Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH2:19](OCC)C>>[CH2:17]([O:16][C:14]([CH:11]1[CH2:12][CH2:13][C:8](=[CH2:19])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C1CCC(C(=O)OCC)CC1

Procedure:
4-Methylenecyclohexanecarboxylic acid ethyl ester is prepared from the Wittig reaction on ethyl 4-oxocyclohexanecarboxylate using Method 3. This ester is reduced to compound III-5 according to the following procedure: To a solution of lithium aluminum hydride (4.0 equiv) in diethyl ether (1.0 M with respect to hydride) is added ethyl 4-oxocyclohexanecarboxylate in diethyl ether (2.0 M with respect to ester). The reaction is heated to reflux for 2 h after which it is cooled in an ice bath and quenched with by subsequent additions of isopropanol, 50% NaOH in water, and water. The mixture is then filtered and the filter cake is washed with excess diethyl ether. The filtrate is then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to provide a clear oil that is used without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([CH2:14]Cl)[CH2:12][Cl:13].[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH:11]([CH2:12][Cl:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)CBr
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCC1CN(Cc2ccccc2)C1
Temperature: 80 °C

Procedure:
59 g of benzylamine was added drop-by-drop over two hours to a stirred, refluxing mixture of 103 g of 1A, 50 ml of water and 200 ml of 100°/120° C. petroleum ether, under nitrogen, at 80° C., the pH of the mixture being maintained at 7-7.5. A solution of 40 g of sodium hydroxide in 60 ml of water was then added slowly to the stirred, refluxing mixture, at a rate sufficient to maintain the pH of the mixture at about 8. The resulting mixture was cooled and the aqueous phase was removed. The organic phase was washed with water, the solvent was evaporated under reduced pressure, and the residue was distilled in a wiped-film evaporator to give 1, as a colorless oil, b.p.: 80° C., 0.01 Torr.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[C:20]([CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[N:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CBr
Reactant: OCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)cc1
Reaction time: 8 h

Procedure:
Compound 1 (0.4 g, 1.75 mmol) and methyl bromoacetate (0.28 g, 1.83 mmol) were dissolved in 40 mL of acetone, and K2CO3 (0.726 mg, 5.26 mmol) was added at room temperature followed by stirring overnight. The reaction mixture was diluted with 100 mL of EtOAc and washed with water (2×50 ml), brine (50 ml), and dried over Mg2SO4. After evaporation of solvents under reduced pressure the residue was purified by silica gel column chromatography (EtOAc:n-hexane 4:6) affording compound 3. Yield: 0.395 g (75%). 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H, Hg), 4.58 (s, 2H, He), 4.92 (s, 2H, Hf), 5.33 (s, 1H, —OH), 7.10-7.14 (m, 2H, Ha), 7.47-7.49 (m, 2H, Hd), 7.80-7.86 (m, 4H, Hb, Hc). 13C NMR (100 MH, DMSO-d6) δ 52.4 (Cg), 62.9 (Cf), 65.3 (Ce), 115.7, 122.6, 124.8, 127.6, 146.3, 147.1, 151.4, 160.6169.4. HRMS (ESI+) m/z: [M+H]+ calcd for C16H17N2O4 301.1188. Found 301.1176.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])(O)=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Cyanuric chloride (2.22 g, 12.0 mmol) in acetone (50 mL) was added to well-stirred ice water (72 mL). To the resulting fine slurry at 0° C. was slowly added a solution of 1-Boc-piperazine (2.24 g, 12.0 mmol) in acetone (20 mL). A solution of NaHCO3 (1.0 g) in water (20 mL) was slowly added to the mixture, which was subsequently stirred at 0° C. for an additional 2.5 h. The resulting precipitate was collected by filtration, washed with water, and dried to yield a white solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 138.7 %

Procedure:
To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol) and p-hydroxyphenyl acetic acid (110 g, 0.72 mol) was added acetic anhydride (240 mL) and triethylamine (161 mL, 1.6 equiv.). This non-homogeneous mixture on heating becomes homogeneous at ˜70° C. After being stirred at 130° C. for 4 hr, the mixture was cooled to room temperature. HCl (15%, 500 mL) was added to the reaction mixture slowly in 30 min keeping temperature below 5-10° C. The solid was dissolved in 3N aqueous NaOH (1.2 L) and stirred for 0.5 hr. The filtrate was acidified, maintaining a temperature at 25-30° C., with conc. HCl (˜700 mL) to pH 1. The precipitated product was filtered and washed with water to give crude product (˜300 g, wet cake). The crude product was dissolved by heating in ethanol and recrystallized by adding equal volume of water. The product was dried overnight in a vacuum oven at 40° C. Yield: 161 g, 74%. Analysis: 1HNMR (DMSO-d6): δ 12.48 (br, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 6.35 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 3.56 (s, 6H).
Reaction SMILES: O=[C:2]([CH3:5])[CH:3]=O.[Cl:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=1>C1COCC1.Cl>[Cl:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[C:9]2[C:10]([N:13]=[CH:3][C:2]([CH3:5])=[N:14]2)=[CH:11][CH:12]=1
Reactant: CC(=O)C=O
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cnc2ccc(Cl)c([N+](=O)[O-])c2n1
Temperature: 65 °C
Yield: 85.7 %

Procedure:
At room temperature, 2-oxo-propionaldehyde (40% aqueous solution, 3.03 ml, 20.15 mmol, 1.0 equiv) was added to a solution of 4-chloro-3-nitro-benzene-1,2-diamine (3.78 g, 20.15 mmol) in THF (600 ml) and aqueous HCl (5N, 9.5 ml). The mixture was warmed to 65° C. for 10 minutes, then it was concentrated to approximately 200 ml and extracted with EtOAc. The combined organic layers were washed with dilute aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 9:1 to 7:3) to afford the title compound (3.86 g, 81%, 92:8 mixture of 7-chloro-2-methyl-8-nitro-quinoxaline and 6-chloro-2-methyl-5-nitro-quinoxaline). 1H NMR (400 MHz, CDCl3): δ=8.81 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 2.79 (s, 3H). MS (ES+): 224 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([NH2:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][NH:32][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)c1ccccn1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 and 1-pyridin-2-yl-ethylamine with NaBH(OAc)3 gave (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine as a pale yellow oil. 1H NMR (CDCl3) 1.48 (d, 3H, J=6.9 Hz), 2.19 (s, 3H), 3.70-3.83 (m, 2H), 4.02 (q, 1H, J=6.9 Hz), 7.06 (dd, 1H, J=5.4, 7.5 Hz), 7.13-7.18 (m, 1H), 7.36-7.40 (m, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.66 (dt, 1H, J=1.8, 7.8 Hz), 8.40 (d, 1H, J=3.9 Hz), 8.55-8.57 (m, 1H).
Reaction SMILES: CC1N=C([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[O:10])ON=1.[N:32]1(C2C=CC=CC=2C(O)=O)[CH:36]=[CH:35][CH:34]=[N:33]1.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[N:32]1([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=2)=[O:10])[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Reactant: O=C(O)c1ccccc1-n1cccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 2-(1H-pyrazol-1-yl)benzoic acid (CAS number 55317-53-8; 53 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][C:26]1([CH3:37])[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:30][CH2:29][O:28][CH2:27]1.C1COCC1.CCN(C(C)C)C(C)C>O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3([CH3:25])[CH3:37])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC1(C)COCCN1CC(=O)NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)COCCN1CC(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To the solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g, 0.7 mmol) and 2-(3,3-dimethylmorpholino)acetohydrazide (0.160 g, 0.85 mmol) in THF (2.5 mL) T3P (0.63 mL, 1.06 mmol) was added dropwise followed by DIPEA (0.18 mL, 1.06 mmol) at −60° C. The reaction mixture was stirred for 1 h, transferred into 25 mL iced-water, and extracted with ethyl acetate (2×25 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was purified by chromatography (0-4% MeOH:CH2Cl2) to give 0.05 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3,3-dimethylmorpholino)acetyl)acrylohydrazide (Yield: 13%). 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.81 (s, 1H), 9.62 (s, 1H), 8.56 (s, 2H), 8.29 (s, 1H), 7.49-7.51 (d, J=10.4 Hz, 1H)), 6.01-6.03 (d, J=10.4 Hz, 1H), 3.65-3.67 (m, 2H), 3.30-3.34 (m, 2H), 3.08 (bs, 2H), 2.55-2.58 (m, 2H), 0.96 (s, 6H). LCMS m/z 521.18 [M+H]+, tR 1.937 min
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:16])[CH3:15]
Reactant: OC1C=CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C=CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 2-cyclohexen-1-ol (16) (45.5 mmol, 5.02 mL) in pyridine (0.27 mol, 22 mL) at 0° C., acetic anhydride was added dropwise and the reaction mixture was stirred at 0° C. for ½ h. The ice bath was removed, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with HCl (1N), saturated NaHCO3, brine, and concentrated in vacuo to give 6 g (94%) of the crude product 17 which was used in the next step without further purification. TLC with 20% EtOAc/Hexane, stained with 5% H2SO4/EtOH, Rf for (16): 0.4, Rf for (17): 0.8.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:25]=2[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2cc(C=O)ccc2s1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 396.76 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20](COCCOC)[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:10]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:51]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CCOCC.CO.ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:17]=[N:18][N:19]([CH3:51])[N:20]=3)[CH2:15][C@@:9]1([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:10]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:32]([C:40]([F:42])([F:43])[F:41])[CH:31]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cn1nnc([C@]2(F)C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]-methoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Example 172; 150 mg, 0.22 mmol), 1M solution of hydrogen chloride in ether (3 ml) and methanol (3 ml) was stirred at reflux for 9 hours. The reaction mixture was concentrated. The residue (170 mg) was treated with dichloromethane (3 ml), methanol (0.5 ml), triphenylphosphine (220 mg, 0.83 mmol) and diethyl azodicarboxylate (0.12 ml, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo to give a 1:3.3 mixture of isomers A and B, respectively. Both isomers were separated by chromatography on silica gel (iso-hexane:ethyl acetate 0-20%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH2:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH:34][CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: Cn1c(-c2cncc(CN[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester are processed according to the method described in Example 170 to give (R)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (ESI) m/z 466.11 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35]([NH:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:36])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([N:17]([S:24]([NH:27][C:28]([O:30]C(C)(C)C)=O)(=[O:26])=[O:25])[CH2:18]C(OCC)=O)[CH2:13]1)[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:18][C:28](=[O:30])[NH:27][S:24]4(=[O:26])=[O:25])[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:35]([NH:37][CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:36]
Reactant: CCOC(=O)CN([C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN([C@H]2CCN(c3ccc4c(C(=O)NCC5CCCCC5)c(Cl)ccc4n3)C2)S(=O)(=O)N1
Reaction time: 3 h
Yield: 3.8 %

Procedure:
N-[(3S)-1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-3-pyrrolidinyl]-N-[[[(1,1-dimethylethoxy)carbonyl]amino]sulfonyl]-glycine, ethyl ester (Example 112 (b)) (670 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the mixture stirred for 3 hours before being concentrated. Sodium methoxide (25% in methanol, 3 mL) was added and the mixture was stirred under nitrogen for 2 hours. The products were concentrated onto silica gel and purified by chromatography (SiO2, dichloromethane:methanol 92:8 as eluant). Further purification by HPLC (Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) gave the title compound as a solid (20 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][OH:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]=[O:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1c2cccc(CCO)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1c2cccc(CC=O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.67 h
Yield: 87.1 %

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (160 mg, 0.31 mmol) in CH2Cl2 (3.1 mL). Add NaHCO3 (160 mg, 1.90 mmol) and 3,3,3-Triacetoxy-3-iodophthalide (156 mg, 0.37 mmol) at room temperature. Stir 40 min. Add saturated NaHCO3 solution and saturated Na2S2O3 solution, extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give the title compound as a white foam (140 mg, 0.27 mmol). MS (m/z): 520.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C:13]2[S:14][C:15]([C:24](O)=[O:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:62]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]>CN(C=O)C>[C:65]([O:64][C:62]([N:69]1[CH2:74][CH2:73][N:72]([C:24]([C:15]2[S:14][C:13]([NH:12][C:10](=[O:11])[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)([CH3:27])[CH3:28])=[N:17][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:25])[CH2:71][CH2:70]1)=[O:63])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carboxylic acid (46 mg, 0.11 mmol), HBTU (50 mg, 0.13 mmol), triethylamine (22 uL, 0.16 mmol) and N-Boc piperazine (27 mg, 0.15 mmol) in DMF (2 mL) was stirred at RT for 18 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 596.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.CO.[C]=O.[C:42]([O:45][CH2:46]C)(=[O:44])C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:14])[CH3:15])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:3][C:2]([C:42]([O:45][CH3:46])=[O:44])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Yield: 95 %

Procedure:
A mixture of tert-butyl (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methylcarbamate (0.79 g, 1.7 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.047 g, 0.084 mmol), palladium acetate (0.019 g, 0.084 mmol), triethylamine (0.26 ml, 1.9 mmol), methanol (10 ml) and tetrahydrofuran (10 ml) was stirred in a sealed tube under a 0.5 MPa carbon monoxide atmosphere at 110° C. for 3 hrs. The reaction mixture was cooled and added to a mixture of ethyl acetate (50 ml) and water (50 ml), and insoluble materials were filtered off. The organic layer was separated, washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography and crystallized from diisopropyl ether-ethyl acetate to give methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylate (0.71 g, yield 95%) as colorless crystals.