Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].C(N(CC)CC)C.[C:40]([CH2:44][C:45](Cl)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.C(OCC)(=O)C>[CH3:17][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]-4-(phenylmethoxy)benzenepropanamide (1.15 g, 2.67 mmol) and triethylamine (0.37 mL, 2.67 mmol) in THF (50 mL) was added tert-butylacetylchloride (0.39 mL, 2.80 mmol) dropwise. The resulting slurry was warmed to 25° C. and stirred (1 hour, 25° C.). The resulting slurry was diluted with ethyl acetate (200 mL). The organic layer was washed with 1.0N aqueous HCl (1×65 mL), with brine (1×65 mL), with saturated aqueous sodium bicarbonate (1×65 mL), with brine again (1×65 mL), then dried (MgSO4) and concentrated. The resulting oil was triturated with ether, and cooled. The resulting solid was collected by filtration, washed with cold ether, and dried in a vacuum oven at 40° C. to yield 1.2 g (85.1%) of the title compound as a white solid, melting point 209°-211.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(#N)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3ccnn23)CC1
Temperature: 100 °C

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (896 mg, 4.8 mmol) was added along with tert-butyl 4-aminopiperidine-1-carboxylate (954 mg, 4.8 mmol), triethylamine (664 μL, 4.8 mmol), and acetonitrile (16 mL). The reaction was heated at 100° C. for 12 hours then cooled to room temperature, diluted with water, filtered and washed with water. The product, tert-butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was collected as a solid in quantitative yield and dried under vacuum overnight. LCMS (M+1=352)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)C(C)(C)c1ccc(F)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(C)(C)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-ol (18 g, 69 mmol) in DCM (300 mL) at 0° C. was added PCC (29.7 g, 2 eq) portionwise. After stirring 24 h at room temperature, the reaction mixture was combined with water and extracted with DCM. The combined extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=10:1) to give 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-one (13 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.47-7.45 (m, 1H), 7.17-7.14 (m, 1H), 7.09 (t, J=8.8 Hz, 1H), 1.98 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O.C([O-])(=O)C.[NH4+:23].Cl>C(O)C>[NH2:23][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccc(Cl)cc1

Procedure:
10 g (71.1 mmol) of 4-chlorobenzaldehyde, 9.40 g (71.1 mmol) of monoethyl malonate and 10.9 g (142.3 mmol) of ammonium acetate were taken up in 60 ml of ethanol, and the mixture was stirred at reflux temperature overnight. After cooling, 50 ml 1N hydrochloric acid were added to the residue and the mixture was washed with ethyl acetate. The aqueous phase was made basic with potassium carbonate and then extracted with dichloromethane (2×). The organic phase was dried with magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 1.80 g (11% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[NH:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.O>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH2:13][CH2:14][N:55]2[CH2:56][CH2:57][CH:52]([NH:51][C:43]3[N:42]([CH3:41])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:53][CH2:54]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: Cn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(Nc4nc5ccccc5n4C)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Combine the above solution of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine, potassium carbonate (4.07 kg, 29.5 mol), (1-methyl-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (12.0 mol), and water (3.3 gal). Heat to about 70° C. When the reaction is complete, dilute the reaction mixture with methyl ethyl ketone (18.1 kg) and after 15 minutes of stirring, separate the layers. Extract the organic layer with water (3.4 gal) and then concentrate in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[CH2:21]([Sn+:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn+](CCCC)CCCC
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1
Agent: C[O-]
Product: CCCC[Sn](CCCC)(CCCC)OC(=O)Cc1ccc(C(=O)c2ccccc2)cc1

Procedure:
The title product is prepared according to the method as described in example 7 by reacting (4-benzoyl-phenyl)-acetic acid with tri-n-butyltin methoxide.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:27])[NH:9][N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)O[CH2:31][CH2:30][O:29]1>CN(C)C=O>[OH:29][CH2:30][CH2:31][N:9]1[C:8](=[O:27])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[N:10]1
Reactant: O=C1OCCO1
Reactant: Cc1ccc(-c2n[nH]c(=O)c(-c3ccccc3)c2-c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nn(CCO)c(=O)c(-c3ccccc3)c2-c2ccc(C)cc2)cc1

Procedure:
4-Phenyl-5,6-bis(p-methylphenyl)-2H-pyridazin-3-one (1.8 g) and 0.88 g of ethylene carbonate were charged to a flask in 100 ml dimethylformamide. The flask was placed in an oil bath, preheated to 150° C. and the reaction was heated for 4 hours. The hot solution was quenched in an equal volume of 1 N HCl, causing a white solid to precipitate. The cooled solution was filtered and the solid recrystallized from ethyl acetate and dried for 5 hours, m.p. 192°-194° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1>C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:18]3[CH:19]=[C:20]4[C:25]([CH:24]=[CH:23][CH:22]=[CH:21]4)=[N:17]3)[N:7]=2)=[CH:10][CH:11]=1.[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:7]=2)=[CH:10][CH:11]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Solvent: CC#N
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(-n2cc3ccccc3n2)n1
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(-n2ncc3ccccc32)n1
Temperature: 160 °C
Yield: 14 %
Yield: 5.3 %

Procedure:
(2-Chloro-6-methyl-pyrimidin-4-yl)-(4-chloro-phenyl)-amine (300 mg, 1.18 mmol) was dissolved in acetonitrile (4 mL), indazole (150 mg, 1.3 mmol) was added and the mixture was heated in a microwave oven at 160° C. for 30 minutes. The solvent was removed in vacuo and the remaining residue was basified with aqueous sodium hydrogencarbonate and extracted with chloroform. The combined organic phases were dried with sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography with ethyl acetate-hexane as eluent to give (4-chloro-phenyl)-(2-indazol-2-yl-6-methyl-pyrimidin-4-yl)-amine (56 mg, 14%, mp=224.7-226.7° C.) (LC-ESI-HRMS of [M+H]+ shows 336.1019 Da. Calc. 336.101598 Da, dev. 0.9 ppm) as a white solid and (4-chloro-phenyl)-(2-indazol-1-yl-6-methyl-pyrimidin-4-yl)-amine (21 mg, 5.3%, mp=166.7-168.7° C.) (LC-ESI-HRMS of [M+H]+ shows 336.1007 Da. Calc. 336.101598 Da, dev. −2.7 ppm) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Sn](CCCC)(CCCC)[C:20]1[N:21]=[CH:22][S:23][CH:24]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:5]1[C:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:2]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[N:3]=[CH:4]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(C)(C)OC(=O)Nc1scnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1scnc1-c1cscn1
Temperature: 140 °C
Yield: 70.6 %

Procedure:
A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (590 mg, 2.1 mmol), tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and 4-tributylstannylthiazole (1.18 g, 3.2 mmol) in anhydrous dioxane (5 mL) was heated to 140° C. in a microwave reactor for 1 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes elution) to give the desired product (420 mg, 71%). MH+ 283.9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(Cl)c(N)cc1S
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture of 9.4 g of 2-chloro-4-methyl-5-mercaptoaniline, 20 g of 2,2,2-trifluoroethyl iodide, 13 g of potassium carbonate and 200 ml of N,N-dimethylformamide was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.5 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)aniline.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[OH-].[K+].Cl[CH:18]([F:20])[F:19].O>CC(O)C>[F:19][CH:18]([F:20])[O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: FC(F)Cl
Reactant: Cc1c(C(F)(F)F)nn(C(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C(F)(F)F)nn(C(C)C)c1OC(F)F
Reaction time: 2 h
Yield: 75 %

Procedure:
Into 17.1 g (82.1 mmol) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole in 100 ml of 2-propanol was added 23.0 g (410.7 mmol) of powdery potassium hydroxide at room temperature, followed stirring. Furthermore, stirring was continued while an excess amount of chlorodifluoromethane was introduced into the reaction solution. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 15.9 g (yield: 75.0%) of 5-difluoromethoxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.C(N(CC)CC)C.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:28]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1 g, 4.03 mmol), DMAP (49.2 mg, 0.40 mmol) and triethylamine (611 mg, 6.05 mmol) in DMF (50 mL) was added tert-butylchlorodimethylsilane (665 mg, 4.43 mmol). After stirred overnight at 50° C., the resulting mixture was concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 2-5% MeOH in dichloromethane to give compound 8 as a yellow solid (1.0 g, 65%). (ES, m/z): [M+H]+ 263.0; 1H NMR (300 MHz, CDCl3) δ 6.33-6.35 (d, J=6.3 Hz, 1H), 4.35-4.39 (t, J=5.7 Hz, 1H), 4.18-4.21 (t, J=4.5 Hz, 1H), 3.81-3.84 (m, 3H), 3.62-3.67 (m, 1H), 3.05 (s, 6H), 0.93 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:29][CH2:28][C@@H:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@H:20]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@H:20]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Temperature: -65 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Dimethylsulfoxide (0.145 mL, 2.049 mmol) was added to a methylene chloride (10 mL) solution of oxalyl chloride (0.768 mL, 1.537 mmol) at −20° C. under nitrogen. The reaction was then cooled to −65° C. and tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.2 g, 0.512 mmol) was added to the reaction all at once. The reaction was stirred for 2 h. Triethylamine (0.428 mL, 3.07 mmol) was added to the reaction mixture and the reaction was allowed to warm to room temperature. The reaction was diluted with methylene chloride and washed with water three times. The methylene chloride layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 45% to 65% gave the desired product (199 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#N.[CH:13]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14]1.O.S(=O)(=O)(O)[OH:22]>C1COCC1.C(OCC)C>[CH:13]1([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: Cl[Mg]C1CCCC1
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 3,5-dimethoxybenzonitrile (5.0 g) in anhydrous THF (60 mL) were added a solution of cyclopentylmagnesium chloride (20 mL of 2 M solution in diethyl ether) and cuprous bromide (88 mg). The resulting reaction mixture was refluxed for 1 h. Then water (10 mL) and 10% sulfuric acid (20 mL) were added and the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with diethyl ether and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 5.9 of the title compound (82% yield). HRMS calcd for C14H18O3 [M+H]+ 253.1329, observed 253.1328.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(OCC)C>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Temperature: 25 °C
Yield: 115 %

Procedure:
4-Chloro-3-nitro-6-trifluoromethyl-pyridin-2-ol (65.1 gm 268 mmol) was dissolved in tetrahydrofuran (350 mL) and stirred at room temperature under N2. Benzylamine (86.3 gm 805 mmol) in tetrahydrofuran (50 mL) was added drop wise over 30 minutes to give a bright yellow solution. The reaction was heated in an oil bath at 50° C. for 18 hours, (a solid formed during the reaction). Cooled to ambient temperature, diluted the reaction mixture with diethyl ether (200 mL) and filtered off the solid (benzylamine hydrochloride). The filtrate was evaporated to low bulk under reduced pressure to give a thick yellow slurry. Added diethyl ether (300 mL) and filtered off the yellow solid, dried on the filter pad to give the benzylamine salt (96.5 gm). The desired product was liberated by partition of the solid between aqueous 2N HCl and dichloromethane and crystallization from ethyl acetate/n-pentane gave 4-benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol as a pale yellow solid (61.7 gm 73.4% yield).
Reaction SMILES: C([Li])(C)(C)C.[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:40][N:41](C)CCN(C)C.C1(N=C=O)C=CC=CC=1>O1CCCC1>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:40]#[N:41])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O=C=Nc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(c1)cc(C#N)n2S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of tert-butyllithium (1.7 M in pentane, 3.42 mmol) was added at −78° C. to a mixture of 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole CCLXVIII (865 mg, 1.71 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.51 mL, 3.42 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred for 1 hour and then a solution of phenyl isocyanate (300 mg, 2.565 mmol) in tetrahydrofuran (2 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1.5 hour and at 0° C. for 1.5 hours. The reaction was then quenched by addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was diluted with water and diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 10/90 to 20/80) to give 0.56 g (62% yield) of 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole-2-carbonitrile CCLXIX.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21]C(OCC3C=CC=CC=3)=O)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4].C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:21])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
cis-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (322 mg, 0.71 mmol), 10% palladium on carbon (32 mg) and cyclohexene (9 ml) in 16 ml ethanol was heated to 80° C. for 1.25 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 1% isopropanol-dichloromethane afforded the title product (208 mg, 91%). 1H NMR (DMSO-d6)δ 1.02 (d, 3H), 6.68 (s, 1H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[CH2:12]([O:19][CH2:20][CH2:21][SH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O>[CH2:12]([O:19][CH2:20][CH2:21][S:22][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Reactant: SCCOCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1SCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2-nitrobenzonitrile (5.85 g) in DMF (20 mL) was treated with 2-(benzyloxy)ethanethiol (Example 320a, 6.64 g) and a solution of potassium hydroxide (3.76 g) in water (5 mL) was added dropwise under nitrogen. The resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with 50% diethyl ether in iso-hexane) to afford the subtitle compound as a solid (7.08 g). 1H NMR δ (CDCl3) 7.60 (d, 1H), 7.46 (d, 2H), 7.32-7.23 (m, 6H), 4.54-4.53 (m, 2H), 3.72 (t, 2H), 3.24 (t, 2H)