Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([CH:17]([CH2:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH:19]([CH3:20])[CH3:21])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)[O-]
Reactant: C=C(c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)C(CS(C)(=O)=O)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of 3-{4-(5-chloropyridin-3-yl)-2-(3-methylbut-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 20 mg, 0.046 mmol) in dry ethanol (0.7 mL) was added sodium methanesulfinate (47 mg, 0.46 mmol) followed by acetic acid (27 μL, 0.046 mmol). The reaction mixture was heated to 60° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by reverse phase prep-HPLC (Kromasil C18, water/MeOH+0.1% TFA) to give 3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (TFA salt, racemate). 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br s, 1H), 8.86 (s, 1H), 8.85 (s, 1H), δ 8.43 (s, 1H), 8.24 (s, 1H), 4.07-3.96 (m, 2H), 3.84-3.79 (m, 1H), 3.67-3.64 (m, 2H), 3.02 (s, 3H), 2.21-2.16 (m, 1H), 1.39 (d, J=11.6 Hz, 2H), 1.22-1.15 (m, 2H), 1.04 (d, J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.78-0.41 (m, 6H). MS ES/APCI calc'd. for C27H33ClN6O4S [M+H]+ 573. found 573.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 86 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.4 g, 1.5 mmoles) was dissolved in methylene chloride (10 ml) and pyridine (0.4 ml) and acetic anhydride (0.2 ml) were added to the solution. The mixture was allowed to stand at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give 1-acetoxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (0.4 g, 86%) (Compound I-19) as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:23](Cl)(=[O:29])OC(Cl)(Cl)Cl.[F:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:31][C:32]1[CH:33]=[C:34]([NH:35][C:23]([NH:20][O:19][CH:16]2[CH2:17][CH2:18][N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=3)(=[O:11])=[O:12])[CH2:14][CH2:15]2)=[O:29])[CH:36]=[CH:37][CH:38]=1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
A solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (1.02 g, 3.00 mmol) in tetrahydrofuran (20 ml) was added over 1 hour at 0° C. to a solution of trichloromethyl carbonochloridate (890 mg, 4.50 mmol) in tetrahydrofuran (60 ml) and stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with tetrahydrofuran (18 ml). 3-Fluoroaniline (100 mg, 0.90 mmol) and N,N-diisopropylethylamine (290 mg, 2.25 mmol) were added and stirred at room temperature for 16 hours. The reaction mixture was quenched with H2O (10 ml) and aqueous 1 N HCl solution (pH=3) and extracted with CH2Cl2 (70 ml×3). The combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 33/67) to give 1-(3-fluorophenyl)-3-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)urea (232 mg, 65%) as a white solid: LCMS: 478 [M+1]+. 1H NMR (DMSO-6) δ: 1.78 (m, 2H), 1.92 (m, 2H), 2.85 (m, 2H), 3.22 (m, 2H), 3.78 (m, 1H), 6.79 (m, 1H), 7.28 (m, 2H), 7.46 (m, 1H), 7.63 (m, 2H), 7.89 (m, 2H), 8.75 (s, 1H), 9.51 (s, 1H).
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:24]([O:26]CC)=[O:25].Cl.O1CCCC1>C(O)C>[CH3:23][C:8]1[CH:9]=[CH:10][C:11]([N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:16])=[C:12]2[C:7]=1[CH:6]=[C:5]([C:24]([OH:26])=[O:25])[NH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixed solution of ethyl 1-(methoxymethyl)-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (4.0 g), 6N hydrochloric acid (20 mL), tetrahydrofuran (20 mL) and ethanol (60 mL) was stirred at 80° C. for 4 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was dissolved in a mixed solution of tetrahydrofuran (40 mL) and methanol (40 mL), aqueous solution (20 mL) of 85% potassium hydroxide (2.2 g) was added, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was acidified with aqueous citric acid solution. The precipitated crystals were collected by filtration, thoroughly washed with water, and dried to give the title compound (3.3 g, yield 99%) as colorless crystals. MS:351 (MH+). melting point 223-225° C.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.O.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOC(C)=O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20]2
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (13.95 mmol, 6.2 g) in EtOAc (93 mL)/Water (93 mL) was added benzyl carbonochloridate (15.35 mmol, 2.62 g) dropwise at 0° C. under an argon atmosphere. The reaction was left to stir for 18 hrs. The aqueous layer was removed before washing the organic with brine. The organics were dried over MgSO4 before filtering and removing the solvent in vacuo to give the title compound as a white solid (4.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H), 3.25 (m, 2H), 4.53 (d, 1H), 4.93 (brs, 1H), 5.10 (s, 2H), 7.08 (d, 1H) 7.31 (m, 7H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc(F)c(Cl)c1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-fluoroaniline gave the title compound as an off-white solid, mp 194-198° C.
Reaction SMILES: [OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]=O>N(CCO)(CCO)CCO>[OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([CH2:30][S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: Sc1ccccc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Reactant: C=O
Solvent: OCCN(CCO)CCO
Product: C[C@]12CCC(=O)C(CSc3ccccc3)=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Under argon, 9.2 g of 17β-hydroxy-17α-methylandrosta-4,15-dien-3-one in 80 ml of triethanolamine is allowed to react at 110° C. with 2.1 ml of thiophenol and 2.1 ml of aqueous formaldehyde solution (37%). After 5 hours and another 18 hours, respectively 2.1 ml of thiophenol and 2.1 ml of formaldehyde solution are added. In total, the reaction mixture is stirred for 32 hours and subsequently introduced into ice/water. The precipitated product is suctioned off, washed with water, taken up in methylene chloride, dried, and concentrated under vacuum. After chromatographing the crude product on silica gel with a hexane-ethyl acetate gradient, 7.9 g of 17β-hydroxy-17α-methyl-4-(phenylthiomethyl)androsta-4,15-dien-3-one is obtained, mp 146.8° C. (from acetone/hexane).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CC(=O)OC
Reactant: CCCCCNC
Solvent: CO
Product: CCCCCN(C)CCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
106 g (1.05 mol) N-methyl-N-pentylamine was added to cooled methanol of a temperature of 0-5° C. 108 g (1.25 mol) methyl acrylate was added to the solution and the mixture was stirred at room temperature for 8 hours. Then methanol was distilled off in vacuo and the residue was purified by distillation to obtain 188.6 g N-methyl-N-pentyl-β-alanine methyl ester (96.1%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:3]1.[OH:23][C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>C1COCC1>[OH:23][C:24]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)[CH2:3]2)[CH2:28][CH2:29]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccccc3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of the pyrrolidine intermediate from step C (0.3 g, 0.85 mmol) and the ketone from step E (0.16 g, 0.85 mmol) in THF (5 mL) was added Na(OAc)3BH (0.35 g, 2.5 mmol) followed by triethylamine (0.2 mL, 1.5 mmol). The reaction was continued at room temperature overnight and quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with EtOAc and the EtOAc layer was dried over MgSO4 and concentrated. Separation on silica gel eluting with 10% to 30% MeOH/EtOAc provided the cis (fast moving spot) and trans (slow moving spot) isomers of the title compound. MS (M+H)+ 490.0.
Reaction SMILES: S(C)C.ClCCl.[F:7][C:8]1[CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[C:11]2[O:16][CH:15]([C:17](O)=[O:18])[CH2:14][CH2:13][C:12]=2[CH:20]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[C:11]2[O:16][CH:15]([CH2:17][OH:18])[CH2:14][CH2:13][C:12]=2[CH:20]=1
Reactant: O=C(O)C1CCc2cc(F)cc([N+](=O)[O-])c2O1
Solvent: ClCCl
Solvent: CSC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)cc2c1OC(CO)CC2
Yield: 103.9 %

Procedure:
A 1M solution of (CH3)2S.BH3 in dichloromethane (0.28 mol) was added dropwise to a mixture of intermediate 13-b (0.25 mol) in tetrahydrofuran (800 ml), stirred under N2 flow. About 60 ml of the solvent was removed by distillation. The reaction mixture was stirred and refluxed for 2 h. The mixture was cooled, decomposed with CH3OH (20 ml), poured out into H2O/NaOH and this mixture was extracted with CH2Cl2. The separated organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 59 g of (±)-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-methanol (104% crude residue) (interm. 14-b).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([N+:15]([O-])=O)[C:13]=1[NH2:14])=[O:7])[CH3:4]>CO.ClCCl.O.[Ni](Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:18]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([NH2:15])[C:13]=1[NH2:14])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1N
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
Sodium borohydride (151 mg, 4.1 mmol) was added to a solution of nickel (II) chloride hydrate (261 mg, 1.1 mmol) in MeOH (26 mL). After 30 min. at room temperature, a solution of 4-amino-6-bis(phenylmethyl)amino-5-nitro-pyridine-3-carboxylic acid ethyl ester (0.9 g, 2.2 mmol) in dichloromethane (5 mL) was added followed by the addition of sodium borohydride (353 mg). The mixture was stirred over night then filtered through a layer of silica gel. The organic was diluted with dichloromethane, washed with brine and dried over sodium sulfate. The organics were filtered, concentrated and purified by column chromatography (dichloromethane:methanol, 20:1). 11 was obtained as a white solid (200 mg). 1H NMR (400 MHz, d6-DMSO) δ: 1.26 (t, J=7.1 Hz, 3H), 4.21 (s, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.52 (s, 2H), 6.73 (s, 2H), 7.14-7.31 (m, 10H), 8.01 (s, 1H). ESIMS, M/Z, 377 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:21](COCC[Si](C)(C)C)[C:20](=[O:30])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:18]=3)[N:13]=2)[CH:11]=1)=[O:6])[CH3:3].O1CCOCC1>CCOCC>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:21][C:20](=[O:30])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:31][C:32](=[O:39])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:18]=3)[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)[nH]2)c1
Yield: 79.8 %

Procedure:
Hydrochloric acid (4M in dioxane, 2.0 mL, 8.0 mmol) was added to a solution of 1-[6-benzoylamino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.239 g, 0.488 mmol) and dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 18 h, at which point ether (10 mL) was added and the precipitate was collected to yield the titled compound (0.157 g, 86% yield). MS (ESI/Cl): mass calcd. for C21H17N5O4, 403.1; m/z found, 404.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.87 (s, 1H), 10.62 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 8.06-7.96 (m, 2H), 7.84-7.49 (m, 4H), 4.31 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.Cl[CH:7]([Cl:9])Cl.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:27])[C:25]=1[F:26])[NH:22][C:21](=[O:28])[CH2:20][CH2:19]2>O>[Cl:9][C:7]1[NH:22][C:23]2[C:18]([CH2:19][C:20]=1[CH:21]=[O:28])=[CH:17][C:16]([F:15])=[C:25]([F:26])[C:24]=2[F:27]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCc2cc(F)c(F)c(F)c2N1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=C(Cl)Nc2c(cc(F)c(F)c2F)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (50 cc) is added in the course of 40 minutes with stirring at between 5° and 10° C. to a mixture of trichloromethane (525 cc) and dimethylformamide (49 cc), the mixture is stirred for 15 minutes at this temperature and the temperature is allowed to rise to approximately 20° C. To the solution obtained, 6,7,8-trifluoro-3,4-dihydrocarbostyril (46.8 g) is added gradually in the course of 20 minutes at approximately 20° C. with vigorous stirring. The mixture is left stirring for 30 minutes at a temperature in the region of 20° C., heated to approximately 60° C. and maintained at the same temperature for 2 hours and a half. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 50° C. The oily residue is poured with vigorous stirring into ice (500 g). Sodium acetate (100 g) is added in small portions in the course of 30 minutes. The suspension obtained is poured in the course of 15 minutes with vigorous stirring into water (1 liter) heated beforehand to approximately 90° C., and the mixture is stirred for a further 15 minutes at the same temperature. The insoluble matter is drained at approximately 90° C. and washed with water (3×250 cc). 2-Chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline (47.7 g) is obtained in the form of a colorless solid, decomposing at 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:18][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)CNS(=O)(=O)c1ccc(C=CC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a mixture of 1-(4-chloro-2-phenylaminophenyl)ethanone (0.401 g) and 4-formyl-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.420 g) in MeOH (10 mL) was added NaOH (1.35 mL, 2 N, aq), and the mixture stirred overnight at RT. The product was concentrated under reduced pressure, washed with EtOAc, H2O and brine, then dried over Na2SO4. The partially-purified product was chromatographed on anhydrous silica (DCM for 0-10 min, then MeOH/DCM for 11-30 min) to provide 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propenyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.540 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:22][CH3:23])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:6]1[C:5]([C:3]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:2])=[C:10]([OH:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:23]
Reactant: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2ccccc2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
A mixture consisting of 1.65 gm (5 millimols) of 2-ethyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester -1,1-dioxide, 0.56 gm (6 millimols) of aniline and 150 ml of anhydrous xylene was refluxed for 24 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. After cooling, 1.8 gm (90% of theory) of 2-ethyl-4-hydroxy-N-phenyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 245°-247° C (from xylene), crystallized out of the reaction mixture.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[C:19]#[CH:20])[CH3:16].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:20]#[C:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Temperature: 55 °C
Yield: 37.2 %

Procedure:
To a mixture of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (420 mg, 1.5 mmol) and propargylaldehyde diethyl acetal (0.32 mL, 2.25 mmol) in DMF (6 mL) is added PdCl2(PPh3)2 (105 mg, 0.15 mmol) and CuI (28 mg, 0.15 mmol), followed by Et3N (0.42 mL, 3 mmol). The mixture is degassed, and heated at 55° C. for 16 h. After cooling to room temperature, the reaction mixture is diluted with EtOAc, washed with water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, EtOAc/heptane 5:95 to 40:60) to give 182 mg of [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[CH2:25]([NH2:28])[CH2:26][NH2:27].O>CS(C)=O.C(N(CC)C(C)C)(C)C>[NH2:1][C:2]1[N:23]=[C:22]([NH:27][CH2:26][CH2:25][NH2:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: NCCN
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 120 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (150 mg, 0.417 mmol) described in Preparation Example A+-11, ethane-1,2-diamine (418 μl, 6.25 mmol) were dissolved in a mixture solution of dimethylsulfoxide (2 mL) and N,N-diisopropylethylamine (1 mL), and the solution was stirred at 120° C. for 15 hours. The reaction solution was cooled to room temperature, water was added, then extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, tetrahydrofuran and NH silica gel were added to the residue, the solvent was evaporated in vacuo adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate:methanol=10:1), and the title compound (95 mg, 0.25 mmol, 59%) was obtained as a white solid.