Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[NH:51][C:52]([CH:54]1[NH:62][C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53]>C(Cl)Cl.CCOC(C)=O>[F:50][C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[C:45]=1[NH:51][C:52]([CH:54]1[N:62]([C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53].[F:50][C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[C:45]=1[NH:51][C:52]([CH:54]1[N:62]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53]
Reactant: O=C(Nc1c(F)cccc1F)C1Cc2cccnc2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2 h-pyran-4-yl)acetic acid (94.2 mg, 363 μmol, Eq: 2) and diisopropylethylamine (127 μL, 727 μmol, Eq: 4) in DCM (2 mL) was added N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (115 mg, 436 μmol, Eq: 2.4) and the resulting solution was stirred at rt for 1 h. N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (50 mg, 182 μmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH and brine and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes) to give tert-butyl (1R)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate (48 mg) and tert-butyl (1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate (46 mg), m/z=517 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:8])=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29](O)=[C:28]([Cl:34])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.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>O1CCCC1>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([O:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=2)=[C:30]([Cl:32])[CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccc(C(F)(F)F)cc1

Procedure:
A reaction vessel was charged with 5.25 g (21.2 mmol) of 3-(4-(trifluoromethyl)benzamido)propan-1-ol, 5.72 g (21.2 mmol) of 4-benzyloxy-2,6-dichlorophenol, 5.29 g (20.2 mmol) of triphenylphosphine and 100 ml of tetrahydrofuran, and a solution of 4.08 g (20.2 mmol) of diisopropyl azodicarboxylate dissolved in 20 ml of tetrahydrofuran was added dropwise, while stirring. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and the residue was subjected to silica gel chromatography, which afforded 1-benzyloxy-3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)benzene. 1-Benzyloxy-3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)benzene was dissolved in ethyl acetate, which was put into a reaction vessel, and the air in the vessel was replaced with nitrogen gas. A catalytic amount of 10% palladium on carbon was added, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, after which the reaction mixture was filtered through cerite and the filtrate was concentrated to give 3,5-dichloro-4-(33-(4-trifluoromethylbenzamido)propyloxy)phenol.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:24])[CH3:2].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.O.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:24])[C:14]2[C:15](=[CH:19][C:20]([NH:23][C:38](=[O:40])[CH3:39])=[CH:21][CH:22]=2)[C:16](=[O:18])[O:13]1
Reactant: CCn1c(C)c(C(=O)c2ccc(N)cc2C(=O)O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(NC(C)=O)ccc32)c2ccccc21
Temperature: 50 °C

Procedure:
A mixture of 3.22 g (0.01 mole) of 2-[(1-ethyl-2-methyl3-indolyl)carbonyl]-5-aminobenzoic acid, 118 g (0.01 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 10.0 ml of acetic anhydride was heated to 50° C. for one-half hour. After cooling to ambient temperature, 50 ml of water was added and the reaction mixture was filtered. The filtrate was rendered alkaline with dilute aqueous sodium hydroxide in the presence of 100 ml of toluene. The toluene layer was separated, dried and evaporated to obtain as tan crystals 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-acetamidophthalide (Formula III: R°=R1 =R3 =Y1 =H; R2 =NHCOCH3 ; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3) having a melting point of 204°-206° C. Infrared analyses showed maxima at 1733 cm-1 (C=O; s) and 1695 cm-1 (C=O; s). Nuclear magnetic resonance analsis was consistent with the structure. An acetone solution of the above compound developed an intense grape color when spotted on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A solution of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (2.5 g, 0.0124 mol) in acetic anhydride (60 ml) was heated to 140° C. and then treated with concentrated sulfuric acid (5 drops). After 15 minute at that temperature, HPLC showed clean conversion and the reaction mixture was quenched by the addition of ice cold water (150 ml). The mixture was extracted with ethyl acetate (3×150 ml). The combined extracts were washed with a saturated aqueous sodium chloride solution (300 ml), dried over magnesium sulfate and concentrated in vacuo as a brown solid. Trituration from a mixture of hexanes/ethyl acetate (1:1) provided 2.2 g (72.6%) of a pale yellow solid. M.p.=173° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.25-8.19 (m, 2H), 7.75-7.68 (m, 2H), 7.35-7.25 (m, 2H), 2.15 (s, 3H). LCMS: 245 [M+H].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.3 %

Procedure:
2.0 g of 5-(4-acetoxybenzylidene)thiazolidine-2,4-dione [prepared as described in step (a) above] were dissolved in 80 ml of acetic acid and the mixture was hydrogenated by passing hydrogen at atmospheric pressure through the solution at 90° C. for 5 hours in the presence of 2.0 g of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was filtered off, and the filtrate was diluted with toluene. The acetic acid solvent was then removed by distillation as a toluene azeotrope. The crystals which separated out on adding toluene and hexane to the concentrate were collected by filtration and dried to give 1.8 g of the title compound, melting at between 115° C. and 117° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[H-].[Na+].Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].ClCCl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1cc(F)c2c(c1)CCCN2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a stirred solution of 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (670 mg, 3.42 mmol) in N,N-Dimethylformamide (15 ml), cooled to 0° C. was added sodium hydride, 60% (437 mg, 10.93 mmol) with vigorous stirring. When bubbling subsided, 2-chloro-N,N-dimethylethanamine hydrochloride (984 mg, 6.83 mmol) was added and the reaction mixture (dark red) was stirred at room temperature. After 2 h, no product was observed so the reaction was heated to 90° C. and stirred. After 1 h, TLC showed the reaction to be complete. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with 1:1 water:brine (2×), then brine (1×). The organic phase was dried, filtered and concentrated, then chromatographed in 0-10% (2M NH3 in methanol) in 1:1 ethyl acetate:dichloromethane, giving the desired 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (514 mg, 1.923 mmol, 56.3% yield). NMR (DMSO-d6) δ 7.77 (dd, J=15 Hz, 2.7 Hz, 1H); 7.72 (m, 1H); 3.55-3.48 (m, 2H); 3.43-3.39 (m, 2H); 2.78-2.74 (m, 2H), 2.49-2.44 (m, 2H); 2.16 (s, 6H); 1.88-1.79 (m, 2H). ESI-MS (m/z, %): 268 (MH+, 100); 223 (5).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CO.O>C1OCCC1>[CH3:34][C:3]1([CH3:2])[C:12]2[CH:11]=[C:10](/[C:13](/[CH3:14])=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCO2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)CCO2
Yield: 19.1 %

Procedure:
16.5 g of [1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphonium bromide and 3 g of benzaldehyde were heated under reflux in 100 ml of butylene oxide for 20 hours. The reaction mixture obtained was poured into a methanol/water mixture (6:4) and extracted with hexane. After drying and evaporating the organic phase the crude product was chromatographed (silica gel, eluting agent hexane) and recrystallized from hexane. There were obtained 1.5 g of 3,4-dihydro-4,4-dimethyl-6-[(E)-α-methylstyryl]-2H-1-benzopyran in the form of colorless crystals, melting point 64°-65° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[Na+]>CN(C=O)C.CCOC(C)=O>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CC#N)c1

Procedure:
Methyl 3-(bromomethyl)benzoate (8.5 g, 37 mmol) and sodium cyanide (1,8 g, 37 mmol) were stirred at room temperature in DMF (40 mL) overnight. The mixture was diluted with EtOAc and extracted several times with water containing a small amount of brine, then brine, dried (MgSO4), and solvent removed in vacuo. The crude product (6.8 g, yellow oil) was sufficiently pure to be used in the next step without purification. IR(neat): cm-1 2249, 1722. 1H-NMR(300 MHz, CDCl3): 8.03-8.01 (m, 2H), 7.57-7.46 (m, 2H), 3.94 (s, 3H), 3.82 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:42][C:25]([CH3:41])([CH3:24])[CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]5=[O:22])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:29]=[N:28]1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)OCC4(C)C)nc2-3)cn1
Yield: 22 %

Procedure:
3-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-yl)-4,4-dimethyloxazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 356. Yield 22%. MS(ESI+): 455.1. 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.3, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.37 (dd, J=8.3, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.71 (s, 1H), 4.32 (d, J=6.9, 4H), 4.05-4.00 (m, 2H), 3.25 (t, J=5.0, 2H), 1.76 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][O:14][CH:15]([CH:36]([OH:37])[C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.25 h

Procedure:
To tetrahydrofuran (50 ml), cooled to -78° C. under argon, was added diisopropylamine (5.7 ml, 0.041 mole) followed by n-butyllithium (16 ml, 0.041 mole) slowly. After 15 minutes, methyl methoxyacetate (4.25 g, 0.041 mole) in tetrahydrofuran (10 ml) was added dropwise. The resulting solution was stirred for 30 minutes after which a solution of 2-(8-phenyloctyl)benzaldehyde in tetrahydrofuran (10 ml) was added dropwise. After 2 hours the reaction mixture was quenched with a solution of saturated ammonium chloride and then diluted with ice water. The aqueous layer was extracted with ether. The combined ether extract was washed with 10% sodium hydroxide (ice cold), dried over magnesium sulfate, filtered and evaporated to give the desired product.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:4].[I-].[K+].C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9]3)=[O:4])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)CC(=O)N2
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2c(c1)CC(=O)N2
Yield: 64.2 %

Procedure:
A mixture of 0.9 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 0.6 ml (4 mmol) of triethylamine, 0.53 ml (3 mmol) of 4-benzyl-piperidine and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is treated with diethylether and the precipitated crystals are filtered off to yield 0.7 g (64%) of the title compound. Melting Point: 176-180° C. (diethylether)
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.C(OC(C)C)(=O)C.[CH3:60][S:61](O)(=[O:63])=[O:62]>O>[CH3:60][S:61]([O:18][C@H:16]1[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]2[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]([C@@H:40]([F:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=3)=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]3)[C:17]1=2)(=[O:63])=[O:62]
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Reactant: CS(=O)(=O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(C)(=O)=O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To 40.7 mg (0.055 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, 0.28 ml of isopropyl acetate and 0.008 ml of ultrapure water were added, and the reaction mixture was stirred at room temperature to obtain a homogeneous solution. Then, 0.004 ml (0.062 mmol) of methanesulfonic acid was added thereto, and the reaction mixture was stirred at the same temperature for 90 minutes. The precipitated solid was obtained by filtration, washed with 0.04 ml of isopropyl acetate three times and then dried under reduced pressure at 40° C. to provide 38.7 mg of the title compound as a white powder (yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[S:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>C(O)C.CO.C(O)(=O)C>[Cl:15][C:4]1[CH:3]=[C:2]([NH:1][CH2:22][C:20]2[S:21][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(Cl)s1
Reactant: Nc1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of N-(4-Amino-2-chlorophenyl)-2,2,2-trifluoroacetamide (4.567 g, 19.14 mmol) and 5-chloro-thiophene-2-carboxaldehyde (3.97 g, 27.1 mmol) in anhydrous ethanol (50 mL) was heated to reflux for 15 minutes and evaporated in vacuo at 70° C. (0.1 mbar, 30 min). The obtained crude imine as a crystalline solid was dissolved in methanol followed by addition of sodium cyanoborohydride (NaBH3CN) in methanol (50 mL) and acetic acid (9 mL) by portions. The obtained reaction mixture was stirred at room temperature for 60 minutes and evaporated in vacuo to small volume. The concentrated solution was quenched with water and filtered after 30 minutes to give 6.98 g (99% yield) of the title compound as a brown-yellow solid. 1H NMR (DMSO-d6): 4.43 (d, 2H), 6.63 (dd, 1H), 6.77 (d, 1H), 6.79 (t, 1H, NH), 6.94 (d, 1H), 6.97 (d, 1H), 7.10 (d, 1H), 10.85 (br. s, 1H, NHCO). LC/MS (m/z) 367.9 (M+); RT=3.36, (UV, ELSD) 99%, 100%.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:12][S:13]([OH:16])(=O)=[O:14].[CH2:17](Cl)Cl>>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:13]([Cl:12])(=[O:16])=[O:14])[C:8]([CH3:17])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: ClCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Product: Cc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reaction time: 0.67 h

Procedure:
12.3 g (0.075 mol) of 4-(1,1-dimethylethyl)phenol in 30 ml of methylene chloride are added dropwise, cooling in ice, to 16.5 ml of chlorosulfonic acid dissolved in 20 ml of methylene chloride. The mixture is stirred for 40 minutes and then poured onto ice-water. The organic phase is separated off, washed with water, dried with MgSO4 and evaporated. The product is recrystallized from toluene petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-chloro-6-methylbenzoic acid (4.0 g, 23.4 mmol) in methanol (50 mL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated, and the residue was dissolved in ethyl acetate (50 mL) The solution was extracted with saturated NaHCO3 (3×50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-6-methylbenzoate (3.07 g, 71% yield). The product was used without further purification.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([C:13]1[O:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:9]([C:13]1[O:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(C(C)(C)C)o1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)o1
Yield: 22.8 %

Procedure:
Sodium hydride (7.09 g-50% suspension in oil, 0.148 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (52.74 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-furancarboxaldehyde (22.46 g, 0.148 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether) to give (5-t-butylfuran-2-yl)-ethylene (11.03 g, 50%). Ethyl diazoacetate (4.45 g, 0.039 mol) in dry dichloromethane (70 ml) was added dropwise to a solution of (5-t-butylfuran-2-yl)-ethylene (5.85 g, 0.039 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (30 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give ethyl 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylate (2.1 g, 23%).