Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Cl:28][C:20]1[N:19]=[C:18]2[C:23]([C:24](=[O:26])[CH:25]=[C:16]([N:9]([CH3:3])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C)c1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2CO3 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf=0.76 (4:1 Hex:EtOAc).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidine-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (52 mg, 31%). LCMS (m/e) 499 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.70 (bs, 1H), 8.05 (s, 1H), 7.34-7.22 (m, 2H), 7.14 (s, 1H), 7.09 (d, 1H, J=8.1 Hz), 6.88 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.10-6.0 (m, 1H), 3.59-3.52 (m, 2H), 3.37 (s, 3H), 2.90 (d, 3H, J=4.8 Hz), 2.89-2.60 (m, 10H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH2:8][CH3:9])[CH2:11][CH2:12]1)[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCC1CCC(O)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CCC(OC(=O)OC(C)Cl)CC1
Reaction time: 20 h

Procedure:
A solution of 1-chloroethyl chloroformate (5.46 g) in dry dichloromethane (20 ml) was added dropwise, under nitrogen at 0°, to a stirred solution of 4-ethylcyclohexanol (5 g) in dry dichloromethane (20 ml) in presence of 3A molecular sieves. A solution of pyridine (3 g) in dry dichloromethane (20 ml) was added dropwise to the reaction mixture during 20 min at 0° the mixture was then warmed to 20°, stirred for 20 hours, washed with brine (2×50 ml) and dried. The solvent was removed under vacuum and the residue was distilled to give the title compound as a colourless oil (7.9 g; b.p. 130°/5.2 mbar; t.l.c. cyclohexane/ethyl acetate 9/1 Rf=0.88; IR (CDCl3), Vmax (cm-1): 1757 (C=O); 1H-NMR (300 MHz, CDCl3): 6.43 (q), 6.42 (q), 4.93 (bs), 4.59 (tt), 2.14-2.01 (bs), 2.00-1.88 (bs), 1.88-1.78 (m), 1.83 (d), 1.82 (d), 1.60-1.50 (m), 1.50-1.32 (m), 1.30-1.15 (m), 1.28-1.18 (m) 1.05-0.95 (m), 0.95-0.85 (m).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 38 %

Procedure:
Method F2 was used with 8-(4-aminophenoxy)pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione and 4-chloro-3-trifluoromethylphenyl isocyanate to obtain the title compound (yield 38%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:26]=[N:27][C:28]([CH:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.O>CS(C)=O>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:30]=[N:29][C:28]([CH:31]([NH:33][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:32])=[N:27][CH:26]=1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: CC(N)c1ncc(-c2cccc(Cl)c2Cl)cn1
Solvent: O
Solvent: CS(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2cccc(Cl)c2Cl)cn1
Yield: 30.8 %

Procedure:
A solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (18.6 mg, 0.082 mmol) and 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol) in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water (20 mL), and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography ((25% MeOH in EtOAc)/Heptane to 100%) provided (4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (12 mg, approx 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd, J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t, J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd, J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz, 2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H), 0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20].[H-].[K+]>C1COCC1>[CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2,2-dimethyl-1-propanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-(2,2-dimethyl-propoxy)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17]([CH3:24])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:23])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-hydroxybenzaldehyde (20 g, 0.164 mol) in acetone (300 mL) was added K2CO3 (34 g, 1.5 equiv.) and the reaction was stirred at room temperature during 30 minutes. Ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) was added dropwise and the mixture was heated under reflux during 3 hours. K2CO3 (34 g, 1.5 equiv.) and ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) were added and the mixture was heated under reflux during 16 hours and then pourred into water and extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated to afford crude intermediate. After chromatography on silicagel, eluting with cyclohexane/CH2Cl2 (6/4, then 8/2) and then with CH2Cl2, the titled compound was obtained as an oil (27 g, 69.85%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)[CH3:12]>C1COCC1>[CH2:11]([O:13][C:14](=[O:17])[CH2:15][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 4-methylbenzenethiol (5 g, 40.25) in dry THF was added dropwise to a suspension of NaH (60% in mineral oil, 1.98 g, 48.30) in THF at room temperature and stirred for 30 min. under N2 atmosphere. Ethylbromoacetate (4.9 mL, 44.27) was added slowly to this solution and further stirred at room temperature for 3 h. The solvent was removed under vacuum. The residue was dissolved in dil. HCl and extracted by ethylacetate. The combined organic phase was washed successively with saturated NaHCO3 solution, water and brine then dried over Na2SO4. Evaporation of organic phase yielded 8.46 g (99%) colorless oil. 1H NMR (CDCl3): δ 1.22 (t, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.57 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H). EIMS m/z 210 (M+1), 233 (M+23).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:30]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCBr
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CCCCCCCCCCCCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(n-Dodecyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and n-dodecyl bromide.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>C(#N)C>[C:24]([O:23][CH2:22][CH2:21][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])(=[O:26])[CH3:25]
Reactant: CC(=O)OCCBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCOC(C)=O
Yield: 85.5 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.27 g, 10 mmoles) (prepared in Preparation No. 3) in acetonitrile (100 ml) and 2-bromoethylacetate (2 g, 12 mmoles) was stirred for 48 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with ice-cold 0.4N sodium hydroxide solution, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100), methanol (2), ammonia (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated to leave a residue of 3.18 g (85%) of the title compound. Crystallization from toluene gave a sample, mp. 101°-102° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>ClCCCl>[C:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc2cc(OCCCCCCO)ccc2c1
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClCCCl
Product: C=CC(=O)OCCCCCCOc1ccc2cc(C(=O)O)ccc2c1

Procedure:
In 270 g of 1,2-dichloroethane were added 108.11 g (1.5 mmol) of acrylic acid, 21.63 g (75 mmol) of 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid obtained in Step 1, 4.28 g (23 mol) of p-toluenesulfonic acid monohydrate, and 0.83 g (7.5 mmol) of hydroquinone, and the solution was refluxed for 4 hours. After evaporation of the solvent, 270 g of water was added to the residue, and the precipitate was collected by filtration and dried in an oven at 40° C. overnight. The dried product was recrystallized from acetone to yield the desired product, 6-(6-acryloyloxy-hexa-1-yloxy)-2-naphthoic acid, as light-yellow powder (16.97 g, Yield: 65%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=C1CC[CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:2]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of (methyl)triphenylphosphonium bromide (5.18 g, 14.51 mmol) in THF (50 mL) at 0° C. was added n-butyllithium (9.07 mL, 14.51 mmol). The reaction mixture was stirred at 0° C. for 30 min. Ethyl 4-oxocyclohexanecarboxylate (1.9 g, 11.16 mmol) in THF (8 mL) was then added at 0° C. and the reaction was warmed to rt and stirred for 2 h. The reaction was quenched with sat′d aq. NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (1.58 g, 84% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.65 (s, 2H), 4.17-4.11 (m, 2H), 2.44 (tt, J=11.1, 3.8 Hz, 1H), 2.35 (dt, J=13.7, 4.0 Hz, 2H), 2.11-1.96 (m, 4H), 1.64-1.54 (m, 2H), 1.28-1.23 (m, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:30])C.[Cr]([O-])(OC(C)(C)C)(=O)=O.C(O)(=O)C(O)=O>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:30])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(C)(C)O[Cr](=O)(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 12 h
Yield: 61.66 %

Procedure:
A solution of 5-androstene-3β,17β-diol diacetate (5 g, 13.35 mmol) in a mixture of dry carbon tetrachloride (30 Ml), acetic anhydride (4.5 Ml) and glacial acetic acid (1.25 Ml) was treated while stirring with t-butyl chromate solution (35 Ml). The brown reaction mixture was brought to reflux temperature and further stirred for 12 h. The mixture was then cooled in an ice bath and treated in small portions with 10% oxalic acid solution (75 Ml). After adding a further quantity of solid oxalic acid (5.5 g), the reaction mixture was stirred for 2 h at room temperature. The organic phase was removed and the aqueous phase was extracted with carbon tetrachloride (4×50 Ml). The combined carbon tetrachloride extract was successively washed with 5% sodium carbonate solution (2×25 Ml), water and dried. Removal of solvent under reduced pressure gave a pale yellow solid, which was crystallized from methanol to afford the product 7-oxo-5-androstene-3β,17β-diol diacetate (3.2 g, 61.66%), mp 220-221° C. (lit 216-219° C.) [Singh. H., et al Indian J. Chem. 1969, 7, 1084-1087].
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[C:12]=3[CH3:28])[O:5][CH2:4]2)[CH2:2]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:2]1[C:3]2([CH2:4][O:5][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]4[NH:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[O:37])[C:12]=3[CH3:28])[O:7][CH2:8]2)[CH2:1]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
The 2-(((4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (629 mg, 1.58 mmol) obtained by the step (2e) was mixed with methanol (5 ml) and toluene (15 ml) and the mixture was cooled to −50° C. Then, 3-chloroperbenzoic acid (378 mg, 1.42 mmol as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9) to obtain the title compound (623 mg, yield: 95.4%) as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11])[CH3:16]
Reactant: COc1ccc(F)cc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc(F)ccc1OC
Temperature: 25 °C
Yield: 63.7 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (4.3 g, 28 mmol) in dry CH2Cl2 (40 mL) at 0° C. was added carbethoxymethylenetriphenylphosphorane (10.7 g, 30 mmol) portionwise and the reaction was warmed to room temperature for 12 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (8% EtOAc in Hexane, Rf=0.20) to yield the product (4 g, 95%) as an oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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:42]([NH:41][C:38]1[CH:39]=[CH:40][C:35]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][N:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:36][CH:37]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (55 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: C(OO)(C)(C)C.C([O:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([OH:24])[C:18]([CH3:26])([CH3:25])[CH2:17]1)(=O)C1C=CC=CC=1.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>[Mo](=O)(=O)=O.O>[OH:15][CH:16]1[CH2:17][C:18]([CH3:25])([CH3:26])[N:19]([O:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]([CH3:22])([CH3:23])[CH2:21]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCCCCCCC
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
A solution of 121.8 grams (946 mmol) of 70% aqueous tert-butyl hydroperoxide is added over a 3-hour period to a mixture of 101.5 grams (367 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 1.3 gram of molybdenum trioxide, and 650 ml of n-octane that is preheated to 120° C. The reaction mixture is maintained at reflux temperature throughout the addition, and water is collected in a Dean-Stark trap. The reaction mixture is heated at reflux for 8.5 hours after the addition is complete in order to discharge the red color of the nitroxyl starting material. The crude reaction mixture is purified by flash chromatography (50:1 heptane:ethyl acetate) and then hydrolyzed using potassium hydroxide in ethanol to obtain the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)cc1-c1cccc(Cl)c1
Yield: 89.5 %

Procedure:
To a mixture of 2-(3-chlorophenyl)-4-nitroanisole (0.5 g, 1.9 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added platinum(IV)oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chlorophenyl)-4-methoxyaniline as a light yellow oil (405 mg, 1.7 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:27](CC)C(C)C)(C)[CH3:25].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N)C>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([NH:27][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.0067 g, 0.022 mmol, Example 58, Step 4) in DMF (0.3 mL) was added N,N-diisopropylethylamine (0.015 mL, 0.087 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.015 g, 0.039 mmol, Aldrich). After 2 minutes, ethylamine (0.0123 mL, 0.219 mmol, Aldrich) was introduced. When the reaction was determined complete by LCMS, the mixture was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (5 mg, 70%).