Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OC(C)C)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][N:15]([C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C)CC(=O)O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)CC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.2 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (100 mg, 0.245 mmol) obtained in Example 260, N,N-dimethylglycine (40 mg, 0.39 mmol) and N-methylmorpholine (0.142 ml, 1.29 mmol) were dissolved in dichloromethane (5 ml), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) at room temperature. After stirring at room temperature for 14 hours, a saturated aqueous solution (0.5 ml) of sodium bicarbonate was added. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The resulting solid was washed with diisopropyl ether, whereby the title compound (70 mg, 0.15 mmol, 62%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([S:15][CH:16]=[CH:17][C:18](Cl)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(#N)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[CH:17]=[CH:16][S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)C=CSc1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)C=CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
p-Toluidine (2.46 g) was dissolved to acetonitrile (20 ml), then acetonitrile (3 ml) solution of 3-(phenylthio)acryloyl chloride (2.0 g) was added dropwise thereto under ice-cooling. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 ml of ice-water, and adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystal was collected by filtration, washed with water and dried to obtain N-(4-methylphenyl)-3-(phenylthio)acrylamide (2.62 g) as light brown crystal.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])[S:8][C:4]=2[CH:3]=1.[CH3:16][C:17]1([CH2:24][C:25](O)=O)[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:11][C:25]([CH2:24][C:17]4([CH3:16])[NH:18][C:19](=[O:23])[NH:20][C:21]4=[O:22])=[N:13][N:12]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NNC(=O)Cc1nc2ccc(Br)cc2s1
Reactant: CC1(CC(=O)O)NC(=O)NC1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(Cc2nnc(Cc3nc4ccc(Br)cc4s3)o2)NC(=O)NC1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (1.0 g, 3.5 mmol) (prepared as described in WO 2011/074560) in dioxane (10 mL) was added 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetic acid (0.80 g, 4.2 mmol), T3P (50% in EtOAc, 5.20 mL, 8.74 mmol) and DIPEA (3.1 mL, 17.5 mmol). The reaction mixture was stirred at 90° C. for 6 h. Additional DIPEA (3.1 mL, 18 mmol) and T3P (50% in EtOAc, 3.1 mL, 1.8 mmol) were added. The reaction mixture was heated at 95° C. for 12 h. The reaction mixture was diluted with DCM, and the organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO silica gel chromatography eluting with 0-15% MeOH/DCM over 30 min gradient to give racemic material (811 mg, 1.92 mmol, 55.0% yield) as a yellow solid. The enantiomers were separated by preparative chiral SFC (Kromasil 5-Cellucoat 21×250 mm ID, 5 μm, 65 mL/min, 150 bar, 35° C., 25% MeOH/77% CO2) to afford isomer A as Example 23A (Rt=7.8 min, 37% yield), LCMS (method B) Rt=1.6 min, m/z=423.9 (M+H)+; and isomer B as Example 23B (Rt=11.2 min, 35% yield), LCMS (method B) retention time=1.6 min, m/z=423.9 (M+H)+. For Example 23B: 1H NMR (400 MHz, CDCl3) δ 8.26 (br. s., 1H), 8.01 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 6.54 (s, 1H), 4.71 (d, J=2.0 Hz, 2H), 3.40-3.21 (m, 2H), 1.59 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:29][CH3:30])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:29]([N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:30]
Reactant: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 88.6 %

Procedure:
1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid (133.0 mg) was prepared by following General Procedure E starting from 1-ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid methyl ester (155.0 mg) and sodium hydroxide (2.0 N solution, 1.0 mL) MeOH (0.5 mL) and THF (1.0 mL).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([O:24][CH3:25])(=[O:23])[CH:20]([CH3:22])[CH3:21].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[O:33]>C1COCC1>[OH:33][CH:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)[C:20]([CH3:22])([CH3:21])[C:19]([O:24][CH3:25])=[O:23]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.8 %

Procedure:
To a solution of diisopropylamine (1.675 mL, 11.75 mmol) in THF (10 mL) was added n-BuLi/hexane (4.70 mL, 11.75 mmol) dropwise at −78° C. The reaction mixture was stirred in the bath for 5 min and then stirred in ice bath for 30 min. The reaction mixture was added dropwise a solution of methyl isobutyrate (1 g, 9.79 mmol) in THF (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. The solution of picolinaldehyde (1.258 g, 11.75 mmol) in THF (2 mL) was added dropwise at −78° C. Then the solution was allowed to warm to room temperature and stirred for 1 hr. The reaction was quenched with NH4Cl, then diluted with EtOAc. Then organic phase was washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, and concentrated to yield an oil. The crude was purified by silica chromatography with 0-100% EtOAc/Hex to yield methyl 3-hydroxy-2,2-dimethyl-3-(pyridin-2-yl)propanoate (1.0 g) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.61-8.44 (m, 1H), 7.66 (td, J=7.7, 1.8 Hz, 1H), 7.26-7.12 (m, 2H), 4.96 (d, J=7.5 Hz, 1H), 4.67 (d, J=7.5 Hz, 1H), 3.74 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [N:1]1[N:5]2[C:6]([C:10]#[N:11])=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1>CO.N.[Ni]>[N:1]1[N:5]2[C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1
Reactant: N#Cc1cccc2ccnn12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc2ccnn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of pyrazolo[1,5-a]pyridine-7-carbonitrile (1 equiv.) in methanol and aq. ammonia solution (9:1), catalytic amount of Raney Nickel was added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 2-5 h. On completion of reaction, it was filtered through celite bed and filtrate was concentrated under reduce pressure to afford the title compound (quant. yield).
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23](=[O:34])[C:22]2=[O:35].O1C2C=CC(O)=CC=2OC1.[O:46]1[C:50]2[CH:51]=[C:52]([OH:55])[CH:53]=[CH:54][C:49]=2[CH2:48][CH2:47]1>>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23](=[O:34])[C:22]2([OH:35])[C:53]1[C:52]([OH:55])=[CH:51][C:50]2[O:46][CH2:47][CH2:48][C:49]=2[CH:54]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCOC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br, 1H), 7.31-7.24 (m, 2H), 6.92 (d, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.53-4.46 (m, 2H), 5.09-4.40 (d, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 387.8 (M−17).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH2:19][C@@H:20]([CH3:36])[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=2)=[N:23]1>>[Cl:35][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][N:22]([CH2:21][C@@H:20]([NH:19][C:16]([C:14]3[N:15]=[C:11]([CH:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]4)[O:12][CH:13]=3)=[O:18])[CH3:36])[N:23]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: CS(=O)(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Yield: 87 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylic acid (0.4 g, 01.458 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.317 g, 01.215 mmol). The product was purified by extracting it from DCM with 0.1 M HCl, 1 M Na2CO3, water and brine. Yield 87%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 1.97 (m, 2H), 2.15 (m, 2H), 2.83 (s, 3H), 2.89 (m, 3H), 3.81 (m, 2H), 4.30 (dd, 1H), 4.41 (dd, 1H), 4.57 (m, 1H), 6.63 (d, 1H), 7.46 (d, 1H), 7.49 (d, 1H), 7.68 (dd, 1H), 7.79 (dd, 1H), 8.01 (dd, 1H), 8.11 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@H:14]([NH:16][CH2:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH3:15])[CH:6]=1.C(O)(=O)C.[Cl:31][C:32]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CCCCCC.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@H:14]([N:16]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:43])[F:42])[C:32]=2[Cl:31])[CH2:17][C@H:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19])[CH3:15])[CH:6]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: COC(=O)Cc1cccc(OCC[C@@H](C)NC[C@@H](C)c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OCC[C@@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Yield: 26.8 %

Procedure:
To a solution of {3-[(R)-3-((S)-2-Phenyl-propylamino)-butoxy]-phenyl}-acetic acid methyl ester (0.12 g, 0.34 mmol) in dry dichloromethane was added acetic acid followed by 2-chloro-3-trifluoromethylbenzaldehyde (0.1 g, 0.51 mmol) and sodium triacetoxyborohydride (0.149, 0.68 mmol). After the resulting mixture was stirred at room temperature overnight water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacco. The crude mixture was purified by silica gel column chromatography using EtOAc:Hexane/25:75 as the eluent to give 50 mg (40% yield) of the title compound as an oil MS m/e 548.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH3:16])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: Clc1cc(-c2cccnc2Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Cl)ncn1
Temperature: 80 °C

Procedure:
4-Chloro-6-(2-chloro-pyridin-3-yl)-pyrimidine (450 mg, 1.99 mmol), methylamine hydrochloride (202 mg, 2.99 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (3.0 mL) were combined. The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield the title compound. MS m/z=221 [M+1]+. Calc'd for C10H9ClN4: 220.66.
Reaction SMILES: [CH2:1]([C:5]1([O:10][CH2:11][CH3:12])[CH2:7][C:6]1(Cl)[F:8])[CH2:2][CH2:3]C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:5]([O:10][CH2:11][CH3:12])([CH2:1][CH2:2][CH3:3])[C:6]([F:8])=[CH2:7])[CH3:20]
Reactant: CCO
Reactant: CCCCC1(OCC)CC1(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(F)C(CCC)(OCC)OCC

Procedure:
A stirred solution of 58.4 g. of 2-butyl-1-chloro-2-ethoxy-1-fluorocyclopropane and 166 g. of anhydrous potassium carbonate in 400 ml. of absolute ethanol is heated at reflux for 18 hours. The solution is cooled and the bulk of the ethanol is removed in vacuo. The residue is partitioned with 500 ml. of water and 750 ml. of ether. The ether phase is washed with three 100 ml. portions of brine, dried over potassium carbonate and concentrated in vacuo to provide 54 g. of a pale yellow oil. A 4.45 g. portion of this oil is distilled through a 6 inch Vigreux column giving 2.5 g. of the desired product as a colorless liquid, b.p. 80°-81° C., 24 mm.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=3)=[CH:38][CH:37]=2)=[C:27]([CH2:26][CH2:25][NH:9][CH:10]2[CH2:19][CH2:18][CH2:17][C:16]3[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]2=3)[CH:32]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.2 ml of a 4 N solution of hydrogen chloride in dioxane were added to 500 mg (0.69 mmol) of rac-ethyl 5-[(tert-butoxycarbonyl)(2-{5-fluoro-2-[(4-{2-[4-(trifluoromethyl)phenyl]-ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 157A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness. This gave 479 mg of the target product which was reacted further without further analytical characterization.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:30][CH2:31][O-:32].[Na+]>C(O)C>[CH2:31]([O:32][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:30]
Reactant: CC[O-]
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Agent: [Na+]
Solvent: CCO
Product: CCOCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
The mixture of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (23 mg, 0.056 mmol), NaOEt (10 mg) in ethanol (1 mL) was refluxed at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15.0 mg, 59%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25].Cl>O1CCOCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(Cc3cccs3)S(C)(=O)=O)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a stirred solution of tert-butyl 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetate (580 mg, 1.287 mmol) in dioxane (15 ml), aqueous 12M HCl (1 ml, 12.00 mmol) was added drop wise. The resulting mixture was stirred at 50° C. for 4 hours. The volatiles were removed under vacuum and the crude 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido) isoindolin-2-yl)acetic acid (490 mg, 1.242 mmol, 97% yield, MS/ESI+ 395.0 [MH]+). was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]>[Ni].C(O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O=CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 8 h
Yield: 85.5 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 1.0 g of a developed Raney nickel, and 10 mL of formic acid. The reaction was carried out at 70° C. for 8 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.77 g (reaction yield: 85.0%) of methyl 5-methoxy-4-(3-chloropropoxy)-anthranilate.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:8]=2[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCOCC1.[ClH:33]>CO.[Pd]>[ClH:33].[CH:1]1([S:4]([C:7]2[C:8]([CH2:9][NH:10][CH3:11])=[CH:19][C:20]([NH2:24])=[CH:21][C:22]=2[F:23])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1S(=O)(=O)C1CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCc1cc(N)cc(F)c1S(=O)(=O)C1CC1
Reaction time: 22 h
Yield: 100 %

Procedure:
To a fine suspension of 11D (985 mg, 2.54 mmol) in MeOH (10 mL) was added 10% Pd—C (50 mg, 0.047 mmol). The mixture was evacuated and flushed with hydrogen (3×), then was stirred under an atmosphere of hydrogen for 22 h. The reaction mixture was filtered and concentrated to afford a colorless solid. The solid was suspended in 4N HCl in dioxane (6 mL, 24.00 mmol). The suspension was stirred at rt for 1 h, then concentrated to give 11E (840 mg, 2.54 mmol, 100% yield) as an off-white solid. MS (ESI) m/z: 259.1 [M+1]+. 1H NMR (400 MHz, MeOD) δ ppm 6.60 (1H, d, J=2.0 Hz), 6.54 (1H, dd, J=13.6, 2.3 Hz), 4.31 (2H, s), 2.87-2.97 (1H, m), 2.75 (3H, s), 1.24-1.31 (2H, m), 1.05-1.13 (2H, m).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[CH:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1.[Cu]>[OH:17][CH:11]([CH:6]1[CH:5]([CH:2]=[CH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8][C:7]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)C1C=CC(=O)CC1
Reactant: CCCCCC=O
Agent: [Cu]
Solvent: C1CCOC1
Product: CCCCCCC=CC1C(C(C)C)CCC(=O)C1C(O)CCCCC
Reaction time: 2 h
Yield: 82 %

Procedure:
Following the procedure of Example 1, a mixed solution was formed of the cuprate and Me3ZnLi (0.52 mmol) comprising 10 mol-% of copper per mole of enone. The solution was treated with 4-isopropyl-2-cyclohexenone (77 μL, 0.5 mmol) as a neat liquid over 70 minutes and then stirred for an additional 2 hours. Hexanal (0.25 mL, 2.0 mmol), in 1.0 mL THF at -78° C., was then added. After 5 minutes the mixture was quenched with 5 mL of 10% NH4OH in saturated NH4Cl. The product was extracted with 3×20 mL of ether and dried over Na2SO4. The solution was then filtered through flitted filter paper and the solvent removed in vacuo. The resulting residue was submitted to flash chromatography on silica gel (Petroleum Ether/Ethyl Acetate, 30/1) to give an 82% yield of 2-(1-hydroxyhexyl)-3-(1-octen-1-yl)-4-isopropyl cyclohexanone as a colorless oil which gave satisfactory IR, NMR, MS, and HRMS data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:20][CH2:21][OH:22])[CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].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>COC(C)(C)C>[C:1]([O:5][C:6]([N:7]1[CH2:20][CH2:21][O:22][CH:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=2)[CH2:8]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nccc(C(O)CN(CCO)C(=O)OC(C)(C)C)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: CC(C)c1nccc(C2CN(C(=O)OC(C)(C)C)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
(2-Hydroxyethyl)-[2-hydroxy-2-(2-isopropyl-pyrimidin-4-yl)-ethyl]-carbamic acid tert-butyl ester (396 mg, 1.22 mmol) was dissolved in methyl-t-butylether (MTBE) (15 ml). Triphenylphosphine (383 mg, 1.46 mmol) was added. To this mixture was added diisopropyl azodicarboxylate (295 mg, 288 μl, 1.46 mmol) dropwise. The solution was stirred at room temperature overnight. A white solid was filtered off, washed with MTBE (2×10 mL). The combined filtrate and washes were concentrated and the resulting residue was purified by Analogix flash column chromatography (40 g silica gel, 0% to 20% ethyl acetate in hexanes gradient) to afford 2-(2-isopropyl-pyrimidin-4-yl)-morpholine-4-carboxylic acid tert-butyl ester (256 mg) as a white solid. (M+H)|=308 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (d, J=6.82 Hz, 6H) 1.52 (s, 9H) 2.80 (br. s., 1H) 3.06 (d, J=10.61 Hz, 1H) 3.22 (dt, J=13.71, 6.92 Hz, 1H) 3.72 (td, J=11.62, 2.53 Hz, 1H) 3.98 (br. s., 1H) 4.07 (d, J=9.60 Hz, 1H) 4.48 (dd, J=10.48, 2.15 Hz, 2H) 7.31 (d, J=5.05 Hz, 1H) 8.69 (d, J=5.05 Hz, 1H).