Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O.B1([O-])O[O:20]1.O.O.O.O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:10]1[CH:11]=[C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:20])[CH:8]=[N:9]1
Reactant: [O-]B1OO1
Reactant: C1=C(c2cnn(C3CCCCO3)c2)CCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1CCCC[C@@H]1c1cnn(C2CCCCO2)c1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of the 4-cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (775 mg, 3.34 mmol) prepared in Example 33a in THF (4 mL), a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added with cooling on ice, and the reaction solution was stirred for 30 minutes with cooling on ice. To the reaction solution, a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added again, and the mixture was stirred at room temperature for 90 minutes. To the reaction solution, water (5 mL) and subsequently sodium perborate tetrahydrate (1.00 g, 6.50 mmol) were added, and the mixture was stirred for 5 hours. To the reaction solution, sodium thiosulfate (2.0 g) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (dichloromethane/methanol=97:3) to yield the title compound (590 mg, 71%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc([N+](=O)[O-])c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc([N+](=O)[O-])c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 36 (0.900 g, 1.88 mmol) and pyridine hydrochloride (0.600 g, 5.1 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 55 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and morpholine (0.016 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (36 mg, 0.088 mmol, yield 55%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH3:35]>O>[F:22][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH3:35])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4]
Reactant: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2[nH]c(C(=O)NC)c(CCNC(=O)C(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (102 mg) and N,N-dimethyl formamide (3.00 mL) were added potassium carbonate (55.2 mg) and ethyl iodide (0.0318 mL), followed by stirring at room temperature for 2 hours, then warming to 60° C., and stirring overnight. To this mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and subsequently dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane:ethyl acetate=2:1 to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-ethoxy-N-methyl-1H-indole-2-carboxamide (9.00 mg) as a colorless solid.
Reaction SMILES: Cl.Cl.[CH2:3]1[CH:7]2[CH2:8][NH:9][CH2:10][CH:6]2[CH2:5][N:4]1[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][C:15]=2[O:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[O:48]1[CH2:52][CH2:51][CH:50]([C:53](O)=[O:54])[CH2:49]1>CN(C=O)C>[O:48]1[CH2:52][CH2:51][CH:50]([C:53]([N:9]2[CH2:10][CH:6]3[CH:7]([CH2:3][N:4]([CH2:11][C:12]4[C:16]5[CH:17]=[CH:18][C:19]([O:21][C:22]6[S:23][C:24]7[C:25]([N:30]=6)=[N:26][CH:27]=[CH:28][CH:29]=7)=[CH:20][C:15]=5[O:14][CH:13]=4)[CH2:5]3)[CH2:8]2)=[O:54])[CH2:49]1
Reactant: O=C(O)C1CCOC1
Reactant: c1cnc2nc(Oc3ccc4c(CN5CC6CNCC6C5)coc4c3)sc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(C1CCOC1)N1CC2CN(Cc3coc4cc(Oc5nc6ncccc6s5)ccc34)CC2C1
Yield: 44.5 %

Procedure:
A solution of 2-[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzofuran-6-yloxy]-thiazolo[4,5-b]pyridine dihydrochloride (50 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbdiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (73 mg, 0.54 mmol), N-methylmorpholine (33 mg, 0.32 mmol), and tetrahydro-furan-3-carboxylic acid (13 mg, 0.11 mmol) in DMF (0.4 mL) was stirred at rt. Upon reaction completion, the mixture was concentrated, re-dissolved in DMF and purified using reverse phase HPLC to provide the title compound (24 mg, 45%). MS (ESI): mass calculated for C26H26N4O4S, 490.17; m/z found, 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=8.0, 1.5, 1H), 7.70 (dd, J=8.5, 2.9, 1H), 7.59 (dd, J=5.6, 3.4, 2H), 7.27-7.18 (m, 2H), 4.08-3.95 (m, 1H), 3.94-3.60 (m, 7H), 3.53-3.42 (m, 1H), 3.40-3.26 (m, 1H), 3.17-3.06 (m, 1H), 2.99-2.77 (m, 2H), 2.71-2.46 (m, 4H), 2.29-2.14 (m, 1H), 2.14-1.99 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][C:18](=[O:20])[CH3:19])=[O:5]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2',5-dichlorobenzophenone, acetyl chloride and pyridine were reacted in ether to give 2'-(o-chlorobenzoyl)-4'-chloroacetanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].C([BH3-])#N.[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:12]=2)[CH:3]=1
Reactant: CN(C)CCN
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 90.6 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), N,N-dimethylethylenediamine (90 μL, 72 mg, 0.82 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(2-dimethylaminoethylamino)methyl]-phenoxy}benzonitrile fumarate (315 mg, 90%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:14]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([C:27]2[C:28]([CH3:38])=[C:29]([F:37])[C:30]([C:33](OC)=[O:34])=[N:31][CH:32]=2)[CH:21]=3)=[O:15])[CH2:13][CH2:12]1>C(Cl)Cl>[F:37][C:29]1[C:28]([CH3:38])=[C:27]([C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([NH:16][C:14]([CH:11]4[CH2:13][CH2:12]4)=[O:15])[N:18]=[CH:19]3)=[CH:24][CH:23]=2)[CH:32]=[N:31][C:30]=1[CH2:33][OH:34]
Reactant: COC(=O)c1ncc(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c(C)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cnc(CO)c1F
Temperature: -15 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
Diisobutylaluminum hydride (1.0M solution in tetrahydrofuran, 0.73 mL) was added dropwise to a solution of methyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-3-fluoro-4-methylpicolinate (60 mg, 1.8 mmol) in methylene chloride (1.5 mL) cooled at −15° C. After 1 hour at this temperature, the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (3 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid solution in water (20 mL). The organic layer was separated, and the aqueous layer was neutralized via addition of solid sodium bicarbonate solution and then extracted with ethyl acetate (50 mL). The combined organic portions were dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 23%). 1H NMR (400 MHz, DMSO) 10.94 (s, 1H), 9.21 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 5.31 (s, 1H), 4.65 (s, 2H), 2.26 (s, 3H), 2.12-2.04 (m, 1H), 0.91-0.80 (m, 4H). LCMS (Method G): RT=7.53 min, M+H+=352.1.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(O)c1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)c1

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.798 g, 5.54 mmol), 3-methoxy phenol (769 mg, 6.19 mmol) and cuprous oxide (403 mg, 2.82 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 101.24° C. (DSC).
Reaction SMILES: [CH2:1]([O:8][CH:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH3:18].O>O1CCCC1>[CH2:17]([O:14][CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:18]
Reactant: CCCCC(O)OCc1ccccc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(OCC)OCc1ccccc1
Yield: 86.4 %

Procedure:
A solution of 194 g (1 mol) of pentanediol monobenzyl ether in 1 L of tetrahydrofuran (hereinafter referred to THF) was added to a solution of 48 g (2 mol) of sodium hydride in 100 ml of THF under cooling. Then, the mixture was heated under reflux for 2 hours and cooled to the room temperature before 140 g (1.3 mol) of ethyl bromide in 300 ml of THF was added dropwise. The mixture was heated under reflux for 6 hours. 500 ml of water was added and extraction was carried out with 500 ml of diethyl ether. After the organic layer was neutralized and washed with water and dried over anhydrous magnesium sulfate and concentrated. The oily residue was purified by distillation under the reduced pressure, to obtain 192 g of pentanediol benzyl ethyl ether. Boiling point; 110-117° C. (1 mmHg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH:21]([C:25]6[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=6)[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:33])[C:6]([C:34]([O:36]CC)=[O:35])=[CH:5]2)[CH2:3][CH2:2]1>[OH-].[K+].C(O)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH:21]([C:25]6[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=6)[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:33])[C:6]([C:34]([OH:36])=[O:35])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C3CC3)CCN2)cc1
Yield: 105.7 %

Procedure:
(RS)-1-Cyclopropyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 29, but starting with (RS)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.5 g) in N aqueous potassium hydroxide (18.4 cc) and ethanol (18.4 cc). After 1 recrystallization in dimethylformamide (50 cc), (RS)-1-cyclopropyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine-3-carboxylic acid (1.5 g) is obtained in the form of a yellow solid, decomposing at 287° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1

Procedure:
A solution of tert-butyl-4-(2-hydroxyethyl)-piperazine-1-carboxylate (Maybridge, 0.29 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[Cl:11][CH2:12][CH2:13][C@@H:14]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: O[C@@H](CCCl)c1cccs1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1cccs1

Procedure:
Using 4-chloro-2-hydroxybenzonitrile (303 mg, 1.97 mmol) and (S)-α-(2-chloroethyl) thiophenemethanol (349 mg, 1.97 mmol), and the procedure described in Example 5(a), the title compound was prepared as a white crystalline solid (373 mg, 61%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)([Cl:16])=O>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 11.2 g (0.056 mol) of p-methylsulfonyl-benzoic acid prepared in Example 4 and 30 ml of thionyl chloride were heated under reflux to give a clear solution. Removal of the excess of thionyl chloride under reduced pressure obtained white solid and without purification put into the next reaction.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]2[NH:11][N:12]([SH:14])[CH:13]=[C:5]2[CH:4]=1.S(OC)(O[CH3:19])(=O)=O>>[CH3:19][S:14][N:12]1[CH:13]=[C:5]2[N:6]([C:7]([S:9][CH3:10])=[N:8][C:3]([S:2][CH3:1])=[CH:4]2)[NH:11]1
Reactant: CSC1=CC2=CN(S)NN2C(SC)=N1
Reactant: COS(=O)(=O)OC
Product: CSC1=CC2=CN(SC)NN2C(SC)=N1

Procedure:
Using the method of Example 28 and starting with 5,7-bis(methylthio)triazolo[1,5-c]pyrimidine-2-thiol (from Example 23) and dimethyl sulfate, a solid was obtained which was recrystallized from an ethyl acetate-hexane mixture to provide 2,5,7-tris(methylthio)triazolo[1,5-c]pyrimidine, m.p. 165°-167° C. Analysis: Calculated for C8H10N4S3 : %C, 37.2; %H, 3.9; %N, 21.7; Found: %C, 37.5; %H, 3.9; %N, 22.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:40])/[CH:24]=[CH:25]/[CH2:26][N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:40])/[CH:24]=[CH:25]/[CH2:26][N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C/C=C/C(=O)N2CCc3c(sc4ncnc(Nc5ccc(F)c(Cl)c5)c34)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/CN1CCNCC1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-[(2E)-4-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-4-oxobut-2-en-1-yl]piperazine-1-carboxylate from Example 3 (150 mg, 0.255 mmol) in dichloromethane (15 mL) was added TFA (1.0 mL, 13 mmol), and the mixture was stirred at rt for 5 h. The solvent was removed in vacuo. 1 M aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was crystallized from dichloromethane/diethyl ether to yield 108 mg (87%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[NH2:13])[CH3:2].C([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=O)C.O=P(Cl)(Cl)Cl>>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[NH:13][C:18]1[NH:19][CH2:20][CH2:21][N:17]=1)[CH3:2]
Reactant: CCc1ccc2ccccc2c1N
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc2ccccc2c1NC1=NCCN1

Procedure:
2-Ethylnaphthyl amine is reacted with N-acetyl-2imidazolidinone in the presence of POCl3 to produce the imidazoline intermediate. This intermediate is treated with sodium hydroxide and water to remove the aceto group and yield the name compound (VIII).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][CH2:21][O-:22].[Na+]>C(O)C>[CH2:21]([O:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:20]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1Cl)OCO3
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3

Procedure:
To a mixture containing 126 g of ethyl 4-chloro-6,7-methylenedioxyquinoline-3-carboxylate and 200 ml of absolute ethanol was added dropwise an ethanolic sodium ethylate solution prepared from 34 g of sodium ethylate and 250 ml of ethanol with stirring. The resulting mixture was refluxed for 1.5 hours and the ethanol was removed under reduced pressure. The residue was poured into ice-water, the insoluble solid was filtered, washed with water and dried to provide 126 g of almost pure ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-caboxylate, m.p. 84°-86°C. Recrystallization from petroleum ether gave colorless needles, m.p. 85°-85.5°C.
Reaction SMILES: [F:1][C:2]([F:22])([CH2:20][OH:21])[C@@:3]([NH:13]S(C(C)(C)C)=O)([CH2:11][F:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].Cl>CO.O1CCOCC1>[NH2:13][C@@:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])([CH2:11][F:12])[C:2]([F:22])([F:1])[CH2:20][OH:21]
Reactant: CC(C)(C)S(=O)N[C@](CF)(c1ccccc1F)C(F)(F)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@](CF)(c1ccccc1F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [(S)-2,2-difluoro-1-fluoromethyl-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-amide (intermediate F4.1) (145.5 mg, 426 μmol) in methanol (2.5 ml) was cooled to 0° C. and treated with hydrochloric acid (4 M in dioxane; (533 μl, 2.13 mmol). The solution was left to warm to room temperature and stirred for 1 hour. After removal of the solvent at reduced pressure the solid residue was dissolved in water (5 ml), then extracted with ethyl acetate (2×10 ml). The organic layers were extracted with water (5 ml), thereafter the combined aqueous layers treated with a solution of sodium carbonate (2 M) to adjust the pH to 9-10. Extraction with ethyl acetate (3×35 ml), combination of the organic layers and evaporation at reduced pressure after drying over sodium sulphate yielded the crude (S)-3-amino-2,2,4-trifluoro-3-(2-fluoro-phenyl)-butan-1-ol (78 mg, 78% yield) as a colorless oil. Evaporation of the first 2 ethyl acetate layers followed by the treatment with a solution of sodium carbonate and proceeding as described above yielded another fraction (22 mg) of product. MS (ISN): m/z=238.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1cccc(C2(O)CCC(=O)CC2)c1
Product: COc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.