Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.59 g, 8.46 mmol), p-toluenesulfonyl chloride (1.93 g, 10.1 mmol) and triethylamine (TEA) (2.35 mL, 16.9 mmol) in CH2Cl2 (15 mL), dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) was added. As soon as the DMAP was added, the suspension became clear. The solution was then stirred at room temperature for 1 h. It was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (2.55 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of the product of Example 353E (16.1 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and ethanesulfonyl chloride was added (0.0036 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 40%). The sodium salt of the title compound was prepared by adding 1 N sodium hydroxide (0.029 mL, 0.0029 mmol) to a solution of the title compound (7.7 mg, 0.014 mmol) in water (0.4 mL) and stirring for thirty minutes. The reaction mixture was concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.46 (d, 2 H) 0.99 (m, 1 H) 1.19 (t, 3 H) 3.01 (q, 2 H) 4.23 (s, 2 H) 5.85 (t, J=6.62 Hz, 1 H) 6.79 (s, 1 H) 6.93 (t, J=7.54 Hz, 1 H) 7.35 (t, J=6.99 Hz, 2 H) 7.59 (d, J=8.09 Hz, 1 H) 7.95 (d, J=6.62 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36]C(C[AlH]CC(C)C)C.C[Zn]C>C1COCC1.CCOC(C)=O>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH3:36])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: CC(C)C[AlH]CC(C)C
Agent: C[Zn]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Yield: 744.4 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (112 mg, 0.180 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (7.33 mg, 8.98 μmol) in THF (5 ml) at 0° C. was added DIBAL-H (1.0 M solution in dichloromethane) (0.018 ml, 0.018 mmol), followed by dimethylzinc (1.0 M solution in heptane) (0.197 ml, 0.197 mmol), and the reaction mixture was stirred with heating at 60° C. for one hour. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (75 mg, 0.134 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 8.72-8.86 (m, 1H), 7.98 (s, 1H), 7.45 (dd, J=8.6, 1.4 Hz, 1H), 7.30-7.40 (m, 1H), 7.01 (s, 1H), 6.71 (d, 2H), 5.49 (s, 2H), 4.47 (d, 2H), 3.38 (t, 2 H), 2.25 (s, 3H), 0.75 (t, 2H), −0.09 (s, 9H
Reaction SMILES: [N:1]#CN.[Pb].C[NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.CN(C)C=O>C(#N)C>[CH3:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1[CH2:13][S:12][CH2:11][CH2:10][NH:9][C:7]([NH2:1])=[NH:6]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Agent: [Pb]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=N)N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"[(2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine, m.p. 139°-141°. (Found: C. 47.3; H, 6.6; N, 33.4; S, 12.6. C10N16N6S requires: C, 47.6; N, 6.4; N. 33.3; S, 12.7).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1ncccc1-c1cc[nH]c(=O)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1-c1ccn(CCCCCl)c(=O)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of 4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (199 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.38 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (160 μl, 1.38 mmol) was added and the mixture was stirred at room temperature for 1 hour and heated at 70° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 161 mg of the title compound that was used in the next step without further purification (54% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[O:14]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[OH:14][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(prop-2-en-1-yl)-2-benzofuran-1(3H)-one (13.5 g, 45.2 mmol) in 200 mL DCM/MeOH (V/V=1:1) was bubbled O3 at −78° C. for 30 min, and N2 was bubbled for another 15 min at −78° C. Then 20 mL of Me2S were added, and the mixture was stirred at r.t. overnight before concentrating to dryness. The residue was dissolved in MeOH (100 mL) and then cooled to 0° C. NaBH4 (5.90 g, 155 mmol) was added in portions. The resulting mixture was stirred at 0° C. for 1 hr, then quenched with citric acid (aq.) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with NaHCO3 (aq.) and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via silica column chromatography (EtOAc/Petrol Ether=1:5) to give 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:5]=1.[F:20][C:21]([F:25])([F:24])[CH2:22][OH:23]>CN(C=O)C>[CH:17]1([CH2:16][NH:15][C:6]2[N:5]=[C:4]([O:23][CH2:22][C:21]([F:25])([F:24])[F:20])[CH:14]=[CH:13][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:19][CH2:18]1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)nc1NCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(F)(F)F)nc1NCC1CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Sodium hydride was added at room temperature to a DMF solution of ethyl 6-chloro-2-[(cyclopropylmethyl)amino]nicotinate and 2,2,2-trifluoroethanol, followed by stirring at 80° C. for 20 hours. By post-treating the reaction liquid, ethyl 2-[(cyclopropylmethyl)amino]-6-(2,2,2-trifluoroethoxy)nicotinate was obtained.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[Cl:21].[BH4-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH:24][CH2:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:13])([F:1])[O:3][C:4]=3[CH:10]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Product: FC1(F)Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2O1

Procedure:
[2-(3,4-dichloro-phenyl)-ethyl]-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-amine was synthesized in analogy to the above procedure using 100 mg of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (0.54 mmol), 102 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.54 mmol) and 31 mg of sodium borohydride (0.81 mmol). The isolated colorless semisolid (98 mg, 51%) was used in the following step without further purification. MS (ISP) 360.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[CH2:11][CH:12]([CH3:13])[CH3:14])(=[O:26])=[O:25]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
To a stirred solution of (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (1.6 g, 7.36 mmol) in dichloromethane (15 mL) was added triethyl amine (2.052 mL, 14.73 mmol) at 0° C. and the solution was stirred for 5 min. To this mixture at 0° C. was added methanesulfonyl chloride (0.574 mL, 7.36 mmol) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated under reduced pressure to yield (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 5.75 mmol, 78% yield) as a yellow solid which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 1 H), 4.25 (m, 1 H), 4.16 (m, 1 H), 3.92 (m, 1 H), 3.05 (s, 3 H), 1.66 (m, 2 H), 1.56 (m, 10 H), 0.92 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH2:16])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:19][N:20]=[C:21]=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH:16][C:21]([NH:20][CH3:19])=[S:22])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Solvent: c1ccncc1
Product: CNC(=S)Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 100 °C
Yield: 58 %

Procedure:
A solution of obtained amine from Example 263 (150 mg, 0.542 mmol) in 5 mL of pyridine was treated with methyl isothiocyanate (198 mg, 2.71 mmol). The solution heated to 100° C. under a nitrogen atmosphere for 5 days. All volatiles were removed under reduced pressure. The resulting product was purified by flash column chromatography on silica gel eluting with chloroformn/NH4OH, affording 110 mg (58.1%) of the title compound.
Reaction SMILES: [O-][CH2:2]CCC.[K+].[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]4[C:28](=[C:29]([F:31])[CH:30]=3)[O:27][C:26](=[O:32])[CH2:25][CH2:24]4)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:31][C:29]1[CH:30]=[C:21]([CH:18]2[CH2:17][CH2:16][CH:15]([CH:12]3[CH2:11][CH2:10][CH:9]([CH:7]=[CH2:2])[CH2:14][CH2:13]3)[CH2:20][CH2:19]2)[CH:22]=[C:23]2[C:28]=1[O:27][C:26](=[O:32])[CH2:25][CH2:24]2
Reactant: O=CC1CCC(C2CCC(c3cc(F)c4c(c3)CCC(=O)O4)CC2)CC1
Reactant: CCCC[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(C2CCC(c3cc(F)c4c(c3)CCC(=O)O4)CC2)CC1
Temperature: -30 °C
Yield: 66 %

Procedure:
Methyltriphenylphosphonium bromide (3.5 g) was suspended in THF (30 ml), to which was then added potassium butoxide (1.2 g) with stirring while cooling at −30° C. After continuing the stirring at the same temperature for 30 minutes, a solution of 6-(4-(4-formylcyclohexyl)cyclohexyl)-8-fluoro-3,4-dihydrocoumarin (3.2 g) in THF (30 ml) was added dropwise to the reaction mixture. After completion of the dropwise addition, the temperature of the reaction mixture was raised to room temperature, and the resulting reaction mixture was added in ice water and extracted with toluene. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The resulting oily material was subjected to isolation and purification by silica gel column chromatography and recrystallized, thereby obtaining a titled compound (2.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CSc2cc(O)ccc21
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CSc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
To a solution of ethyl(6-hydroxy-2,3-dihydro-1-benzothiophen-3-yl)acetate (17.2 g) in DMF (300 mL) were added 2,4-dichlorobenzyl chloride (17.0 g) and K2CO3 (15.0 g) and the resulting solution was stirred at 20° C. for 72 h. The mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc) to give the title compound (19.6 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)[CH2:14][CH2:13]1.Br.Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>CC(N(C)C)=O>[CH3:10][N:11]([CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][N:26]=3)[N:23]=2)[CH2:14][CH2:13]1
Reactant: BrCc1cccnc1
Reactant: CNC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: Br
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccnc1)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 150 °C
Yield: 84.9 %

Procedure:
DIPEA (0.174 mL, 1.00 mmol) was added to N-methyl-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (100 mg, 0.34 mmol) and 3-(bromomethyl)pyridine hydrobromide (127 mg, 0.50 mmol) in DMA (2 mL) and the mixture was sealed into a microwave tube. The reaction was heated to 150° C. for 15 minutes in the microwave reactor and cooled to ambient temperature. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-methyl-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (113 mg, 78%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:21][CH2:22][CH3:23])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Reactant: CCC[Mg]Cl
Solvent: CCOCC
Product: CCCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (1.52 g, 5.26 mmol) in absolute Et2O (52 mL), under argon, was added a solution of propylmagnesium chloride (2.0 M in Et2O, 5.3 mL, 11 mmol) over 5 min at 20° C. An immediate crystallisation occurred along with an exotherm. The reaction mixture was cooled to 20° C. using an ice/water bath. The reaction mixture was stirred at r.t. for 1 h then poured onto sat. aq NH4Cl and EtOAc. The pH was adjusted to 7 with sat. aq NH4Cl and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica gel, hexanes/EtOAc (1:0→7:3)) to give product as colorless crystals (409 mg, 23%). m.p.: 97-101° C., ESI-MS: m/z 334 [M+H]+, m/z 332 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([C:22]([OH:24])=[O:23])[O:19][C:18]3=[O:25])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:28]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:21][CH:20]([C:22]([OH:24])=[O:23])[O:19][C:18]3=[O:25])=[CH:15][CH:16]=2)=[O:8])=[CH:26][CH:27]=1)(=[S:28])[NH2:2]
Reactant: S
Reactant: N#Cc1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1
Product: NC(=S)c1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1

Procedure:
In analogy to Example 10, reaction of 3-[4-(4-cyanobenzamidomethyl)phenyl]-2-oxo-5-oxazolidinylcarboxylic acid with hydrogen sulfide gives 3-[4-(4-thiocarbamoylbenzamidomethyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid, m.p. 105°-110°.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1)=[O:4]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=C(F)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 10.7 g (0.09 mol) of 4-cyanophenol and 9.1 g (0.09 mol) of triethylamine in 150 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-hexane. 11.2 g (65% of theory) of 4-cyanophenyl α-fluoroacrylate were obtained, melting point 78° to 79° C.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1(C)[O:12]C(=O)C[C:9](=O)[O:8]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][CH2:2][C:3](=[O:4])[CH2:6][C:7]([O:8][CH3:9])=[O:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CF
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
Fluoroacetyl chloride (7.1 g, 73 mmoles) was added dropwise to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.65 g, 74 mmoles) and pyridine (16.85 ml, 210 mmoles) in methylene chloride (75 ml) keeping the temperature below 10°. After stirring for 16 hours at room temperature the solution was diluted with methylene chloride (100 ml) and then washed with 1N hydrochloric acid (200 ml) and water (100 ml). The organic extract was dried (Na2SO4) and the solvent removed in vacuo. The residue was dissolved in methanol (150 ml) and the solution heated at reflux for 2.5 hours. Removal of the solvent followed by distillation at 60°-80° (bath temp)/14 mm Hg gave methyl 4-fluoro-3-oxobutanoate (6.4 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH:29]=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH2:33]([N:35]([CH2:36][CH3:37])[CH2:29][CH2:28][N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:31])([F:32])[F:1])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1)[CH3:34]
Reactant: CCNCC
Reactant: O=CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 40 °C

Procedure:
To a reaction vial charged with 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol 150 (0.250 g, 0.540 mmol) was added 4 mL DCM to give a slurry. Next, Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 0.2522 g, 0.594 mmol) was added portion-wise and the reaction mixture was stirred at room temperature with LCMS monitor. Full conversion was seen after 30 minutes reaction time. The reaction mixture was diluted with water to give a white precipitate. This solid was collected by vacuum filtration, washed with EtOAc and dried on high vacuum to give the intermediate aldehyde, 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanal. To a suspension of the aldehyde (0.160 g, 0.347 mmol) and diethylamine (0.127 g, 1.74 mmol) in 1.0 ml of DCM was added acetic acid (0.0198 mL, 0.347 mmol) and the reaction mixture was heated at 40 C for 1 hour. Finally sodium cyanoborohydride (0.0350 g, 0.556 mmol) was added in portions. The reaction mixture was heated at 40° C. for 45 minutes with complete conversion to product as determined by LCMS. The cooled reaction mixture was diluted with DCM, washed with water and saline, and concentrated to a solid which was purified by RP-HPLC to give 484. MS: (ESI+)=518.2