol). The mixture was warmed to 20° C. and stirred at this temperature for 1 hour 15 minutes when effervescence had ceased. Water (2.7 L, 3 vol) was added, followed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 1 hour when effervescence had ceased. To the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes and the mixture stirred vigorously for 10 minutes at 20° C. The basic aqueous layer was separated. The organic phase was diluted with isopropylacetate (3.6 L, 4 vol) and washed with water (2.7 L, 3 vol). The aqueous phase was separated and the organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C. To the mixture was added isopropylacetate (5.4 L, 6 vol), followed by water (6 L, 6.7 vol) and the mixture stirred vigorously for 10 minutes at 20° C. The aqueous phase was separated and the organic phase was concentrated by vacuum distillation on a rotary evaporator. The solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration, washed with heptane (2×0.9 L, 2×1 vol) and dried in vacuo at 40° C. for 23 hours 30 minutes. Yield of the title compound obtained was 739 g/90% theory yield/82% w/w yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28]
Reactant: COc1ccccc1B(O)O
Reactant: CC(=O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccccc1C(C)=O
Temperature: 65 °C
Yield: 88.8 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 2-methoxyphenylboronic acid (228 mg, 1.5 mmol), and potassium phosphate (425 mg, 2.0 mmol). The tube was evacuated and backfilled with argon, and toluene (3 mL) and 2′-chloroacetophenone (0.13 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 65° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 201 mg (89%) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.C[O:45][C:46](=O)[C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:48]1[CH2:49][CH2:50][CH2:51][C@H:47]1[CH2:46][OH:45])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCC[C@H]1CO

Procedure:
6.78 g (30 mmol) o-benzoylbenzoic acid and 2.96 ml (30 mmol) of S(+)-2-pyrrolidinemethanol were reacted with 4.05 g (30 mmol) 1-hydroxybenzotriazole hydrate and 6.18 g (30 mmol) of DCC in 150 ml methylene chloride as described in Example 25 for the coupling of o-benzoylbenzoic acid with L-proline methyl ester. The crude reaction mixture was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent removed in vacuo to afford a yellow residue. Flash chromatograohy on silica gel (20:1/methylene chloride:methanol) afforded the title compound which crystallized from ethyl acetate as a white solid (3.99 g (43%)) by the addition of ether until crystallization took place. TLC (90:10/CH2Cl2 :MeOH): Rf =0.50. mp=113-114. 1H NMR (CDCl3) δ: 7.35-7.80 (9m,5H); 4.40-4.50(m,1H); 3.15-4.20(m,5H); 1.55-2.15(m,4H). I.R. (KBr): 1589, 1603, 1660 cm-1. Standard Combustion Analysis Calculated: C,73.77; H,6.19; N,4.53. Found: C,73.40; H,6.16; N,4.41. High Resolution Mass Spectrum: 309.1378±1.3 ppm (calculated for C19H19 NO3).