Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)NCCC(C)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 2.25 g of 3-p-biphenylyl-butylamine, 20 ml of benzene, 1 ml of pyridine and 1 ml of acetic anhydride is stirred for 3 hours at 25°. 1-Acetamido-3-p-biphenylylbutane is obtained after working up in the customary manner.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])=O)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.N1C=CC=CC=1.C(=O)=O>CC(C)=O>[Cl:19][CH2:15][S:13][C:7]1[C:6](=[O:16])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Reactant: O=S(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cn1cc(SCCl)c(=O)c2ccc(F)cc21
Temperature: -5 °C
Yield: 74 %

Procedure:
3.59 g (5 mmole) of racemic flosequinan (1) were added (over the course of one minute) to a mixture of thionyl chloride (12 ml) and pyridine (3 ml) with efficient stirring and gentle cooling in a bath of dry ice and acetone, to keep the temperature in the range of 0° C. to 6° C. The mixture was stirred at approximately 0° C. for 5 minutes, cooled to −5° C. and poured as a thin stream into 350 ml of ice-water with efficient stirring. After 10 minutes of stirring at 0° C., a solid was filtered off, washed with water and dried over phosphorous pentoxide, under high vacuum producing 2.82 g (74% yield) of 95% pure (by 1H NMR) 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone (6). 1H NMR, CDCl3, δ=8.50 dd, 1H, J=6.6 & 9.0 Hz, H at C5; 8.01 s, 1H, H at C2; 7.18 ddd, 1H, J=2.1 & 9.0 & 10.2 Hz, H at C6; 7.09 dd, 1H, J=2.1 & 10.2 Hz, H at C8; 5.01 s, 2H, CH2; 3.83 s, 3H, N—CH3.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[C:4]=1[CH3:18])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][C:4]1[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:14])[CH:10]=2)=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)O)c1
Reactant: C1COCCN1
Product: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)N2CCOCC2)c1

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid was reacted with morpholine using General Amidation Procedure 1 to give 3,5-dimethyl-4-[3-(morpholine-4-carbonyl)-phenyl]-1H-pyrrole-carbaldehyde. MS m/z 326 [M+1].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CN(C)C=O.O.CO>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[C:10]([F:13])([F:12])[F:11])=[O:9])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (241 mg, 1.23 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (268 μL, 3.08 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (6 mL). The mixture was stirred at room temperature, N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol) was added thereto, and the mixture was stirred at room temperature for 62 hr. Methanol (5 mL), tetrahydrofuran (5 mL), water (5 mL) and sodium carbonate solution (2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. A white precipitate was collected by filtration, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and a white precipitate obtained above was added to the residue. The mixture was recrystallized from ethanol to give the title compound (252 mg, 81%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Br)c(OC)c(C=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(OC)c(CO)c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a cooled (0° C.) solution of 51 (8.0 g, 33 mmol) in THF (100 ml) was added LiAlH4 (15 ml of 1.0M in THF) dropwise. After 15 min, the reaction was quenched with 2N HCl and the aqueous layer was extracted with EtOAc. The EtOAc layer was dried concentrated to give a solid (7.5 g, 93%): Mp=65-67° C.; 1H NMR (DMSO-d6) δ 7.05 (d, 1 H, J=3.0 Hz), 6.98 (d, 1 H, J=2.5 Hz), 5.28 (t, 1 H, J=4.9 Hz), 4.47 (d, 2 H, J=5.7 Hz), 3.73 (s, 3 H), 3.67 (s, 3 H); MS 245 (M−H)−
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
2-(6-Methylthiomethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.10 g, 0.33 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.075 g, 0.33 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give the titled compound (0.052 g, 50%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:23]1[CH2:24][CH2:25][C:20]2([O:27][CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1)=[O:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
To a suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (987 mg, 4.23 mmol) in dry THF (1.0 ml), at room temperature, was added 1,4-cyclohexanedione monoethylene ketal (661 mg, 4.23 mmol), followed by dibutyltin dichloride (129 mg, 0.42 mmol). After 5 min, phenyl silane (575 μL, 4.65 mmol) was added and the reaction mixture was stirred at room temperature for 4 days when a clear solution resulted. It was then concentrated and the residue purified by flash chromatography (0% to 30% EtOAc/Hexane) to obtain 1.22 g (77%) of 3-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:22]1COCC1.[H-].[Na+].IC>O>[CH3:22][N:17]1[CH:18]=[C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:21])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH:15]=[C:16]1[CH:19]=[O:20]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C=O

Procedure:
1.3 g (4.6 mmol) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-pyrrolecarboxaldehyde and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 300 mg (10 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 640 μl (10 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (70/30). After evaporation of the solvents, 600 mg (44%) of the expected product are collected.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc(Cl)cc2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 87.7 %

Procedure:
37.2 g of 1-(4-nitrobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine are reduced at room temperature in 370 ml of tetrahydrofuran in the presence of 20 g of Raney nickel. The filtered reaction solution is concentrated by evaporation and the resulting oil is crystallised from isopropanol/petroleum ether, yielding 30 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 111°-112°.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76]C(=O)C(F)(F)F)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]>O1CCCC1.C(OC)(C)(C)C>[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76][CH2:22][CH2:21][NH:20][C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=c1onc(-c2nonc2NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 2-(tritylamino)ethanol (10 g, 33 mmol) [EP599220 and J. Org. Chem. (2001), 66, 7615] and triphenylphosphine (8.7 g, 33 mmol) in tetrahydrofuran (65 mL) at 0° C. was treated with diisopropyl azodicarboxylate (7.0 mL, 35 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (9.3 g, 24 mmol) in tetrahydrofuran (28 mL), and stirred at 25° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate (350 mL), cooled to 0° C., treated with 1 N HCl (200 mL), and stirred at 25° C. for 1 h. The reaction mixture was treated with additional 1 N HCl (150 mL) and stirred at 25° C. for 3 h. The organic layer was separated, washed with saturated sodium bicarbonate (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow foam which was reconcentrated from hexanes to give an oily solid. The oily solid was treated with methyl tert-butyl ether (50 mL) and stirred to give a heterogeneous mixture. The solid was filtered, washed with methyl tert-butyl ether (30 mL), and dried to give the desired product (10 g, 74%) as a white solid. LCMS for C31H24ClFN6O3Na (M+Na)+: m/z=605.2. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (dd, J=6.7, 2.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.60 (dd, J=9.1, 8.8 Hz, 1H), 7.40-7.37 (m, 6H), 7.28-7.23 (m, 6H), 7.18-7.12 (m, 3H), 6.59 (dd, J=5.9, 5.6 Hz, 1H), 3.37-3.31 (m, 2H), 2.96 (dd, J=7.6, 7.6 Hz, 1H), 2.27-2.19 (m, 2H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:40])[CH:16]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C>C(O)C.Cl.C(OCC)(=O)C>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[O:31][C:27]1[CH:26]=[N:25][N:24]([CH:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:40])[C:29](=[O:30])[CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(CCO)n1)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (540.6 mg, 0.89 mmol) in ethanol (4.5 mL) at 25° C. was treated with concentrated aqueous hydrochloric acid (9 drops). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and then concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 1-10% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (298 mg, 68%) as a white solid; ES+-HRMS m/e calcd for C23H25N5O5F2 [M+H+] 490.1897 found 490.1895. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.34 (m, 2H) 1.34-1.46 (m, 1H) 1.46-1.59 (m, 2H) 1.90 (ddd, J=13.6, 9.0, 4.3 Hz, 1H) 2.12-2.28 (m, 1H) 3.08-3.29 (m, 2H) 3.69 (q, J=5.5 Hz, 2H) 3.74-3.89 (m, 2H) 4.02 (t, J=5.5 Hz, 2H) 4.86 (t, J=5.5 Hz, 1H) 5.54 (dd, J=11.0, 4.3 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.32-7.43 (m, 2H) 7.43-7.53 (m, 1H) 7.56 (d, J=2.1 Hz, 1H) 8.29 (d, J=2.7 Hz, 1H) 10.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[N:25]=[N:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:26]2[N:25]=[N:24][N:23]([CH2:21][CH3:22])[CH:27]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCn1cc(N)nn1
Product: CCn1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)nn1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-ethyltriazol-4-amine (11.0 mg, 0.12 mmol). The title compound was obtained as a solid (7.1 mg, 16% yield). MS m/z: 458.00, 460.00 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([Cl:24])=[CH:18][C:17]=3[Cl:25])=[N:10][CH:11]=[N:12]2)=[C:7]([O:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:6]=1)(=O)C.N>>[Cl:25][C:17]1[CH:18]=[C:19]([Cl:24])[C:20]([O:22][CH3:23])=[CH:21][C:16]=1[NH:15][C:9]1[C:8]2[C:13](=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc(Nc2ncnc3cc(OC(C)=O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Agent: N
Product: COc1cc(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [22] immediately above, 7-acetoxy-4-(2,4-dichloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazoline was reacted with a saturated methanolic ammonia solution to give 4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline; NMR Spectrum: (DMSOd6) 1.75–1.9 (m, 2H), 2.18 (d, 2H), 3.52 (t, 2H), 3.9 (s, 3H), 3.95 (m, 2H), 4.95 (m, 1H), 6.7 (d, 1H), 6.82 (d, 1H), 7.7 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.85 (s, 1H), 10.5–10.7 (br s, 1H); Mass Spectrum: M+H+ 436 and 438.
Reaction SMILES: Cl.N1C=CC=CC=1.C([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[S:22])[N:20]([CH3:23])[N:19]=[C:18]2[C:24]([F:27])([F:26])[F:25])=[CH:13][CH:12]=1)C>O>[F:26][C:24]([F:25])([F:27])[C:18]1[N:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[C:21](=[S:22])[N:20]([CH3:23])[N:19]=1
Reactant: CCOc1ccc(-n2c(C(F)(F)F)nn(C)c2=S)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1nc(C(F)(F)F)n(-c2ccc(O)cc2)c1=S
Temperature: 215 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 12.6 g (0.109 mole) of pyridine hydrochloride and 11.0 g (0.0363 mole) of 4-(4-ethoxyphenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione was heated at 215° C. and stirred for one hour. The mixture was cooled and dissolved in water. The aqueous solution was extracted with a mixture of tetrahydrofuran:diethyl ether (50:50). The organic phase was extracted with an aqueous, 10% sodium hydroxide solution. The basic extract was acidified, forming a precipitate. This solid was collected by filtration and dried to yield 7.1 g of 3-trifluoromethyl-4,5-dihydro-4-(4-hydroxyphenyl)-1-methyl-1,2,4-triazol-5(1H)-thione, mp 150°-152° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[C:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Product: Fc1c(-c2ccncc2)cccc1-c1ccnc2nc(C(F)(F)F)ccc12
Yield: 45.5 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2-fluoro-3-pyridin-4-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (37 mg, 47%). δH (360 MHz, CDCl3) 7.45-7.54 (4H, m), 7.65 (1H, d, J 4.2), 7.68-7.74 (1H, m), 7.84 (1H, d, J 8.4), 8.35 (1H, dd, J 2.5 and 8.8), 8.72-8.74 (2H, m), 9.34 (1H, d, J 4.2). m/z (ES+) 370 [MH]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH:1]1[C:11]2[CH2:10][N:9]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:21]4[CH:20]=[CH:19][O:18][C:17]=4[CH3:16])=[O:23])=[N:30][CH:29]=3)=[O:32])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1occc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Nc3ccccc32)cn1

Procedure:
As described for Example 20, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine is reacted with 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9]>>[C:1]1(=[C:10]([C:8]#[N:9])[C:11]([NH2:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: N#CCC(N)=O
Product: N#CC(C(N)=O)=C1CCCCC1

Procedure:
Reaction 1. consists of condensing the cyclohexanone (I) with cyanoacetamide, to obtain 2-cyclohexylidene-2-cyanoacetamide (IX); this reaction can be undertaken for example in toluene, in the presence of ammonium acetate and acetic acid, heating to a temperature between 20 and 150° C., and preferably to the reflux temperature of the reaction mixture; the compound IX is separated from the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[I:15]Cl>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:13])([CH3:14])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[I:15])[CH3:2]
Reactant: ClI
Reactant: CCOc1cccc(C(C)(C)C#N)c1
Solvent: CC(=O)O
Product: CCOc1cc(C(C)(C)C#N)ccc1I
Reaction time: 72 h
Yield: 51 %

Procedure:
2-(3-Ethoxy-phenyl)-2-methyl-propionitrile (2.96 grams, 15.65 mmol) was dissolved in a freshly prepared acetic acid solution of iodine monochloride (20 mL of a 1.54 M iodine monochloride solution in acetic acid, 30.8 mmol). The reaction was slightly exothermic. The reaction mixture was allowed to stand at room temperature for 3 d. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 10% sodium carbonate (1×), brine (1×), and dried (anhydrous magnesium sulfate). The solids were filtered off, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography 110 g of silica gel, eluting with a gradient of ethyl acetate in hexanes) to give 2-(3-ethoxy-4-iodo-phenyl)-2-methyl-propionitrile (2.53 g, 51%). LR-MS: 316.21 [(M+H)+]
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH:36]3[CH2:38][CH2:37]3)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:31]2[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3C3CC3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M201) (245 mg, 0.443 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (122 mg, 63%).