Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[N:29]=[C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:31][C:32]=3[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])=[O:5])C.[OH-].[Li+]>C(O)C.O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([N:16]4[CH2:17][CH2:18][N:13]([C:11]([CH:7]5[CH2:8][CH2:9][CH2:10][CH:6]5[C:4]([OH:5])=[O:3])=[O:12])[CH2:14][CH2:15]4)=[CH:20][CH:21]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1CCCC1C(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC3C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of racemic 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester (100 mg, 0.171 mmol) in 10 mL ethanol was added a solution of lithium hydroxide (14 mg, 0.342 mmol) in 5 mL water. The reaction mixture was stirred at room temperature for 4 hrs and then heated to 50° C. for 1 hr. The reaction mixture was cooled, diluted with water, and washed with diethyl ether. The pH of the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (eluted with ethyl acetate/methylene chloride) to yield rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid (27 mg, 28%). ES-MS calcd for C28H27F3N4O5 (m/e) 556.54, obsd 557.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH:16](=[O:18])[CH3:17].O>C1COCC1>[Cl:1][C:2]1[C:7]([CH:16]([OH:18])[CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cccnc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A solution of 2-chloropyridine (I) (9.39 mL, 0.1 mol) in anhydrous THF (50 mL) was added slowly to a solution of LDA (2.0 M solution in THF/hexane/ethylbenzene, 50 mL, 0.1 mol) in THF (200 mL) stirred at −78° C. under nitrogen. The stirring was continued at −78° C. for an additional 3 h before adding acetaldehyde (6.17 mL, 0.110 mol). The solution was stirred at −78° C. for another 2 h before allowing the temperature to rise to −40° C. A solution of water (4 mL) in THF (40 mL) was added slowly to the solution. When the temperature reached −10° C., additional water (200 mL) was added to the solution. The solution was extracted with ethyl ether (3×100 mL). The combined organic phase was dried over MgSO4, filtered and evaporated under reduced pressure to get a brown viscous residue. The crude product was purified on a flash silica gel column (1:1 DCM:hexane→100% DCM) to produce 1-(2-chloropyridin-3-yl)ethanol (II) as a brown viscous oil (6 g, 38.1 mmol, 38% yield). 1H NMR (CDCl3) δ ppm 1.52 (d, J=6.41 Hz, 3H), 2.51 (bs, 1H), 5.24 (m, 1H), 7.28 (m, 1H), 7.97 (dd, J=7.72, 1.70, 1H), 8.27 (dd, J=7.72, 1.79, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(Cl)=[O:13]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C=O
Temperature: 0 °C
Yield: 88 %

Procedure:
2-Methyl-4-nitroaniline (35.0 g, 230 mmol) was dissolved in ethyl acetate (400 ml) and cooled to 0° C. Phosgene (180 ml, 20% in toluene) was added drop wise over 30 min, precipitation of a white salt followed instantly. After the last addition the temperature was allowed to slowly rise to room temperature, and then the reaction mixture was brought to reflux (˜100° C.). It was refluxed for 2 h 30 min, after which 200 ml of solvent was distilled off before the temperature was lowered to 80° C. and phosgene (140 ml, 20% in toluene) was added drop wise. After the last addition the reaction solution was refluxed for 3 hours, allowed to cool to room temperature and concentrated to dryness. The brown/yellow material was dissolved in diethyl ether (250 ml), filtered and concentrated to give a pale brown powder (36 g, 88%).
Reaction SMILES: [CH3:1][C:2]1(C)C[CH:6]([OH:8])[CH2:5][C:4](C)(C)N1.[CH3:12][N:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]1([CH3:23])[CH3:22].C=C.C(OCC)(=O)C=C>>[CH2:1]=[CH2:2].[C:6]([O:21][CH:16]1[CH2:17][C:18]([CH3:19])([CH3:20])[N:13]([CH3:12])[C:14]([CH3:23])([CH3:22])[CH2:15]1)(=[O:8])[CH:5]=[CH2:4]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: C=C
Agent: C=CC(=O)OCC
Product: C=CC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The above-named copolymer was prepared by the general procedure of Example 1 by substituting for the 2,2,6,6-tetramethylpiperidin-4-ol an equivalent amount of 1,2,2,6,6-penta-methylpiperidin-4-ol, and reacting with an ethylene/ethyl acrylate copolymer (77/23).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 94.2 μmol) in dichloromethane (4.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol38), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane added to allow solid formation, light yellow flakes were separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 85.3 μmol, 90.5%). MS (M+H)+=528; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.77-7.98 (m, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.57 (t, J=5.7 Hz, 2H), 3.49 (br. s., 4H), 2.26 (br. s., 6H), 2.00-2.15 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=C(O)c1cccc(N=C=S)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3-carboxyphenyl isothiocyanate (0.185 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (10 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration, washed with ethyl acetate, and air-dried to give the product (0.379 g), mp 221-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:10][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:10][C:11]=2[C:12]2[NH:24][N:23]=[N:22][N:13]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2nnn[nH]2)cc1
Yield: 4.7 %

Procedure:
To a solution 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbonitrile (167 mg, 0.536 mmol) in DMF (3.5 mL) was added sodium azide (104 mg, 1.61 mmol) and ammonium chloride (86 mg, 1.61 mmol) and the resulting mixture was heated at 100 degrees overnight. The reaction was cooled and taken up in ethyl acetate and water. The aqueous layer was concentrated in vacuo, and the residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 9 mg (5% yield) of the title compound. LC/MS (FA) ES+ 355, 357. 1H NMR (400 MHz, DMSO-d6) δ: 8.74-8.73 (m, 2H), 7.93-7.92 (m, 2H), 7.38-7.32 (m, 4H), 4.62 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[O:20]1[CH2:21][CH2:22][N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl bromoacetate (8.47 mL, 57.4 mmol) in THF (50 mL) was added a 1:1 mixture of triethylamine (8 mL, 57.4 mmol) and morpholine (5.02 mL, 57.4 mmol), dropwise (a mild exotherm was observed) and the resulting white suspension was stirred at 60° C. for 2 h. The mixture was diluted with water (100 mL) and saturated sodium carbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated sodium carbonate (100 mL), water (3×50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated then chromatographed in 0%-100% ethyl acetate in hexanes. Product-containing fractions were concentrated in vacuo giving the title product (11.5 g, quantitative) as a pale yellow liquid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 3.78-3.71 (m, 4H), 3.10 (s, 2H), 2.59-2.54 (m, 4H), 1.46 (m, 9H).
Reaction SMILES: [N+:1]([CH:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([O-:3])=[O:2].O.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:12]([CH:4]([N+:1]([O-:3])=[O:2])[C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:14])=[O:13])[CH3:17]
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)C1[N+](=O)[O-]
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Nitroindane-1,3-dione (20.5g; 0.107 moles) in ethanol (100 ml) was heated under reflux for 4 hours, cooled, poured into water (1 liter), allowed to stand overnight and filtered. The solid was extracted with 5% sodium bicarbonate solution (3 × 100 ml) and filtered. The insoluble solid was predominantly the Ψ-ethyl ester, 3-ethoxy-3-nitromethylphthalide, contaminated with some α-ethyl ester. Acidification of the combined sodium bicarbonate filtrates, filtration and recrystallisation from ethanol gave the α-ethyl ester, 2-ethoxycarbonyl-ω-nitroacetophenone, m.p. 81°.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13]Cl.O>CS(C)=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: ClCCBr
Reactant: N#CCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccs2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (19.1 g) in DMSO (200 mL) was added dropwise a solution of thiophen-2-ylacetonitrile (25 g) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 0.5 hr. To the obtained reaction mixture was added dropwise a solution of 1-bromo-2-chloroethane (25 mL) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a pale-brown oil (29.2 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:13]([O:14][CH3:15])=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[F:16])[CH2:3][CH2:2]1.P([O-])(O)(O)=[O:18].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:13]([O:14][CH3:15])=[CH:12][C:9]([C:10]([OH:18])=[O:11])=[CH:8][C:7]=2[F:16])[CH2:3][CH2:2]1
Reactant: COc1cc(C=O)cc(F)c1OCC1CC1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(C(=O)O)cc(F)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
To a mixture of 4-(cyclopropylmethoxy)-3-fluoro-5-methoxybenzaldehyde (1.00 g), sodium dihydrogen phosphate (1.61 g), 2-methyl-2-butene (2.49 mL), water (2 mL) and tert-butanol (10 mL) was added sodium chlorite (0.756 g), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (0.890 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:25])[C@@H:9]([O:17][Si](C(C)(C)C)(C)C)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(C)(C)C.Cl>CO>[ClH:16].[NH2:7][C@H:8]([CH3:25])[C@H:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[OH:17]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)[C@@H](O)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of (1R,2S)-[2-(tert-butyl-dimethyl-silyloxy)-2-(4-chloro-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (354 mg, 0.88 mmol) in MeOH (10 mL) at rt was treated with HCl (4 M in dioxane, 3 mL). After 1 h, the mixture was concentrated to provide the desired amine as the hydrochloride salt (200 mg, quant.). 1H NMR (400 MHz, CD3OD): 7.43-7.37 (m, 4H), 4.91 (d, J=3.4, 1H), 3.50 (dq, J=6.8, 3.5, 1H), 1.07 (d, J=6.8, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@H:5]([OH:26])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)[C@@H:9]([CH3:24])[C:8]1=[O:25].[OH-].[Li+]>>[Cl:23][C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C@@H:5]([OH:26])[CH2:4][C:3]([OH:27])=[O:2])[C:8](=[O:25])[C@@H:9]2[CH3:24])[CH:18]=[CH:17][C:16]=1[C:19]([F:20])([F:21])[F:22]
Reactant: COC(=O)C[C@H](O)CN1CCN(c2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)O)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Yield: 82 %

Procedure:
In analogy to intermediate 3B, (S)-4-[(S)-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-3-hydroxy-butyric acid methyl ester was hydrolyzed with 1 M aqueous lithium hydroxide (1 h) to give after extraction (EtOAc) and precipitation (dichloromethane/n-pentane) the titled compound in 82% yield as light yellow foam. MS: 393.08 (MH+)
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH:5]=[CH:4]1.C(OC(=O)C)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.CCCCCC>[Br:1][C:5]1[C:6]2[C:7]([C:12]#[N:13])=[CH:8][CH:9]=[CH:10][C:11]=2[NH:3][CH:4]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.41 %

Procedure:
Bromine in DMF (0.796 g, 4.975 mmol) was added to a stirred solution of 1H-indole-4-carbonitrile (700 mg, 4.9295 mmol) in DMF (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was poured into ice water containing 0.5% ammonia and 0.5% sodium metabisulphite. The precipitate was collected, washed with cold water and dried to afford 850 mg of 3-Bromo-1H-indole-4-carbonitrile (78.41% yield).
Reaction SMILES: [F:1][C:2]1([F:60])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42](O)[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:60][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39](/[CH:42]=[CH:43]/[CH:44]([CH3:45])[CH3:46])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:58])[F:57])=[CH:53][CH:54]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)CC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)/C=C/c1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 72.9 %

Procedure:
To a solution of 118 mg (0.141 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxy-3-methylbutyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 27, in 2 ml of 1,4-dioxane, 2 ml of 2 N hydrochloric acid was added, and the reaction solution was stirred at 100° C. for 3.5 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=92/8-88/12 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 72 mg of the title compound as a white solid (yield: 73%).
Reaction SMILES: ClC1C=CC(S([N:11]2[CH:16]([C:17]3[CH:22]=CC(F)=C[CH:18]=3)[CH2:15][C:14]3[NH:24][N:25]=[CH:26][C:13]=3[CH2:12]2)(=O)=O)=CC=1.FC1C=CC(C2CC(=O)CCN2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=CC=1.ClC1C=CC(C2CC(=O)CCN2C(OCC2C=CC=CC=2)=O)=CC=1.FC1C=CC([Mg]Br)=CC=1.O.NN.N1CCC(=O)CC1>>[CH:17]([CH:16]1[N:11]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:12][C:13]2[CH:26]=[N:25][NH:24][C:14]=2[CH2:15]1)([CH3:18])[CH3:22]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2)C1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1c1ccc(F)cc1
Agent: Fc1ccc([Mg]Br)cc1
Agent: NN
Agent: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
5-(4-Chlorophenylsulfonyl)-6-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Enantiomers A and B) Benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example using 4-fluorophenylmagnesium bromide, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using HPLC Method [2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6](O)=[O:7].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7]
Reactant: COc1cc(C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Reactant: Nc1ccccc1
Product: COc1cc(C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 11 %

Procedure:
The compound was prepared by reaction of 3-methoxy-5-(6-methoxynaphthalene-2-yl)benzoic acid (500 mg, 1.62 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/dichloromethane 1/1 as the eluent yielded the desired product in a yield of 11%, 68 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1cccc(Cl)c1C(=O)O
Product: Nc1cccc(Cl)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 46 %

Procedure:
Starting from 2-amino-6-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (100 mg; 46% yield).