Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1.C=O.Cl.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:22](O)(=O)[CH3:23]>>[CH:15]1([N:21]2[CH2:5][CH2:6][C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:23][C:22]=4[CH2:4][CH2:3][C:2]=3[CH2:1]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)O
Reactant: CC1=CCCc2ccccc21
Reactant: NC1CCCCC1
Agent: C=O
Agent: Cl
Product: c1ccc2c(c1)CCC1=C2CCN(C2CCCCC2)C1

Procedure:
Following the procedure of Example 1, step 3, 1.00 g (6.93 mmol) of 1-methyl-3,4-dihydronaphthalene in 7 ml of acetic acid was reacted with 2.25 ml of 37% formaldehyde solution and 2.16 g of cyclohexylamine hydrochloride. Work up gave 2.41 g of crude 3-cyclohexyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 0.397 g of lithium wire in 200 ml of liquid ammonia, 40 ml of anhydrous THF and 1 ml of aniline. Chromatography on silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 5-7% ethyl acetate/petroleum ether gave 0.333 g (18%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 281°-285° C. (dec). NMR δ(D2O) 1.16-1.96 (12H, m), 2.10 (2H, m), 2.69 (2H, m), 2.92-3.05 (3H, m), 3.20-3.31 (2H, m), 3.55 (1H, m), 3.69 (1H, m), 7.25-7.29 (3H, m), 7.35-7.36 (1H, m). m/z (CI+, NH3) 270 (M+H)+, 226.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2/[CH:33]=[CH:34]\[CH3:35])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:46][O:47][CH3:48].O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:32][CH2:46][O:47][CH3:48])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:25])[F:26])=[CH:19][C:18]=2/[CH:33]=[CH:34]\[CH3:35])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCOCc2ccccc2)CC1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.6 %

Procedure:
(Z)-2-(4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40 mg, 0.0796 mmol) was dried with a vacuum pump, and dissolved in dichloromethane (796 μL). Under ice-cold conditions, diisopropylethylamine (42 μL, 0.239 mmol) and chloromethylmethylether (6.6 μL, 0.0876 mmol) were added sequentially, and the mixture was stirred at room temperature for 20 hours. Further, under ice-cold conditions, diisopropylethylamine (84 μL, 0.478 mmol) and chloromethylmethylether (26 μL, 0.350 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (32 mg (yield 73%)) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12]1([CH2:18][C:19]#[N:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:19]([CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])#[N:20]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#CC(C(=O)c1cccnc1)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of ethyl nicotinate (10 g) and phenylacetonitrile (5.1 g) in tert-butyl alcohol (30 mL), was added potassium tert-butoxide (6.4 g), and the mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, dried, and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain the title compound (6.0 g, yield 62%).
Reaction SMILES: [BrH:1].[CH:2]([CH:5]([CH2:8][OH:9])[CH2:6]O)([CH3:4])[CH3:3].[C:10]([OH:13])(=O)[CH3:11]>>[C:10]([O:9][CH2:8][CH:5]([CH2:6][Br:1])[CH:2]([CH3:3])[CH3:4])(=[O:13])[CH3:11]
Reactant: Br
Reactant: CC(=O)O
Reactant: CC(C)C(CO)CO
Product: CC(=O)OCC(CBr)C(C)C

Procedure:
A solution of hydrobromic acid in acetic acid (30%, 0.5 ml) was added to a solution of 2-isopropylpropane-1,3-diol (10 g) in glacial acetic acid (20 ml) and the mixture heated to reflux for 20 minutes. A further portion of 30% hydrobromic acid in acetic acid (26 ml) was then added dropwise and the resulting mixture maintained at reflux for a further 6 hours. The solvent was then removed in vacuo, and residues removed by azeotroping with hexane, to leave 2-bromomethyl-3-methylbutyl acetate (15 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1)(=[O:17])[CH3:16]>>[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1cccc(CO)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(=O)Oc1cccc(COc2ccnn2-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-(hydroxymethyl)phenyl acetate according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.24 (3H, s), 5.17 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.01-7.03 (1H, m), 7.14 (1H, s), 7.20-7.22 (1H, m), 7.32-7.36 (2H, m), 7.49 (1H, d, J=1.6 Hz), 7.97 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:3][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-methoxyphenyl)piperazin-1-yl) (phenyl)methanone (2 g, 6.4 mmol) and phenylboronic acid (2.34 g, 19.2 mmol) in DCM (100 mL) was added triethylamine (2.7 mL, 19.2 mmol) and Cu(OAc)2 (1.74 g, 9.6 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-methoxy-3-(phenylamino) phenyl)piperazin-1-yl)(phenyl)methanone (2.0 g), 80% yield. 1H NMR (500 MHz, CDCl3): δ 3.0 (bs, 2H), 3.15 (bs, 2H), 3.59 (bs, 2H), 3.89 (s, 3H), 3.95 (bs, 2H), 6.18 (s, 1H), 6.46 (dd, J=2.5, 3 Hz 1H), 6.85 (d, J=9 Hz, 1H), 7.01 (m, 2H), 7.19 (d, J=7.5 Hz, 2H), 7.34 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Cl:15][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Cl:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Reactant: C[Si](C)(Cl)Cl
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (2.50 g, 11.8 mmol), dichlorodimethylsilane (4.57 g, 35.4 mmol), benzyltriethylammonium chloride (0.16 g, 0.70 mmol) and isoamyl nitrite (2.07 g, 17.7 mmol) were added to o-dichlorobenzene (10 ml), and the mixture was heated to 25-30° C. and stirred for 8 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the reaction mixture was added dropwise to 2M aqueous sodium hydroxide solution (20 ml) and partitioned. The aqueous layer was adjusted to pH 4-5 with 35% hydrochloric acid. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give 2,6-dichloropurine as a white powder (1.62 g, yield 72.6%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[C:14]#[N:15])[CH3:9].CO.C([O-])([O-])=O.[Na+].[Na+].[N:30]1[CH:35]=[CH:34][C:33]([C:36]([NH:38][NH2:39])=O)=[CH:32][CH:31]=1>CCOCC>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:15][C:36]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[N:38][N:39]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH3:9]
Reactant: CCOc1ccc(C#N)cc1OCC
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOc1ccc(-c2nnc(-c3ccncc3)[nH]2)cc1OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Cold 4M HCl in dioxane (31.5 mmol, 8.87 mL) was added to a stirred solution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrous MeOH (23.53 mmol, 954 μl) and anhydrous ether (4 mL) The reaction was stirred at 0° C. for 1 h and then placed in the refrigerator (0-5° C.) for 48 h. The mixture was bubbled with N2 to eliminate HCl and concentrated under reduced pressure. To the crude was added anhydrous ether and the methyl 3,4-diethoxybenzimidate salt precipitated as pale orange solid in 63% yield (1.3 g). The product was used without further purification. To a stirred solution of the imidine (0.5 mmol, 130 mg) (freshly liberated from the imidate salt using a solution 1M of Na2CO3 and extracted with ether) in acetonitrile was added pyridine-4-carbohydrazide (0.55 mmol, 75.5 mg) and the reaction was refluxed for 2 h. The mixture was concentrated under reduced pressure and the crude was heated at 180° C. for 2 h. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as a white solid in 65% yield (100 mg, 0.32 mmol). 1H NMR (400 MHz, CDCl3): δ 8.71 (bs, 2H), 8.11 (d, J=5.2 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.07 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.73, 150.89, 149.42, 149.14, 139.66, 121.29, 120.56, 120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS (EI) m/z: 311 (M+), HRMS (EI) for C17H18N4O2 (M+): calcd 311.1502. found 311.1506.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@H:8]1[CH2:21][CH2:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N:15]1[C:16]2[C:11](=[C:10]3[C:19](=[CH:18][CH:17]=2)[CH2:20][CH2:21][C@H:8]([CH2:7][OH:6])[O:9]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CCc2ccc3ncccc3c2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@H]1CCc2ccc3ncccc3c2O1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of (6R)-6-(tert-butyl-dimethyl-silanyloxymethyl)-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene (0.60 g, 1.82 mmole) in tetrahydrofuran (50 mL) was added tetra-n-butylammonium fluoride (2 mL, 1 M in THF). The reaction mixture was stirred for 20 minutes, then diluted with ethyl acetate and washed with water, dried over sodium sulfate, and the solvent removed in vacuum. The residue was purified by column chromatography on silica gel (50% methylene chloride/hexane) to afford 0.38 g (98%) of the title compound as a white solid, mp 128° C., [α]25D=+113.81° (c=5.9, CHCl3).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][O:13][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Oc1cccc(F)c1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.1 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (200 mg) obtained in Example 112 in THF (4 ml) were added 3-fluorophenol (68 mg), tributylphosphine (182 μM) and ADDP (184 mg), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to 2/1) and recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (180 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>C(Cl)Cl.O>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: CCN
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A solution of 2-thiophenecarboxylic acid chloride (7.3 g, 50 mmol) in 30 mL CH2Cl2 was added to 70% ethylamine in water (11 g) at −5° C. and the resulting solution was stirred at RT for 18 h. After that, water was added. The organic layer was separated, washed with water, brine, dried and concentrated. Purification of the residue by flash chromatography with 25% ethyl acetate-hexane gave 6.4 g (83.1% yield) of N-ethyl-2-thiophenecarboxamide as a white solid, m.p. 75-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.Cl[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]>CN(C=O)C.O>[Cl:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:30])[C:23]=1[CH2:22][N:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:12]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Reaction time: 0.67 h
Yield: 84.3 %

Procedure:
4-Methoxy-2-methyl-1H-indole (805 mg, 5 mmol) was added to a mixture of 160 mg (4 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 10 mL of DMF and after stirring for 0.67 hours, 782 mg (4 mmol) of α,2,6-trichlorotoluene was added. The mixture was stirred at room temperature for 5 hours, diluted with water and extracted with ethyl acetate The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.08 g (84% yield) of 1-[(2,6-dichlorophenyl)methyl]-4-methoxy-2-methyl-1H-indole, melting at 154-157° C.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:9]3([O:29][C@@H:10]3[C@H:11](O)[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[C@@H:14]3[CH2:27][C@@H:15]3[C:16]2=[O:26])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:52]>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:9]3([O:29][C@@H:10]3[C@@H:11]([Cl:52])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[C@@H:14]3[CH2:27][C@@H:15]3[C:16]2=[O:26])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1

Procedure:
126 g of 3β-(tert.-butyldimethylsilyloxy)-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in a mixture of 600 ml of methylene chloride, 600 ml of carbon tetrachloride, and 300 ml of pyridine and stirred with 193.8 g of triphenylphosphine for 2.5 hours. The mixture is then washed with water, dried over sodium sulfate, and concentrated under vacuum. Chromatography on silica gel with hexane-acetone yields 117.4 g of 3β-(tert.-butyldimethylsilyloxy)-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one, mp 155.5° C. [α]D =-87° (chloroform).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Reaction time: 8 h

Procedure:
1-Methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for preparation see Intermediate 1) (185 mg), 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151 mg), potassium carbonate (90 mg) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg) were combined in ethanol and toluene under nitrogen and heated to 80° C. for 18 h. The reaction was concentrated, the residue partioned between ethyl acetate (10 ml) and water (10 ml) and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organics were washed with brine (25 ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate ×2) and the collected product dissolved in 1,4-dioxane (0.5 ml) and cooled in a CO2 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40° C. under vacuum overnight to give 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg). LCMS (formate), Rt 0.84 min, MH+ 415
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]#[N:24])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]#[N:24])[CH:16]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1nc(C#N)cc(Br)c1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(F)c(-c2cc(C#N)nc(C)c2C)c1
Yield: 74.4 %

Procedure:
(5-Ethoxy-2-fluoro-phenyl)boronic acid (1.71 g, 9.3 mmol) was added to a solution of 4-bromo-5,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 144) (1.96 g, 9.3 mmol) in monoglyme (50 mL). To this was added a hot solution of sodium carbonate (2.96 g, 27.9 mmol) in water (15 mL) under N2 at ambient temp. Bis(triphenylphosphine)palladium (II) dichloride (326.38 mg, 0.4700 mmol) was then added and the whole stirred mixture was degassed by bubbling N2 through it for 10 mins. The vigorously stirred mixture was then heated at reflux for 2 h. The solution was cooled and diluted with DCM (100 ml) and washed with water (75 ml), dried (Na2SO4) and evaporated to a black solid. This was dissolved in DCM (15 ml) and the solution applied to a 100 g SiO2 chromatography cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc-isohexane (0-30%). Relevant fractions were pooled and evaporated to a colourless solid which was dried at RT for 3 h under vacuum to give 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carbonitrile (D51) (1.87 g):
Reaction SMILES: Cl.O1CCOCC1.CC([N:12]([CH2:16][CH2:17][NH:18][C:19]1[N:24]=[C:23]([C:25]2[S:29][C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:27][C:26]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[F:51])(=[O:43])=[O:42])[C:35]=2[F:52])[CH:22]=[CH:21][N:20]=1)C(=O)[O-])(C)C.CO>C(Cl)Cl>[NH2:12][CH2:16][CH2:17][NH:18][C:19]1[N:24]=[C:23]([C:25]2[S:29][C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])=[N:27][C:26]=2[C:34]2[C:35]([F:52])=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[F:51])(=[O:42])=[O:43])[CH:37]=[CH:38][CH:39]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN(C(=O)[O-])C(C)(C)C)n2)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
A 4N solution of HCl in 1,4-dioxane (1.7 ml, 7.1 mmol) was added to a stirring solution of 1,1-dimethylethyl[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate (0.31 g, 0.47 mmol) (composite batches prepared as described in the previous step) in DCM (10 ml) at rt. MeOH (1 ml) was added to aid in solubility. The reaction was allowed to stir at rt for 3 h. The volatiles were removed and the residue was dried in vacuo to afford the title compound of Step B (0.31 g, quantitative yield) as a hydrochloride salt that was used without further purification; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 7.93-8.18 (m, 4H), 7.20-7.69 (m, 7H), 3.37-3.53 (m, 2H), 2.96 (d, J=5.1 Hz, 2H), 1.41 (s, 9H). MS (ES+): 563 [M+H]+.