Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Fe].C(O)(=O)C>[CH2:1]([NH:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=Cc1ccccc1N

Procedure:
A stirred solution of 15.3 g. of N-decyl-3-(2-nitrophenyl)propenamide in 200 ml. of glacial acetic acid was heated to 85° C. on a steam bath, and then 12.9 g. of iron powder was added portionwise, during 25 minutes. The reaction temperature was kept between 85° and 95° C. during the addition. The reaction mixture was filtered hot, and the residue was washed with hot glacial acetic acid. The cooled, combined acetic acid solutions were evaporated in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed several times with water and then with saturated sodium chloride solution. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo to give the crude title product.
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[NH3:31]>C(O)CCC.CO>[NH2:31][C:7]1[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4[N:19]=[C:18]3[CH3:26])=[CH:13][CH:12]=2)=[N:10][C:4]2[CH:3]=[C:2]([CH3:1])[C:29]([CH3:30])=[CH:28][C:5]=2[N:6]=1
Reactant: N
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Solvent: CO
Solvent: CCCCO
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(N)=N2
Temperature: 120 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of the thioamide (from Example 19) (2.98 g, 7.24 mmol) and red mercuric oxide (1.57 g, 7.24 mmol) in n-butanol (40 ml) was saturated with ammonia gas at room temperature, and then stirred at 120° C. for 3 hours. After being cooled, the mixture was diluted with methanol (150 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate:methanol:diethylamine=100:10:5). Fractions containing the product were evaporated to give the title compound as a bright yellow solid (1.085 g, 38%), m.p. 299°-302° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH2:11][CH3:12])[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]1[CH3:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:11]([N:9]1[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([CH3:18])[CH:4]([CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:10]1)[CH3:12]
Reactant: CCN1CC(CCCl)N(C)c2ccccc2C1=O
Reactant: C1COCCN1
Product: CCN1CC(CCN2CCOCC2)N(C)c2ccccc2C1=O
Yield: 61 %

Procedure:
A solution of 30 g (0.112 mole) of 2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one in 70 ml of morpholine was refluxed for 3 hrs, concentrated on the rotary evaporator and the residue partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator. The residue was crystallized twice from isopropyl ether containing a small amount of ethanol, m.p. 128°-148° C. Recrystallization from toluene gave 19.5 g (61%) of product, m.p. 128°-148° C.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 5.7 g. 3-n-butylsulphonyl-1,2,4-triazole, 5.4 g. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from petroleum ether (60° - 80°C.) to give 1-dipropylcarbamoyl-3-n-butylsulphonyl-1,2,4-triazole, m.p. 46° - 47°C. Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[C:27]([CH3:28])([CH3:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1F)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(=O)(=O)c1ccccc1F
Yield: 79.5 %

Procedure:
A mixture of methyl 2-(2-(2-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (62 mg, 0.13 mmol, 1.0 eq.) and 1.4 mL aqueous solution of sodium hydroxide (2 M, 2.7 mmol, 20 eq.) in tetrahydrofuran (4 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 47 mg of 2-(2-(2-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 79%. MS (ESI+APCI) M+1=455.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH2:16][C:13]2[N:11]3[N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]=[CH:25]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(-c2ccc3nnc(Cn4cnc5cnccc54)n3n2)cc1
Temperature: 60 °C

Procedure:
A mixture of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0650 g, 0.20 mmol), triethyl orthoformate (5.0 ml, 30 mmol), and p-TsOH (0.0039 g, 0.020 mmol) was heated at 60° C. After 2 h reaction is complete. Reaction was concentrated. Took up in DMSO and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles removed. Collected product by filtration. MS m/z=328.1 [M+1]+. Calc'd for C18H13N7: 327.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=O)=O)=[CH:7][CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>O1CCCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:26][C:9]([C:8]3[CH:23]=[CH:24][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[N:11][CH:12]=2)=[CH:16][CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc(C(=O)NCC(=O)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Reaction time: 1 h
Yield: 126.2 %

Procedure:
To a solution of 2-(4-methoxycarbonylbenzamido)-4′-methoxyacetophenone (4.0 g) in tetrahydrofuran (80 ml) was added phosphorus pentasulfide (3.53 g), and refluxed for 2.5 hours. The reaction mixture was additionally added phosphorus pentasulfide (1.0 g), and refluxed for 1 hour. The reaction mixture was filtered, and the filtrate was cooled, and poured into water (1200 ml), and stirred for 1 hour. The resulting precipitate was collected by filtration. The solids were slurried in acetonitrile, and collected by filtration to give methyl 4-[5-(4-methoxyphenyl)thiazol-2-yl]benzoate (3.26 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([NH2:16])=O)=[C:7]2[N:6]=[N:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](=[S:18])[NH2:16])=[C:7]2[N:6]=[N:5]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COCn1nnc2c(C(N)=O)ncn2c1=O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: COCn1nnc2c(C(N)=S)ncn2c1=O
Reaction time: 24 h
Yield: 67 %

Procedure:
3-(Methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.100 g, 0.446 mmol), phosphorus pentasulfide (27 mg; 0.06 mmol), and hexamethyldisiloxane (87 mg; 0.114 mL; 0.535 mmol) were stirred in DCM under reflux for 24 hours. After 24 hours, a second portion of P2S5 (27 mg; 0.06 mmol) was added, and reflux continued for a further 24 hours, after which time the reaction mixture was filtered, and the precipitate was washed with EtOAc, Et2O and air dried to yield the title compound as an orange solid (67% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm 9.95 (1H, bs), 9.47 (1H, bs), 8.85 (1H, s), 5.74 (2H, s) and 3.40 (3H, s).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C@@H:14]([O:17][C@@H:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH3:19])[O:15][CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([C@H:18]([O:17][C@H:14]2[O:15][CH2:16][C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[C@@H:13]2[C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH3:19])[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=1
Reactant: [H][H]
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](O[C@H]1OC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(3aS,6R,7R,7aR)-2-Benzyl-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)octahydropyrano[3,4-c]pyrrole (example 1: 1.60 g, 2.82 mmol) was combined 0.75 g 20% Pd(OH)2 and suspended in 30 mL ethanol in a Parr apparatus. The reaction vessel was shaken vigorously under 45 psi hydrogen for 4 hr. The reaction mixture was filtered through a pad of celite and rinsed copiously with methanol. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of methanol/DCM (1-10% methanol/DCM linear gradient) which furnished the title compound. 1H-NMR (CD3OD): δ 1.38 (d, 3H, J=7.0 Hz), 1.90-2.10 (m, 2H), 2.47 (dd, 1H, J=10.5, 10.5 Hz), 2.56 (dd, 1H, J=10.5, 10.5 Hz), 2.65 (dd, 1H, J=8.0, 11.0 Hz), 2.75 (dd, 1H, J=6.5, 10.5 Hz), 3.11 (dd, 1H, J=6.5, 10.0 Hz), 3.56 (dd, 1H, J=10.5, 10.5 Hz), 4.24 (dd, 1H, J=4.0, 11.0 Hz), 4.37 (d, 1H, J=8.0 Hz), 5.07 (q, 1H, J=6.5 Hz), 6.96 (dd, 2H, J=9.0, 9.0 Hz), 7.16 (dd, 2H, J=5.5, 9.0 Hz), 7.20-7.30 (m, 5H), 7.38 (s, 2H), 7.75 (s, 1H) ppm. MS: (MH)+478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:34])[CH:31]([F:32])[F:33])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16-g of 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (1.34 g) was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][SH:7].[F:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[C:13](F)[CH:12]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:3][Si:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][S:7][C:13]1[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[C:11]([F:10])[CH:12]=1
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Reactant: C[Si](C)(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (360 mg) in DMF (10 mL) at 0° C. was added 2-(trimethylsilyl)ethanethiol (1.8 mL). After 10 min., a solution of 1,3-difluoro-5-phenylbenzene (1.9 g) in DMF (5 mL) was added and the resulting mixture was heated at 110° C. for 2.5 h. Ethyl acetate was added and the solution was washed with 1N HCl, H2O and brine. Concentration and chromatography (silica gel; hexane/EtOAc (98:2)) provided the title compound as a liquid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][C:19]=1[C:25]([F:26])([F:27])[F:28]
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1C(F)(F)F
Yield: 17.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 4-methyl-3-trifluoromethyl-phenylamine (0.03 mL, 0.33 mmol) to provide 236 (14 mg, 17% yield) as a brown solid. LC-MS (M+H=370, obsd.=370). 1H NMR (400 MHz, d6-DMSO): δ 11.73 (s, 1H), 9.11 (s, 1H), 8.52 (dd, 1H), 8.47 (dd, 1H), 8.18 (d, 1H), 7.90 (d, 1H), 7.54 (dd, 1H), 7.43 (m, 2H), 7.28 (m, 2H), 2.41 (s, 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 32.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.21 g, 1.23 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.18 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)[CH:13]=[C:14]([CH2:16][NH:17][CH2:18]C(C)C)[CH:15]=1)#[N:9].[CH3:45]NCC(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)[CH:13]=[C:14]([CH2:16][N:17]([CH3:45])[CH3:18])[CH:15]=1)#[N:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(CNCC(C)C)c4)cc23)CC1
Reactant: CNCC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(CN(C)C)c4)cc23)CC1
Yield: 61 %

Procedure:
The title compound was prepared according to the general procedure of 5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting trimethylamine (300 μL, 0.3 mmol) for methyl(2-methylpropyl)amine to afford 10.5 mg of the title compound (61%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][CH:21]([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(OC(F)F)cc1
Product: FC(F)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(difluoromethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(difluoromethoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]3[CH:35]=[C:34]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[C:33](B4OC(C)(C)C(C)(C)O4)=[CH:32][C:26]=3[C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[CH:19][CH:18]=1.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.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([C:33]2[C:34]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][C:25]3[O:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)=[C:27]([C:28](=[O:29])[NH:30][CH3:31])[C:26]=3[CH:32]=2)[N:3]=1
Reactant: CCOC(=O)CCc1ccc(Cl)nc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Temperature: 70 °C

Procedure:
To a mixture of ethyl 3-(2,6-dichloropyridin-3-yl)propanoate (170 mg, 0.685 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (344 mg, 0.685 mmol), XantPhos Biphenyl precatalyst (60.9 mg, 0.069 mmol), and cesium carbonate (670 mg, 2.056 mmol) was added 1,4-dioxane (5.7 mL) and H2O (1.2 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 70° C. for 16 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/Hexanes as eluent. 1H NMR δ (ppm) (CHCl3-d): 8.01˜7.96 (3H, m), 7.75 (1H, t, J=7.74 Hz), 7.69 (1H, s), 7.55 (1H, d, J=7.70 Hz), 7.27˜7.21 (2H, m) 5.91 (1H, br s), 4.19 (2H, q, J=7.12 Hz), 3.27˜3.20 (3H, m), 3.18˜3.12 (2H, m), 3.03 (3H, d, J=4.92 Hz), 2.90˜2.80 (3H, m), 2.77 (2H, t, J=7.51 Hz), 1.30 (3H, t, J=7.15 Hz). MS (M+H)+: 588.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:26][CH3:27]>C(OCC)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]\[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(/C=C\c3ccccc3)c2)ccc1O
Yield: 33.1 %

Procedure:
4-Hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide (150 mg) obtained in Example 36 is dissolved in ethyl acetate (10 ml), and thereto is added Lindlar catalyst (5% lead-poisoned palladium-calcium carbonate) (15 mg), and the mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (50 mg).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[CH:4]=1.[CH3:11][S:12]S(C)(=O)=O>C(O)C>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[S:12][CH3:11]
Reactant: CSS(C)(=O)=O
Reactant: Cc1cc(O)cc(=O)o1
Agent: [Na]
Solvent: CCO
Product: CSc1c(O)cc(C)oc1=O
Reaction time: 4 h

Procedure:
A mixture of 47.0 g. (0.317 mole) of the monosodium salt of 4-hydroxy-6 -methyl-2-pyrone and 40.0 g. (0.317 mole) of methyl methanethiolsulfonate in 700 ml. of 2B absolute ethanol was heated under reflux with stirring for four hours. The solvent was then removed by evaporation in vacuo, leaving a viscous semi-solid. The crude substance was washed with water and extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to dryness, leaving 24.8 g. of a yellow solid; which, when recrystallized from isopropanol gave 10.6 g. (20 percent) of the pure product m. 141.5°-143°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[CH:24]=2)=[CH:4][CH:3]=1.[OH:25]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[CH:24]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc2CO1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(Cl)cc3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chloro-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([F:6])[F:5].C([O-])([O-])=O.[K+].[K+].[SH:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].Cl>CN(C=O)C.CCCCCC.CC(=O)OCC.O>[F:5][C:4]([F:6])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][CH2:2][S:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: O=C(O)c1cccnc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Yield: 30 %

Procedure:
1.02 g (4.0 mmol) of 1-(3-bromo-1,1-difluoropropyl)-4-fluorobenzene (precursor VC005) and 1.67 g (12.0 mmol) of K2CO3 were added to a solution of 620 mg (4.0 mmol) of 2-mercapto-nicotinic acid in DMF (10 ml), and the mixture was heated for 2 h at 90° C. Dilution with water (20 ml) was then carried out, and the pH was adjusted to −2 with 6M hydrochloric acid. Extraction with EA (3×40 ml) was then carried out. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 1:4) of the residue yielded 400 mg (1.2 mmol, 31%) of 2-(3,3-difluoro-3-(4-fluorophenyl)propylthio)-nicotinic acid.