Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]1([C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=O)[C:18](=[CH:27]N(C)C)[CH2:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.C(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][C:2]1[N:4]=[CH:27][C:18]2[CH2:17][N:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]=2[N:5]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2ccccc2C1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccccc1C(c1ccccc1)=NC2

Procedure:
In five equal portions 9.0 g (95 mmole) of acetamidine hydrochloride and 22.5 ml (0.1 mole) of a 4.46 M methanol solution of sodium methoxide was added over 3 hr to a solution of 4.5 g (15 mmole) of 1-phenyl-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an oil. The oil was dissolved in an excess of 6% methanolic hydrogen chloride and the solvent was removed at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a white solid mp 211°-221° C. Recrystallization from a mixture of methanol and ether gave white flakes, mp 217°-227° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl.Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
A solution of methanesulphonyl chloride (6.3 g) in dichloromethane was added to a stirred, cooled (0-5° C.) solution of methyl 2-amino-4-chlorobenzoate (9.5 g) in dichloromethane. Triethylamine (7.1 g) was then added and the mixture was stirred at 0-5° C. for 10 minutes and then at room temperature for 0.5 hours. The mixture was diluted with 2N hydrochloric acid. The organic phase was separated, washed with water, dried and evaporated. The crude product was purified by column chromatography to yield methyl 4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid, (3.6 g) m.p. 125.5-128.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH:27]=1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cncc(-c3ccc(OC(F)(F)F)cc3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 60 mg (0.26 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 10 mg (0.26 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 80 mg (0.26 mmol) 3-Chloromethyl-5-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 91 mg (72%) of the title compound as ochre powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:27])(CC)(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:27]
Reactant: CCC(C)(C)O
Reactant: COc1cc(N)c(C#N)cc1OCCCN1CCOCC1
Solvent: ClCCl
Product: COc1cc(N)c(C(N)=O)cc1OCCCN1CCOCC1
Temperature: 79 °C

Procedure:
After repetition of the reduction step, a methylene chloride solution (894.3 kg) containing 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile (81.6 kg) was added portionwise to tert-amyl alcohol (186 kg) and the resultant mixture was distilled until the temperature of the distillate reached 57° C. Additional tert-amyl alcohol (726 kg) was added portionwise and distillation was continued until the residual volume of the reaction mixture was approximately 770 liters. Potassium hydroxide (flaked form; 51 kg) was added and the mixture was heated to 79° C. for 4 hours. The resultant mixture was cooled to ambient temperature to provide a solution of 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzamide which was used without being isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([NH2:8])[CH2:5][CH2:4][O:3]1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:9])([CH3:1])[CH2:7]1)=[O:15]
Reactant: CC1(C)CC(N)CCO1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)NCCCl)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A 0° C. suspension of 2,2-dimethyltetrahydro-2H-pyran-4-amine (0.806 g, 6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was treated with additional 2-chloroethyl isocyanate (160 μL) and stirred at RT for an additional 24 hours, then concentrated to dryness, the residue dissolved in EtOAc and washed with saturated NH4Cl (1×), NaHCO3 (1×) and brine (1×), dried over MgSO4 and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg, 48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].N.Cl[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:13]1([P:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:3][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCO
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: N
Product: CCOP(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
330 g (7.17 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 18 g (1.06 mol) of ammonia gas are then introduced at this temperature. 200 g (0.907 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature in one hour. The mixture is then allowed to come to room temperature with stirring and is stirred for a further 3.5 hours. The mixture is then cooled, filtered by suction and washed with ethanol. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is freed from a slight precipitate by filtration through a glass frit. 172 g of ethyl diphenylphosphinite are then obtained by thin film distillation at a bath temperature of 140° C. and 0.3 mbar. This corresponds to a yield of 83% of theory.
Reaction SMILES: [Br:1]Br.[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:1])=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4]
Reactant: BrBr
Reactant: O=CNC1Cc2ccccc2N(C=O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Bromine (10.2 g, 0.064 tool) was added to a stirred solution of N-(1-formyl-1,2,3,4-tetrahydro-3-quinolyl)formamide (14.0 g, 0.065 tool) in acetic acid (70 mL) containing anhydrous sodium acetate (10.2 g, 0.12 mol). The solution was stirred for 30 minutes and water (500 mL) was added. The precipitate was filtered off and air dried to give 15.8 g (86%) of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide, mp 174°-178° C. A sample was recrystallized from ethanol for analysis; mp 178°-181 ° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:42])[C@@H:15]([N:25](CC1C=CC=CC=1C)CC1C=CC=CC=1C)[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:42])[C@@H:15]([NH2:25])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Yield: 97.9 %

Procedure:
Add 2-(R)-[2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-piperidine-1-carboxylic acid tert-butyl ester (0.33 g, 0.56 mmol), 20% palladium hydroxide on carbon (230 mg) and methanol (25 mL) and stir under 1 atmosphere of hydrogen gas for 18 h. Add filter agent, filter and concentrate to give the title compound as a foam (0.203 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:27]2[CH:32]=[C:31]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=2)([NH:16][C:17]2[S:18][C:19]([CH3:26])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:41].C([O-])([O-])=O.[K+].[K+].I[CH:49]([CH3:51])[CH3:50]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([NH:16][C:17]2[S:18][C:19]([CH3:26])=[C:20]([C:22]([F:23])([F:25])[F:24])[N:21]=2)([C:27]2[CH:32]=[C:31]([O:33][C:34]([F:38])([F:39])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:41][CH:49]([CH3:51])[CH3:50]
Reactant: Cc1sc(N[C@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(O)c2)nc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc(N[C@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC(C)C)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (S)-2-fluoro-5-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(5-methyl-4-(trifluoromethyl)thiazol-2-ylamino)-2-phenylethyl)phenol (16 mg, 0.026 mmol) in DMF (0.5 mL) was added K2CO3 (8 mg, 0.058 mmol), followed by the addition of 2-iodopropane (5 mg, 0.03 mmol). The reaction vessel was sealed and stirred at room temperature for 18 h. The solid was removed by filtration and the filtrate was purified by preparative HPLC Phenomenex AXIA Luna S5 30×75 mm Ballistic column 50-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-5-methyl-4-(trifluoromethyl)thiazol-2-amine eluted at a retention time of 10.99 min (13 mg, 77% yield). LCMS: RT=4.38 min [M+H] 649.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.18 ppm, 1H, m; 7.11 ppm, 3H, m; 6.97 ppm, 5H, m; 6.59 ppm, 2H, d, J=7.07 Hz; 5.86 ppm, 1H, m; 4.46 ppm, 1H, m; 3.71 ppm, 2H, s; 2.29 ppm, 3H, m; 1.24 ppm, 6H, dd, J=8.84, 6.06 Hz.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([CH3:54])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([CH3:54])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methylpyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=447, obsd.=447).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][N:18]2[C:19](=[O:28])[C:20]3[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:23])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cn(CCN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g (15.7 mmol) of 3-acetyl-1H-indole are dissolved in 100 ml of dimethylformamide, and 0.41 g (15.7 mmol) of sodium hydride and 4.0 g (16 mmol) of N-(2-bromo-ethyl)-phthalimide are added. The reaction mixture is stirred for 14 h at RT and for 3 h at 50°. 20 ml of water are added and the product is isolated by filtration. After drying at 50° under HV, N-[2-(3-acetyl-1H-indol-1-yl)-ethyl]-1H-isoindole-1,3(2H)-dione is obtained; 1H-NMR (CDCl3): 2.5 (3H,s), 4.1 (2H,t), 4.45 (2H,t), 7.2-7.9 (8H,m), 8.35 (1H n).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([O:25]CC4C=CC=CC=4)[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[C:23]([F:24])=[CH:22][NH:21][C:20](=[O:25])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: Fc1cnc(OCc2ccccc2)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)c(F)c[nH]1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-fluoro-2-[(phenylmethyl)oxy]pyrimidine (240 mg, 0,463 mmol) in methanol (10 mL) was added wet Pd/C (24.61 mg, 0.023 mmol), the suspension was charged with hydrogen and stirred for 30 min, then filtrated. The solvent was removed in vacuum afforded title product (150 mg). LC-MS (ESI): m/z 429[M+H]+; 4.22 min (ret time).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][C:15]([CH2:17][OH:18])=[CH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][C:15]([CH2:17][O:18][Si:30]([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31])=[CH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCCC(CCOCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1=CCCC(CCOCc2ccccc2)C1
Yield: 53.4 %

Procedure:
Intermediate R3 was dissolved in THF (100 mL) and added to a solution of DIBAL (70 mL, 1M in hexanes) in THF (160 mL) at −35° C. for 35 minutes. The mixture was quenched with Rochelle's salt solution, and extracted with ether. The dried residue was purified by chromatography on SiO2 with 30% EtOAc:Hx to yield [5-(2-benzyloxy-ethyl)-cyclohex-1-enyl]-methanol 4.6 g (80%). A solution of the alcohol (4.0 g, 18.7 mmol) in DMF (60 mL) was treated with triethylamine (3 mL) followed by TBSCl (3.0 g, 22.4 mol) for 20 minutes at room temperature. The residue was isolated from an aqueous work-up and purified by chromatography to give [5-(2-benzyloxy-ethyl)-cyclohex-1-enylmethoxy]-tert-butyl-dimethyl-silane (Intermediate R4) 3.6 g (63%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]2)=O)=[CH:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:18][CH:15]1[CH2:16][CH2:17][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14]1
Reactant: O=C(C(=O)N1CCC(O)C1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC1CCN(CCc2c[nH]c3ccccc23)C1

Procedure:
A suspension of 11 g. (0.043 mole) of 1-(indol-3-ylglyoxyloyl)-3-pyrrolidinol in 50 ml. of tetrahydrofuran was added dropwise, under nitrogen, to a stirred suspension of 9.8 g. (0.026 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran. After addition, the mixture was refluxed for 2 hours, cooled, and treated with enough water to destroy the excess lithium aluminum hydride. The resulting aluminum hydroxide was filtered off and washed thoroughly with tetrahydrofuran. The filtrate was evaporated on a rotating evaporator to an oil which solidified on standing. Crystallization from acetonitrile gave a melting point of 144°-146° C.; yield 7.7 g. (78%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1cccc(CBr)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc(CN=[N+]=[N-])n1

Procedure:
2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61 g, 33 mmol) was dissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7 mmol) added. After stirring the resultant mixture overnight at ambient temperature, the reaction was poured into dicholoromethane and washed well with water. The organic layer was dried (magnesium sulphate), filtered and concentrated to dryness. The resulting yellow oil (5.88 g, 93%) was used without further purification; NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz), 4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06 min, (M+H)+ 193.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][CH:3]([C:2]([F:1])([F:18])[F:19])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11]2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(C(C)=O)ccc2OC1C(F)(F)F
Temperature: 0 °C

Procedure:
A 500 mL three neck round bottom flask was fitted with stir bar, thermocouple and heating mantle, condenser, and nitrogen inlet and charged with dichloromethane (150 mL), ethyl 2-trifluoromethyl-2H-chromene-3-carboxylate (14.94 g, 54.882 mmole), and AlCl3 (18.29 g, 137.21 mmole). With stirring, the reaction was chilled to 0° C. followed by addition of acetyl chloride (5.85 mL, 6.46 g, 82.32 mmole). The reaction was stirred at RT for three days and then at reflux for six days. The reaction was poured over ice and was extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield a solid. This solid was triturated with hexanes to provide a slurry. Vacuum filtration of the slurry yielded the title compound as a white solid. (11.78 g, 68.3%): mp 101-103° C. 1H NMR (acetone-d6/300 MHz) 8.14(s, 1H), 8.04 (d d, 1H, J=8.7, 2.2 Hz), 7.98(s, 1H), 7.13 (d, 1H, J=8.6 Hz), 5.95 (q, 1H, J=6.8 Hz), 4.38-4.23 (m, 2 H), 2.57(s, 3H), 1.33(t, 3H, J=7.0 Hz). GCMS m/z 314 (M+).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][CH:18]([CH2:20][OH:21])[CH2:17][C:16]1=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([N:15]1[C:16](=[O:22])[CH2:17][CH:18]([CH:20]=[O:21])[CH2:19]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CC(CO)CN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Triethylamine and a pyridine-sulfur trioxide complex were added to a DMSO solution of 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one and stirred at room temperature for 2Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 1-benzyl-5-oxopyrrolidine-3-carboaldehyde. EI: 203.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(C(C)C)C(C)C>CCO>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)=[N:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2nc(F)c(F)cc2[N+](=O)[O-])n[nH]1
Reaction time: 8 h

Procedure:
To a solution of 2,3,6-trifluoro-5-nitropyridine (Intermediate 40, 1.0 g) in EtOH (20 ml) at 0° C., was added 5-methyl-1H-pyrazol-3-amine (550 mg) and DIPEA (2 ml). The resulting mixture was stirred at this temperature overnight. The title compound was collected via filtration (780 mg). LCMS: 377 [M+1].
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([CH3:38])[CH:24]=1>C1(C)C=CC=CC=1>[CH3:29][C:27]1[CH:28]=[C:23]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][C:10]([C:9]([F:8])([F:20])[F:21])=[CH:11][CH:12]=3)[CH2:17]2)[CH:24]=[C:25]([CH3:38])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(C(F)(F)F)cc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (4.75 g, 42.3 mmol), 7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, filtered through silica gel, and recrystallized from toluene to afford the title compound as a solid. (5.94 g, 85%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([SH:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCS
Product: CCCCSC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=99° C. and MS: m/e=327 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and butanethiol.