Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[C:10]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.[CH2:26]([N:30]1[C:34]([C:35]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[O:36])=[CH:33][N:32]=[CH:31]1)[CH2:27][CH2:28][CH3:29].O>CCCCCC.C1COCC1>[CH2:26]([N:30]1[C:34]([C:35]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[C:10]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:36])=[CH:33][N:32]=[CH:31]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OC)cc(-c3cccc(Cl)c3)c2c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Butyllithium in hexane (1.6 M) (12.75 ml) was added dropwise at −20° C. under N2 to a solution of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (6.7 g) in THF (60 ml) and the mixture was stirred at −20° C. for 30 minutes. A solution of (1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)methanone (3.35 g) in tetrahydrofuran (30 ml) was added at −20° C. under N2 and the mixture was stirred at room temperature for one night. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3/OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 2.5 g (total 48%) of (±)-α-(1-butyl-1H-imidazol-5-yl)-4-(3-chlorophenyl)-a-(4-chlorophenyl)-2-methoxy-6-quinoline-methanol (interm. 2).
Reaction SMILES: [Sb:1]=[O:2].O=[Si]=O.[O-2].[O-2].[O-2].[Sb+3].[Sb+3].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](#[N:22])[CH:20]=[CH2:21]>>[Sb:1]=[O:2].[CH3:19][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](#[N:22])[CH:20]=[CH2:21]
Reactant: C=Cc1ccccc1
Agent: O=[Sb]
Agent: O=[Si]=O
Agent: [O-2]
Solvent: C=CC#N
Product: CC=Cc1ccccc1

Procedure:
An aqueous colloidal dispersion of antimony oxide sold by Nyacol, Inc., Ashland, Mass. under the trade name Nyacol A-1530, containing 30 weight percent antimony oxide was added to an aqueous anionic latex containing 40 weight percent of polybutadiene grafted with 20 parts of an interpolymer containing 70 percent styrene and 30 percent acrylonitrile per 100 parts of polybutadiene and was stirred to provide a uniform blend. The procedure of Example 1 was then carried out to obtain a blend of rubber-occluded antimony oxide in an interpolymer of -methylstyrene and acrylonitrile. The ratio of styrenic interpolymer to (ungrafted) polybutadiene to colloidal antimony oxide was 22:8:1.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:31]3[CH:39]=[C:38]([O:40][CH3:41])[C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH3:30])(=[O:21])=[O:20])=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].O.Cl>C(O)C.O1CCOCC1>[OH:4][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:31]3[CH:39]=[C:38]([O:40][CH3:41])[C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH3:30])(=[O:21])=[O:20])=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
Sodium borohydride (9 mg) was added to a suspension of 6-formyl-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 96, 130 mg, 0.24 mmol) in a mixture of ethanol (3 ml) and 1,4-dioxane (3 ml) at ambient temperature. Stirring was continued for 1.5 hours, and then water was added dropwise until a solution was achieved. After carefully acidifying with drops of concentrated hydrochloric acid, the solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic layer was separated and rewashed with water. The organic layer was dried (magnesium sulphate) and the solvents removed in vacuo. The residue was crystallised from a mixture of methanol and diethyl ether to give the title compound (105 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:14][CH2:13]1)=O)C.O.[OH-].[Na+]>O1CCCC1>[CH3:10][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCC(CCc2cc(-c3ccccc3)nc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(CCc2cc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 0 °C

Procedure:
5 g of lithium aluminum hydride was progressively introduced, incrementally, in 200 ml of dry tetrahydrofuran, under an atmosphere of nitrogen. The suspension obtained is cooled to 0° C., then a solution of 20 g of 4-[2-(1-ethoxycarbonyl-4-piperidyl)-ethyl]-2-phenyl quinoline in 200 ml of tetrahydrofuran is added drop by drop, the temperature of the reaction mixture being maintained below 30° C. After 4 hours of contact at the ambient temperature, there are introduced very slowly and successively 5.85 ml of water, 4.3 ml of a 5 N aqueous solution of sodium hydroxide, then 19.5 ml of water. The mineral products are separated by filtration and washed twice with 30 ml of methylene chloride each time. The filtrates are collected, dried over magnesium sulphate, then evaporated to dryness. The residue obtained, which is constituted by the desired product, is acidified with the equivalent quantity of a solution of hydrochloric acid in ethanol. 11.1 g of 4-[2-(1 -methyl-4-piperidyl)-ethyl]-2-phenyl quinoline in the form of monohydrochloride melting at 206° C. are obtained.
Reaction SMILES: Cl[C:2](=[CH2:26])[CH2:3][N:4]([CH2:17][CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH:27]S(O)(=O)=O>C(Cl)Cl.O>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C:2](=[O:27])[CH2:3]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3, 6.6 g, 16.6 mmol) was dissolved in 40 mL CH2Cl2 and cooled to −78° C. The resulting solution was treated dropwise with conc. H2SO4 (20 mL) and H2O (2 mL). The reaction was placed in a 0° C. bath and stirred 1 h to completion. The reaction was diluted carefully with CH2Cl2 (200 mL) and H2O (400 mL) and the organic layer was separated, dried (MgSO4) and filtered. Concentration of the organic layer followed by flash column chromatography (SiO2, 0-100% EtOAc-hexanes graident over 40 min) provided 1-[(4-nitrophenyl)sulfonyl]-5-phenylpiperidin-3-one (1-4) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (m, 3H), 7.16 (m, 2H), 4.13 (d, J=15.9 Hz, 1H), 3.98 (m, 1H), 3.42 (d, J=15.9 Hz, 1H), 3.36 (m, 1H), 3.00 (dd, J=12.2, 10.4 Hz, 1H), 2.80 (m, 1H), 2.61 (dd, J=16.2, 11.3 Hz, 1H); MS 361.1 found 361.4 (M+H+) required (ionizes poorly).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)=O.N1C=CC=CC=1.O>CS(C)=O>[CH:8]([N:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 170.6 %

Procedure:
Triethylamine (11.6 ml, 42 mmol) was added to a solution of 1-benzhydryl-azetidin-3-ol (2.0 g, 4.2 mmol) in dimethylsulfoxide (60 mL) at room temperature. The resulting mixture was cooled to 10° C., then pyridine sulfur trioxide (8.64 g, 33.6 mmol) in dimethylsulfoxide was introduced. The mixture was stirred at 10° C. for 1 hour and then for 2 hours at room temperature. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude oil was column chromatographed on silica gel (30% ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 1.7 g (86%) of the title compound as a yellow solid, m.p. 52-54° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1Cl
Yield: 63.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D)), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 2-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 118 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:41]([CH3:51])(OCC)([O:45]CC)[O:42][CH2:43][CH3:44]>>[CH2:43]([O:42][C:41](=[O:45])[CH2:51][CH:21]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1)[CH3:44]
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc(C)nc3)n2)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc(C)nc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of the allylic alcohol 16-4 (2.3 g, 5.49 mmol) in (EtO)3CMe (10 mL) was treated with 100 uL of a 1 mL solution of (EtO)3CMe containing 10 uL of propionic acid. The yellow solution was heated at 150° for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to give 2.32 g (86%) of 16-7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH2:14])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2].C(Cl)Cl.[CH3:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][C:10]([NH:14][C:25]([C:23]3[CH:22]=[N:21][CH:20]=[C:19]([CH3:18])[N:24]=3)=[O:26])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCCC(N)(CC1)C2
Reactant: Cc1cncc(C(=O)O)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C12CCCC(NC(=O)c3cncc(C)n3)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
5-Amino-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (0.5 g, 2.53 mmol) was dissolved in methylene chloride (10.0 mL, 156 mmol). 6-Methylpyrazine-2-carboxylic acid (0.35 g, 2.53 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.12 g, 2.53 mmol) and triethylamine (0.71 mL, 5.07 mmol) in methylene chloride (10.0 mL, 156 mmol) were added. The mixture was stirred at rt for 2 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified on the CombiFlash® system (hexane/ethyl acetate: 100/0 to 30/70 in 8 min, then hexane/ethyl acetate: 30/70) to afford 0.60 g (75%) of the desired product. ESI-MS m/z: 318 (M+H)+
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:30])/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.Cl>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:30])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 45 %

Procedure:
A 2.5 ml portion of 10N aqueous sodium hydroxide was added to 2.3 g of 4-[[4-[(3-bromophenyl)amino]-6-quinazolinyl]amino]-4oxo-(E)-2-butenoic acid ethyl ester (Example 5) in 25 ml of ethanol. After stirring for an hour, 2.1 ml of concentrated hydrochloric acid was added, and the reaction was stirred an additional 2 hours. The resulting solid was recrystallized from n-butanol to give 0.97 g of 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid: mass spectrum (m/e): M+H 413.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=CN=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1[S:22]C=NC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:22][CH:14]=[N:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: Brc1cncs1
Product: Cc1ccc(-c2cncs2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 5-bromothiazole. ESI-MS (m/z): 220 [M+1]+.
Reaction SMILES: N[C:2](N)=[S:3].[F:5][C:6]([F:32])([CH2:29]CI)[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>C(O)C>[F:5][C:6]([F:32])([CH2:29][CH2:2][SH:3])[C:7]([F:27])([F:28])[C:8]([F:25])([F:26])[C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: NC(N)=S
Solvent: CCO
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Yield: 93.1 %

Procedure:
A mixture of thiourea (105.7 g, 1.39 moles), 2-(perfluorooctyl)ethyl iodide (531.5 g), 0.926 moles) and anhydrous ethanol (1000 mL) was heated at reflux for 6 hours. Approximately half of the alcohol was removed at reduced pressure and replaced with water. Solid sodium hydroxide (37.0 g) was added and the mixture heated under slow nitrogen purge. The volatile liquid products were collected by steam distillation using a modified Dean-Stark apparatus to yield 414 g (93.1 molar yield) of 2-(perfluorooctyl)ethyl mercaptan. After two consecutive water washes the product was suficiently pure by glc (99.3%) and used without further purification.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@:21]3([OH:39])[CH2:22][CH2:23][C@@H:24]2[C:34]2[CH:38]=[CH:37][O:36][CH:35]=2)[CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>C(O)C>[N:43]1([CH2:42][CH2:41][NH:40][CH2:12][CH2:13][O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@:21]4([OH:39])[CH2:22][CH2:23][C@@H:24]3[C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)[CH2:16]2)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@H](OCCNCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O

Procedure:
To a solution of 0.20 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of absolute ethanol 0.15 g of 1-(2-aminoethyl)pyrrolidine were added. The solution was kept at reflux under nitrogen for 3 hrs, then 10 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.15 g of the title compound (I-ag).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][C:8]([CH3:12])=[C:9]([CH3:11])[CH3:10])=[CH:3][C:4]#[N:5].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[CH2:3][C:4]#[N:5]
Reactant: [H][H]
Reactant: CC(=CC#N)CCC(C)=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC#N)CCC(C)C(C)C
Yield: 98.1 %

Procedure:
3,6,7-Trimethyl-2,6-octadienenitrile (15 g; 0.092 mol), palladium on charcoal (5% Pd/C, 1.5 g) and ethyl acetate (60 ml) were charged in a 500 ml stirred autoclave and hydrogenated (4 bar hydrogen) at 25° C. for 24 hours. Filtration over celite and removal of the solvent afforded 15.1 g of the saturated nitrile as a mixture of two isomers. Distillation using a 10 cm Vigreux column gave 13.8 g of 98.2% pure 3,6,7-trimethyloctanenitrile (mixture of isomers; 56/42) in a yield of 88%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.1 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[2-(morpholin-4-yl)phenoxy]-phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.47 g of the desired compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:29]=[CH:28][C:12]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO>[C:30]([C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([F:32])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:29]=[CH:28][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
Reactant: COc1ccc(B(O)O)cc1F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c(C#N)c2)cc1F
Temperature: 105 °C
Yield: 96.1 %

Procedure:
A 125 ml pressure flask was loaded with tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)benzoyl)piperazine-1-carboxylate (6.55 g, 13.49 mmol), 3-fluoro-4-methoxyphenylboronic acid (2.75 g, 16.19 mmol) and Pd(Ph3P)4 (0.43 g, 0.372 mmol). Toluene (45 mL), MeOH (22.50 mL) and a 2 molar solution of Na2CO3 (16.87 mL, 33.7 mmol) were added, the flask flushed with nitrogen, sealed and heated to 105° C. for 5 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane, the layers separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica. Gradient from 100% CH2Cl2 to 67% CH2Cl2+33 ethyl acetate. Product containing fractions were combined and concentrated in vacuum. 6.88 g tert-butyl 4-(4-(3-cyano-3′-fluoro-4′-methoxybiphenyl-4-ylamino)benzoyl)-piperazine-1-carboxylate were isolated as a pale yellow foam of ˜80% purity. The material was used in then next step without further purification. MS (ESI) m/z 529 (M−H).
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C1SC=C(C(O)=O)N=1.[F:19][C:20]1[CH:21]=[C:22]([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[CH:23]=[C:24]([F:35])[C:25]=1B1OC(C)(C)C(C)(C)O1.Br[C:42]1[N:47]=[C:46]([C:48]([O:50]C)=[O:49])[CH:45]=[CH:44][C:43]=1[F:52]>>[F:35][C:24]1[CH:23]=[C:22]([C:36]2([OH:40])[CH2:37][CH2:38][CH2:39]2)[CH:21]=[C:20]([F:19])[C:25]=1[C:42]1[N:47]=[C:46]([C:48]([OH:50])=[O:49])[CH:45]=[CH:44][C:43]=1[F:52]
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (Intermediate 108) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.