Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=O.[H][H]>>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Agent: O=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C

Procedure:
General screening procedure for asymmetric hydrogenation using the substrate, (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19), to afford optically enriched product, 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-20 or (S)-20): A 300 mL-volume autoclave with glass vial (20 mL) was charged with the substrate (19), the catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) under nitrogen. This autoclave was charged with hydrogen gas to the desired pressure and stirred at room temperature or heated with oil bath. After hydrogen gas was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by eluting through a silica gel pad using a mixture of ethyl acetate and methanol (v/v=9/1) to afford product, 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-20 or (S)-20), for chemical conversion (HPLC and chiral HPLC), LC/MS and NMR spectroscopy and enantiomeric excess (% ee by chiral HPLC) determination.
Reaction SMILES: CON(C)[C:4](=[O:14])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Li]C.[CH3:18]COCC.Cl>C1COCC1>[CH3:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4](=[O:14])[CH3:18]
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Reactant: CCOCC
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1ccccc1

Procedure:
To a solution of N-methoxy-N-methyl-2-phenyl-isobutyramide (example 207E) (16 g, 77.2 mmoles) in THF (300 mL) cooled at −50° C. is added dropwise a 1.6M solution of MeLi in Et2O (80 mL, 131.2 mmoles). The reaction mixture is allowed to reach 0° C. and 1N HCl (130 mL, 130 mmoles) is added. The aqueous phase is extracted with Et2O. The organic phase is washed with brine, dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 3-methyl-3-phenyl-butan-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:9]=[C:8]([Cl:10])[NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1.C(OCC)(=O)C>[Cl:10][C:8]1[NH:7][C:6]2[CH:11]=[C:2]([NH:1][C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[C:24]([F:23])([F:34])[F:35])=[O:28])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:9]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(N)cc2[nH]c(Cl)nc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Reaction time: 1 h

Procedure:
To a stirring solution of methyl 6-amino-2-chloro-1H-benzimidazole-4-carboxylate (400 mg, Example 135, Step 3) and triethylamine (209 μL) in THF (18 mL), 2-(trifluoromethyl)benzoyl chloride (316 μL) was dropped slowly under ice-cooling. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude methyl 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate. This was dissolved in THF (15 mL) and MeOH (7 mL), 1N aqueous lithium hydroxide solution (9 mL) was added, and it was stirred at room temperature overnight. THF and MeOH were removed under reduced pressure. To the residue was added water, and it was neutralized with 1N hydrochloric acid under ice-cooling. The precipitation was collected by filtration to obtain crude 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid. This was dissolved in THF (10 mL), 40% aqueous dimethylamine solution (7 mL) was added, and it was stirred at 120° C. for 14 hours. The reaction mixture was cooled to room temperature, and THF was removed under reduced pressure. To the residue was added water, and the pH was adjusted to 3-4 with 1N hydrochloric acid under ice-cooling. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the titled compound (589 mg) as slightly yellow solid.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][S:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]([F:30])=[CH:10][N:9]=1.[OH2:31]>CO>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][S:17]([CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])(=[O:1])=[O:31])[C:11]([F:30])=[CH:10][N:9]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CC(C)(C)OC(=O)CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)CS(=O)(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxone (5.37 g, 8.73 mmol) was added to a solution of (S)-tert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate, 168a, (1.10 g, 2.91 mmol) in methanol (50 mL) and water (20 mL) and the solution was stirred 3 hours at room temperature. The solution was concentrated in vacuo to give a white residue that was dissolved in water (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic phases was dried (MgSO4), filtered and concentrated in vacuo to afford 750 mg of the desired product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time =1.29 minutes (M+H) 410.19.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28](=[O:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=3)([OH:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
1,3-Dibromobenzene (20.2 ml, 167 mmol) in anhydrous ether (100 ml) in a flame dried 1LRB flask, at −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (58 ml, 145 mmol) via an addition funnel over 20 min. After 1 h at −78° C., the mixture was treated with a solution of 3-benzyl-3-aza-bicyclo[3.2.1]octan-8-one (18.0 g, 83.6 mmol) in anhydrous ether (100 ml) via addition funnel over 20 min. The reaction stirred at −78° C. 30 min, warmed to room temperature and judged complete by TLC. The reaction solution was quenched with saturated aqueous NH4Cl solution (200 ml) and stirred 18 h. The layers were separated and the aqueous layer extracted with ether (2×100 ml). The organic layer was washed with saturated aqueous Na2CO3 solution (150 mL), saturated aqueous NaCl solution (100 ml), dried over Na2SO4, filtered and concentrated to a dark oil. Passage through a silica pad (3×8 in) eluted with 5% EtOAc/hexanes yielded a light yellow oil (31 g, 100%). (TLC 20% EtOAc/hexanes Rf 0.21); 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.41–7.19 (m, 8H), 3.58 (s, 2H), 2.83 (d, J=10.4 Hz, 2H), 2.60 (d, J=8.3 Hz, 2H), 2.35 (br s, 2H), 1.80 (d, J=7.5 Hz, 2H), 1.39 (m, 2H); APCI MS m/z 372.1, 374.1 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([Br:32])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl>C(Cl)Cl.CCOCC>[Br:32][C:29]1[C:28](=[O:33])[N:27]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 0.07 mmol) was suspended in CH2Cl2 (10 mL) and MeOH was added in order to produce a solution (up to 6 mL). 2 M HCl in ether (10 mL) was added with stirring. The reaction mixture was stirred at room temperature for a total of 3 days then the solvents were removed by evaporation at reduced pressure. The remaining solid was suspended in ether and filtered to give 6-bromo-8-cyclopentyl-5-methyl-2-(5-piperizin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid, which was dried in vacuo at 50° C. MS (APCI); M++1: Calc'd, 486.15. Found, 486.1. Analyses for C23H26N7OBr.2.64H2O.2.0HCl: Calc'd: C, 43.68; H, 5.55; N, 16.21; Cl (ionic), 11.72. Found: C, 44.08; H, 5.32; N, 15.23; Cl (ionic), 11.65.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:24]([O:26]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:30][NH:31][C:24](=[O:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccs1)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(F)cc1)C2c1nccs1
Temperature: 45 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (180 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the title compound (3 mg, yield: 2%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.88 (d, J=8.0 Hz, 1H), 5.09 (d, J=8.0 Hz, 1H), 7.01 (t, 2H), 7.21 (d, 1H), 7.36-7.40 (m, 2H), 7.47 (d, 1H), 7.59 (d, 1H), 7.65 (t, 1H), 7.74 (d, 1H); 19F-NMR (400 MHz, CD3OD) δ (ppm): −116.36 (s); LC-MS (ESI) m/z: 365 (M+1)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]=1)#[N:17]>C1COCC1>[C:13]([CH:14]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:18][C:16]#[N:17])#[N:15]
Reactant: CC#N
Reactant: COc1ccc2c(c1)CCC=C2C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)CCC(CC#N)C2C#N
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
To a solution of 1.05 mL (7.5 mmol) of diisopropylamine in 10 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (2.2 mL of a 2.5 M solution in THF, 5.5 mmol) and the resultant solution was stirred at -78° C. for 40 min. To the stirred solution was added, dropwise over a 25 minute period, a solution of 274 μL (5.25 mmol) of acetonitrile in 5 mL of THF. The solution was stirred for 20 min at -78° C. and then a solution of 926 mg (5 mmol) of 1-cyano-6-methoxy-3,4-dihydronaphthalene (the product of Step 2 of Example 1) in 5 mL of THF was added via syringe pump over a 20 min period. The reaction mixture then allowed to warm to ambient temperature and was was stirred at ambient temperature for 1 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 25% ethyl acetate in hexane to give 840 mg (74% yield) of the title compound as a 1:1 mixture of the cis and trans isomers; MS DCI-NH3M/Z: 244 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[C:15]([C:16]([OH:18])=O)[C:5]2=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]=[C:15]([C:16]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:18])[C:5]2=1
Reactant: C1CCNC1
Reactant: Cn1c2ccc(F)cc2c2c(C(=O)O)cn(-c3ccccc3)c(=O)c21
Solvent: CN(C)C=O
Product: Cn1c2ccc(F)cc2c2c(C(=O)N3CCCC3)cn(-c3ccccc3)c(=O)c21
Reaction time: 20 h

Procedure:
A solution of 3.2 g (10 mmol) of 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 3.2 g (20 mmol) of N,N'-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h at 60° C. 2.5 ml (30 zmol) of pyrrolidine are added at room temperature and the reaction mixture is stirred for 20 h.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:34](=[O:35])[CH2:33][Br:32])[C:4]=2[O:3][CH2:2]1
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.18 g, 0.58 mmol) dissolved in DCM (4 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1% B, 80 g, 2 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 4.5 CV, 60 mL/min) to afford 120 mg (47%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Bromo-N-(2-phenyloxy-phenyl)acetamide as a colourless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH3:23][C:12]1[C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]3[CH2:6][CH2:7][O:8][C:9]([C:17]=23)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCOS(C)(=O)=O)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 7-(2-methanesulfonyloxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.30 g, 3.81 mmol), 60% sodium hydride (0.15 g, 3.81 mmol) and N,N-dimethylformamide (65 ml) was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 2/98) to obtain ethyl 2,3-dihydro-7-methyl-pyrrolo [1,2,3-de]-1,4-benzoxazine-5-carboxylate (0.87 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:11](S(C)(=O)=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].CO>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:11]([O:29][CH3:28])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 85.3 %

Procedure:
2 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine, 0.3 g of sodium methoxide and 20 ml of methanol were added to 120 ml of ethylene glycol dimethyl ether, and the resulting mixture was heated under reflux for 5 hours. The solvent was distilled away under reduced pressure. The residue was washed with water, and then dried to obtain 1.5 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methoxypyrimidine (Compound 18).
Reaction SMILES: Br.[CH2:2]([N:9]([CH2:21][C@H:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Br:32])[CH:28]=2)[O:23]1)[CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>ClCCl>[Br:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][C@@H:22]([CH2:21][N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:10][C@H:11]([O:20][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:31][CH2:30]2
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(Br)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(Br)ccc2O1
Reaction time: 15 h

Procedure:
The compound of Example 86 (5.0 g, 10.4 mmol) and imidazole (1.06 g, 15.6 mmol, 1.5 eq.) were dissolved in dichloromethane. tert-Butyldimethylsilylchloride (2.03 g, 13.5 mmol, 1,3 eq.) was added, and the mixture was stirred for 15 hours. Solids were removed by filtration, and the filtrate was concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel eluted with 90:10 hexanes/ethyl acetate. The title compound was obtained as a yellow oil (5.3 g, 85%): 1H NMR (300 MHz, CDCl3) δ7.30-7.26 (m, 5 H), 7.25-7.20 (m, 3 H), 7.09 (s, 1 H), 6.91 (t, 1 H), 6.80 (d, 2 H), 6.63 (d, 1 H), 4.07-4.00 (m, 2 H), 3.81 (s, 2 H), 3.73 (dd, 1 H), 2.88-2.77 (m, 2 H), 2.64-2.56 (m, 4 H), 1.96-1.90 (m, 1 H), 1.61-1.55 (m, 1 H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H); MS m/z 596.3 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([CH:33]4SCCCS4)[OH:32])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2].C1C(=O)N(Br)C(=[O:46])C1>C(#N)C.O>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:32])[CH:33]=[O:46])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C5SCCCS5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a solution of 103 (1.2 g, 1.945 mmol) in acetonitrile (20 ml) and water (5.00 ml) stirred in air at rt was added NBS (1.385 g, 7.78 mmol) in one charge. The reaction mixture was stirred at rt for 0.5 h, then quenched with Na2SO3 (solid), concentrated and the residue was extracted with EtOAc. The organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated in vacuo to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (104) (1.09 g, 1.083 mmol, 55.7% yield) as a light yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([F:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:19])[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:42]=[C:43]=[O:44])[CH:38]=[C:39]([F:41])[CH:40]=1>O1CCOCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]([CH3:19])[C:13]2[N:14]=[CH:15][CH:16]3[CH:11]([CH:12]=2)[N:10]([CH2:29][CH3:30])[C:9](=[O:31])[C:8]([C:6]2[C:5]([F:32])=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:43]([NH:42][C:37]4[CH:38]=[C:39]([F:41])[CH:40]=[C:35]([F:34])[CH:36]=4)=[O:44])[CH:7]=2)=[CH:17]3)=[CH:22][CH:23]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: C1COCCO1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 mL) was treated with 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) and stirred at RT overnight. Additional 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) was added and the mixture stirred for 4 h. The resulting precipitate was collected via filtration and dried to yield 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (112 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.19-7.14 (m, 4H), 6.86 (d, 2H), 6.80-6.77 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][N:9]([CH:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11]
Reactant: ClCC1CO1
Reactant: CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2.1 g (6.6 mmol) of N-α-methylbenzyl-2-nitrobenzenesulfonamide was dissolved in 10 ml of epichlorohydrin, to which was gradually added at room temperature 0.35 g (7.3 mmol) of 50% sodium hydride, followed by agitating at room temperature for 30 minutes and reacting under reflux for 1 hour. The epichlorohydrin was distilled off under reduced pressure, water was added and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous magnesium sulfate, concentrated, and purified by the silica gel chromatography to obtain the intended product (Compound No. 33). The yield was 97% and the nD26.5 value was 1.5572. The results of the elemental analysis are shown below.