Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][C@H:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[Cl:46].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:46][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:36]=1[NH:35][C:2]1[N:3]=[C:4]([O:29][C@H:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:6]=2[N:7]=1)[C:40]([NH:42][CH3:43])=[O:41]
Reactant: CNC(=O)c1ccc(N)c(Cl)c1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(O[C@H]5CCOC5)c34)cc2o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(O[C@H]3CCOC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(Cl)c1
Temperature: 150 °C
Yield: 64.7 %

Procedure:
To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (64.7% yield) as yellow solid; MS (ESI) m/z 649.6 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C=O)n1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1cccc(CO)n1)c1ccccc1
Yield: 49.7 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridine-2-carbaldehyde (0.4 g, 1.24 mmol, 1 eq.) in 100 ml of dry THF, was added sodium triacetoxyborohydride (0.276 mmol, 1.3 mmol, 1.05 eq.) in one portion. The reaction was stirred for 20 hrs, before the addition of 1M aqueous NaOH (100 ml). The mixture was stirred for 15 mins before extraction with EtOAc. The organic phase was dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanol (0.2 g, 47% yield) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.I[CH2:17][C:18]([NH2:20])=[O:19]>C(C(C)=O)C>[NH:1]=[C:2]1[N:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: NC(=O)CI
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCC(C)=O
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CC(N)=O
Yield: 53 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and iodoacetamide (14.8 g) in methyl ethyl ketone (50 cc). The mixture is heated for 18 hours to boiling and then cooled to a temperature in the region of 20.C. The precipitate formed is filtered off, then added to distilled water (100 cc) and treated with IN sodium hydroxide (37 cc). The insoluble matter is filtered off, washed with distilled water (100 cc) and recrystallized in boiling methanol (100 cc). (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)acetamide (6.2 g), m.p. 228° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:23]([OH:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[C:4](=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[NH:14][C:13]3[C:8]([N:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]=1.[CH:27]1[CH:28]=[CH:29][C:24]([C:23]([OH:31])=[O:30])=[CH:25][CH:26]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Agent: O=C(O)c1ccccc1
Solvent: CC(C)=O
Product: Cc1cc2c(s1)=Nc1ccccc1NC=2N1CCN(C)CC1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a clear solution of olanzapine free base (5.0 g) in acetone (150 ml) was added slowly a solution of 1.0 equivalent of benzoic acid (1.96 g) in acetone (20 ml) at room temperature. After stirring at 4° C. overnight, the crystals were isolated by filtration, washed with acetone (20 ml) and dried overnight at 40° C. Yield: 6.23 g (90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([O:17]C)=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[I-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1
Reactant: COc1cc(OC)c(C(=O)c2ccc(F)cc2)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: COc1cc(O)c(C(=O)c2ccc(F)cc2)cc1Cl
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
The above prepared (5-chloro-2,4-Dimethoxy-phenyl)-(4-fluoro-phenyl)-methanone (8.41 g, 28.5 mmol) was dissolved in 115 mL of acetonitrile and treated successively with sodium iodide (6.51 g, 1.5 eq.) and AlCl3 (3.86 g, 1.0 eq.), and the mixture kept at 80° C. for 0.75 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by a short flash chromatography (SiO2, hexane/AcOEt=9/1), afforded 6.94 g of the title compound as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:13])=[CH:4][C:3]=1[O:14][CH3:15].[CH3:16][N:17]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)[CH:23]=2)[C:18]1=[O:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:5]1[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:7][C:2]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:36]4[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=4)[CH:23]=3)[C:18](=[O:42])[N:17]([CH3:16])[CH:26]=2)=[C:3]([O:14][CH3:15])[CH:4]=1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: COc1cc(F)c(CS(C)(=O)=O)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(F)c(CS(C)(=O)=O)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Yield: 19.3 %

Procedure:
1-Bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene (34.0 mg, 0.114 mmol), the title compound of Example 46, step 2 (50.0 mg, 0.137 mmol), Pd(dppf)Cl2 (20.0 mg, 0.027 mmol) and 1 M aqueous K3PO4 (0.47 mL, 0.47 mmol) in dioxane (3.0 mL) were microwaved at 100° C. for 40 min. Preparative HPLC gave the title compound (10.0 mg, 18%) as a light yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 8.47 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.73 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.27 (s, 1H), 7.05 (s, 1H), 6.85 (d, J=12.0 Hz, 1H), 4.32 (d, J=6.4 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H), 3.64 (s, 3H), 2.93 (s, 3H). LCMS: 456.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:31]3[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=3)=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN)c(C)c3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCNC(=O)c4ccc(C)cc4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
A mixture of compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.16 mmol), p-toluoyl chloride (0.028 mL, 0.21 mmol), and PS-DIEA (0.057 g, 0.21 mmol) in CH2Cl2 (4.0 mL) was stirred at room temperature for 16 h. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel to yield N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide (0.037 g, 51%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.80-11.00 (s, 1H), 8.69 (t, J=5.43 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J=8.19 Hz, 2H), 7.28 (d, J=8.00 Hz, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.31 Hz, 1H), 3.94 (t, J=5.59 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m/z 488 [M+H]+.
Reaction SMILES: [Br:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][C:3](=[O:5])[C:2]([Br:1])([F:8])[F:9])[CH:11]=[CH2:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C=CCN
Product: C=CCNC(=O)C(F)(F)Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Ethyl bromodifluoroacetate (100 g) was cooled to 0° C., and allylamine (39 mL) was added dropwise. The mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 105 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[I:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([NH2:24])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[I:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-(4-benzyloxy-3-iodophenoxy)-5-methyl-7-nitroindane (4.18 g) in ethyl acetate (15 mL) was added 5% Pt/C (860 mg). The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (3.89 g).
Reaction SMILES: ClC1C=CC2C3N=C(NC4C=CC(I)=CC=4)N=CC=3CC(=O)NC=2C=1.C([Si](C)(C)C)#C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[C:42]3[N:43]=[C:44]([NH:47][C:48]4[CH:53]=[CH:52][C:51]([C:54]#[C:55][Si](C)(C)C)=[CH:50][CH:49]=4)[N:45]=[CH:46][C:41]=3[CH2:40][C:39](=[O:60])[NH:38][C:37]=2[CH:61]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[C:42]3[N:43]=[C:44]([NH:47][C:48]4[CH:53]=[CH:52][C:51]([C:54]#[CH:55])=[CH:50][CH:49]=4)[N:45]=[CH:46][C:41]=3[CH2:40][C:39](=[O:60])[NH:38][C:37]=2[CH:61]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1
Agent: C#C[Si](C)(C)C
Agent: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Product: C#Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and ethynyltrimethylsilane were converted to 9-chloro-2-(4-trimethylsilanylethynyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one, which was deprotected in a manner similar to I-33 to give I-45 (38%): HRMS Calcd. for C20H13ClN4O: 361.0856, Found 361.0848.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7]=1[F:26])=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:26][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CCl)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CN3CCOCC3)c(F)c2)CC1
Reaction time: 5 h
Yield: 83.4 %

Procedure:
A mixture of tert-Butyl 4-[4-(2-Chloro acetylamino)-3-fluoro phenoxy]piperidine-1-carboxylate (3.31 g, 0.0085 moles, obtained in preparation 3), morpholine (0.89 g, 0.01 moles) and potassium carbonate (1.75 g, 0.012 moles) in acetonitrile (30 mL) was stirred for 5 hours at reflux temperature. The mixture was concentrated under reduced pressure and the residue, thus obtained, was partitioned between ethyl acetate (50 mL) and water (50 mL). The resulted aq. Phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated. The crude compound was purified by flash chromatography (ethyl acetate:hexane, 3:7) to obtain the title compound 3.1 g (Yield: 83.5%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH2:12])=[C:3]1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1>CO>[CH2:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1)[CH3:12]
Reactant: C=Cc1c(-c2cncc(NS(=O)(=O)CC)c2)n(C)c2ccccc12
Solvent: CO
Product: CCc1c(-c2cncc(NS(=O)(=O)CC)c2)n(C)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-3-vinyl-1H-indol-2-yl)-pyridin-3-yl]-amide (35 mg, 0.082 mmol) and MeOH (5 mL). The flask is evacuated and flushed with N2 thrice. Pd/C (4.36 mg) is added and the reaction stirred under H2 overnight at 50° C. The reaction is filtered over celite and the celite layer is washed thoroughly with MeOH. The filtrate is concentrated in vacuo. The crude is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) followed by HPLC purification using Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford the pure product ethanesulfonic acid [5-(3-ethyl-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 1.27 (t, J=7.6 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.25 (q, J=7.3 Hz, 2H), 3.66 (s, 3H), 7.09-7.17 (m, 1H), 7.23-7.31 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.83 (t, J=2.3 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H). HRMS: (ESI) m/z 344.1435 [(M+H)+ Calcd for C18H21N3O2S 344.1427].
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyryl chloride (8.1 μL, 0.077 mmol) was added to a solution of triethylamine (10.8 μL, 0.077 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (30 mg, 0.071 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were remove under reduced pressure and chromotagraphy of the residue over silica gel using 25% ethyl acetate in hexanes gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C28H29N2O2Cl2[(M+H)+]495.1601, observed 495.1606.
Reaction SMILES: [CH3:1][CH:2]([N:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH:7]=O)[C:3](=O)[CH3:4].C([O-])(=O)C.[NH4+:22].C(O)(=O)C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:4][C:3]1[N:22]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:2]=1[CH3:1]
Reactant: [NH4+]
Reactant: CC(=O)C(C)N(C=O)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1ncn(-c2cccc([N+](=O)[O-])c2)c1C
Yield: 73.4 %

Procedure:
A suspension of N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.17 g), ammonium acetate (3.82 g) and acetic acid (1 ml) in xylene (20 ml) was refluxed for 2 hours. After adding ethyl acetate and an aqueous solution of sodium hydroxide (1N, 100 ml), the mixture was stirred for 10 minutes. The separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 1-3% unethanol/dichloromethane to give 4,5-dimethyl-1-(3-nitrophenyl)imidazole (0.79 g, 73.1%).
Reaction SMILES: [CH3:1][C:2]([OH:31])([C@H:4](/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2[OH:29])=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].[N+]([O-])([O-])=O.[K+]>CCOCC.O1CCCC1>[CH3:9][C@@H:8]([C@@H:10]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH2:24]/[C:14](=[CH:15]\[CH:16]=[C:17]3\[CH2:18][C@@H:19]([OH:30])[CH2:20][C@H:21]([OH:29])[C:22]\3=[CH2:23])/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:7]=[CH:6]/[C@@H:4]([C:2]([OH:31])([CH3:1])[CH3:3])[CH3:5]
Reactant: C[C@H](/C=C/[C@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Yield: 22.3 %

Procedure:
(22E)-5,7,22-Ergostatriene-1α,3β,25-triol (Ia) (100 mg, 0.23 mmol) was dissolved in a mixed solution of ether (950 ml) and tetrahydrofuran (50 ml), and the solution was irradiated with high pressure mercury lamp using an 1.5% aqueous potassium nitrate solution as a filter with water cooling in a nitrogen stream for 3 minutes. From the reaction solution was distilled off the solvent and the residue containing previtamin D was dissolved in ethanol (30 ml) and the solution was refluxed for one hour. After distilling off ethanol, the residue was purified by high pressure liquid chromatography (HPLC) (column: LiChrosorb® Si60 (7 μm), φ25×250 mm, Merck Co., Ltd.; column effluent: 4% methanol-methylene chloride; flow rate: 8.0 ml/min; detected at 264 nm) to give 22 mg of the title compound (IIa) which was recrystallized from hexane-ether. m.p. 168°-170° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:24]1C=CC(C)=C[CH:25]=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:25][CH:24]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2nc(NCc3ccccn3)nc(C)c2C)cc1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using p-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 4.71 (d, J=2.8 Hz, 2H), 5.75 (bs, 1H), 6.28 (s, 1H), 7.06 (d, J=7.3 Hz, 2H), 7.15 (t, J=6.8 Hz, 1H), 7.30-7.38 (m, 3H), 7.61 (t, J=7.4 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:11]2[CH:12]=[C:13]3[C:5]([O:4][CH2:3][CH2:2][F:1])=[N:6][NH:7][C:8]3=[N:9][CH:10]=2)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: Nc1cnc2[nH]nc(OCCF)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OCCF)c3c2)c1F

Procedure:
6-Chloro-2-fluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide was prepared according to the general procedure of Example 78, Step D, using 3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.035 g, 0.18 mmol) and 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.058 g, 0.20 mmol). The crude material was purified by silica gel flash column chromatography (5 to 7% 7N NH3-MeOH in CH2Cl2) to afford the desired product which was triturated with Et2O (51 mg, 60% yield). LRMS (ACPI pos) m/e 474.0 (M+1). 1H NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 11.10 (s, 1H), 9.99 (br s, 1H), 8.58 (d, 1H), 8.54 (d, 1H), 7.55 (t, 1H), 7.46 (d, 1H), 4.91 (m, 1H), 4.78 (m, 1H), 4.63 (m, 1H), 4.55 (m, 1H), 3.16 (t, 2H), 1.75 (m, 2H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−124.0, −223.1.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[Cl:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:31])[NH:25]2>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:25]2[C:26]3[C:22](=[C:21]([Cl:20])[C:29]([F:30])=[CH:28][CH:27]=3)[CH2:23][CH:24]2[CH3:31])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC1Cc2c(ccc(F)c2Cl)N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2Cl)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 91 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 55 mg of 4-chloro-5-fluoro-2-methyl-2,3-dihydro-1H-indole. After purification, 44 mg of 2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following: