Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=O.COC(=O)CCCCCCC1C(=O)CCC1C=O.P(=O)([O-])[O:48][CH2:49][C:50]1(OCC[O:58]1)CCCCC(C)C.[H-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.O.C(O)CO.C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]23[O:26][CH2:25][CH2:24][O:23][C:18]2([O:48][CH2:49][CH2:50][O:58]3)[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)CCCCC1(CO[PH](=O)[O-])OCCO1
Reactant: CCCCCC1(C=C[C@H]2CCC(=O)[C@@H]2CCCCCCC(=O)OC)OCCO1
Agent: COC(=O)CCCCCCC1C(=O)CCC1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Solvent: c1ccccc1
Solvent: OCCO
Solvent: CCOCC
Product: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)OC)OCCO2

Procedure:
A mixture of 2 g of 9-oxo-15,15-ethylenedioxy-13-prostenoic acid methyl ester (obtainable from 7-(2-formyl-5-oxo-cyclopentyl)-heptanoic acid methyl ester by reaction with dimethyl-2,2-ethylenedioxyheptyl phosphonate in the presence of NaH), 100 ml of dry benzene, 10 ml of ethylene glycol and 0.2 g of p-toluenesulphonic acid is boiled for 12 hours on a water separator. After cooling, the mixture is diluted with 100 ml of diethyl ether and washed with aqueous NaHCO3 solution and water. The organic phase is dried over Na2SO4 and the solvent distilled. After chromatographic purification of the residue (silica gel/diisopropyl ether), 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid methyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a beige solid: ES-MS: 368.0 [M+H]+; single peak at tR=9.85 min (System 2); Rf=0.36 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:21][C:17]1[NH:29][N:28]([CH2:27][C:26]2[CH:25]=[C:24]([Cl:23])[CH:32]=[C:31]([Cl:33])[CH:30]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)cc(Cl)c2)[nH]1
Reaction time: 8 h

Procedure:
After adding 1 g of p-toluenesulphonic acid to a solution of 49.6 g of β-amino-β-ethoxyacrylic acid ethyl ester in "ml of ethanol, 59 g of 3,5-dichlorobenzylhydrazine were added dropwise under nitrogen. The solution was left to stand overnight and the solids which precipitated melted at 175°-176° after recrystallisation from ethanol. Yield: 40 g (48%) of the compound identified above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D149) (260 mg) in isopropanol (7 mL) and water (7 mL) was added NaOH (5.5 mL, 0.5 M aq) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours, and the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over sodium sulphate. The organic solution was concentrated and purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoic acid (E107) (174 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 2.57 (2H, t), 2.92 (2H, t), 5.40 (1H, m), 7.03 (1H, m), 7.22 (1H, d), 7.74 (1H, m), 8.82 (1H, d), 9.08 (1H, d), 11.04 (1H, s), 12.08 (1H, s). MS (ES): C21H18ClFN4O4 requires 444; found 445.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH2:22]O)[CH:10]=[CH:11][C:12]=2[C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:22][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:8]=1
Reactant: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccc(CCl)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol 66.12C (34.5 mg, 105 μmol) was added DCM (1.1 mL) and DMF (8.2 μL, 105 μmol) followed by thionyl chloride (15 μL, 211 μmol) in an ice bath. The reaction was then stirred at room temperature for 1 hour. The reaction was concentrated and directly purified on silica gel to afford 4-(4-(chloromethyl)-2-(5,5-dimethylcyclopent-1-enyl)phenyl)-5-fluoro-2-methoxypyridine 66.12D (36 mg) as an oil (99%).
Reaction SMILES: COC1N=CC(N2CCC([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)CC2)=CC=1.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][CH:47]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=3)[CH2:16]2)[CH2:46][CH2:45]1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: O=C1CCN(c2ccccc2F)CC1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccccc3F)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(2-fluorophenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.86-1.92 (m, 2H), 2.03-2.22 (m, 3H), 2.41-2.48 (m, 1H), 2.75 (t, J=11.1 Hz, 2H), 3.16-3.26 (m, 1H), 3.36-3.44 (m, 2H), 3.54-3.66 (m, 4H), 4.04 (s, 2H), 4.51-4.55 (m, 1H), 6.96-7.10 (m, 4H), 7.70 (t, J=7.6 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 8.22 (s, 1H), 8.36 (s, 2H). MS m/z: 493 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][O:24]C4CCCCO4)=[O:22])=[N:17][CH:18]=3)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:33]>CO>[ClH:1].[ClH:33].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][OH:24])=[O:22])=[N:17][CH:18]=3)[CH2:8]2)=[CH:31][CH:32]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.43 g) in methanol (16 mL) was added hydrogen chloride in methanol (6.24 mL). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride (1.40 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24][S-:25].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([S:25][CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (200 mg, 0.60 mmol) and sodium thiomethoxide (126 mg, 1.80 mmol) in DMF (5 mL) is heated at 70° C. overnight. After cooling, water (20 mL) is added and the resulting mixture is extracted with EtOAc. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].I[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1
Reactant: C#CCOc1ccc(CCNC(=O)[C@@H](NS(=O)(=O)CC)C(C)C)cc1OC
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2cccs2)c(OC)c1)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2 g of (S)-2-(ethylsulfonyl-amino)-3-methyl-butyric acid N-[2-(3-methoxy-4-propargyloxy-phenyl)-ethyl]-amide, 2.1 g of 2-iodothiophene and 2 ml of triethylamine are heated to 40° C. in 50 ml of chloroform. 70 mg of bis(triphenylphosphine)palladium(II) chloride and 32 mg of copper(I) iodide are added thereto. The reaction mixture is stirred for one hour at 60° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1([CH3:43])[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:33][C:34]([C:36]2[NH:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=2)=[O:35])=[CH:11][CH2:10]1.CCN(CC)CC.Br[CH2:52][C:53]([O:55]CC)=[O:54].[OH-].[K+]>C(Cl)Cl.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:41]([C:38]1[NH:37][C:36]([C:34]([NH:33][C:16]2[CH:17]=[CH:18][C:19]([C:21]3([N:27]4[CH2:32][CH2:31][N:30]([CH2:52][C:53]([OH:55])=[O:54])[CH2:29][CH2:28]4)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:20][C:15]=2[C:12]2[CH2:13][CH2:14][C:9]([CH3:43])([CH3:8])[CH2:10][CH:11]=2)=[O:35])=[N:40][CH:39]=1)#[N:42]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC=C(c2cc(C3(N4CCNCC4)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(N4CCN(CC(=O)O)CC4)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.5 %

Procedure:
To a solution of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-piperazin-1-yl-tetrahydro-pyran-4-yl)-phenyl]-amide trifluoroacetic acid salt (22 mg, 0.036 mmol) (prepared in Example 1, step (h)) in DCM (0.3 mL) was added NEt3 (0.015 mL, 0.11 mmol) and ethyl bromoacetate (0.0044 mL, 0.040 mmol) and the mixture stirred for 10 h at RT. The mixture was concentrated and the residue dissolved in 1 mL of EtOH and 7N KOH (0.031 mL, 0.22 mmol) was added and the mixture stirred for 3 h at RT. The mixture was diluted with 5 mL of H2O, the pH adjusted to 2, and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 20-50% CH3CN in 0.1% TFA/H2O over 10 min to give 22 mg (91%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.41 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 5.81 (m, 1H), 4.00-3.92 (m, 2H), 3.70 (s, 2H), 3.42-3.34 (m, 2H), 3.26-2.86 (m, 8H), 2.70-2.58 (m, 2H), 2.38-2.29 (m, 2H), 2.23-2.05 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.10 (s, 6H). Mass spectrum (APCI, m/z): Calcd. for C30H38N6O4, 545.3 (M−H). found 545.3.
Reaction SMILES: CO[C:3]([C:5]1[C:9]([S:10]([CH3:12])=[O:11])=[C:8]([NH2:13])[N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:6]=1)=[NH:4].Cl.[O:27]([NH2:29])[CH3:28]>CO>[NH2:13][C:8]1[N:7]([C:14]2[C:15]([Cl:25])=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][C:19]=2[Cl:20])[N:6]=[C:5]([C:3](=[NH:4])[NH:29][O:27][CH3:28])[C:9]=1[S:10]([CH3:12])=[O:11]
Reactant: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 4 h
Yield: 27.2 %

Procedure:
To a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (1.0 g) in anhydrous methanol was added anhydrous methoxylamine hydrochloride (0.2 g). After 4 hours at 20° C., the mixture was evaporated and dichloromethane and water added. The organic layer was dried (MgSO4), evaporated and chromatographed on a florisil column, eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide(0.28 g),m.p. 140-145° C.Compound 49. By proceeding in a similar manner the following compounds were prepared:5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p. 169-170° C. Compound 41; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-hydroxy-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidamide, m.p. 222-224° C. Compound 40.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30].[OH-].[Na+]>CN(C=O)C.CO>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
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.[CH3:15][C:16]1[NH:17][C:18](=[O:32])[N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[N: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:17]1[C:16]([CH3:15])=[N:20][N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=2)[C:18]1=[O:32])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(=O)[nH]1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(=O)n1[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 14.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 0.52 g of 5-methyl-2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 0.13 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5-methyl-2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone was obtained as a colorless viscous oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNCCN(C)C
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)CCN(C)C)s2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1 eq), is dissolved in anhydrous DCM (50 ml). The reaction is put under nitrogen. N,N,N′-Trimethyl-ethane-1,2-diamine (0.58 ml; 5.94 mmol; 3 eq) and triethylamine (0.83 ml; 5.94 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. The reaction mixture is washed with NH4Cl sat. (2 times), water (3 times), brine, and dried over MgSO4. After evaporation of the solvents, the crude product is suspended in ACN, filtered and dried under vacuum, affording Compound (5) as a beige solid (309 mg; 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15]2[NH:24][C:18]3=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[F:25]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]2[NH:24][C:18]3=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]3[CH:16]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[F:25]
Reactant: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1F
Temperature: 50 °C
Yield: 99.2 %

Procedure:
A mixture of 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-benzoic acid methyl ester (660 mg, 1.85 mmol) and 10% palladium on activated carbon (198 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butyl]-benzoic acid methyl ester (658 mg, 97%): LC/MS m/e calcd for C20H20F2N2O2 [M+H]+ 385.43, observed 384.9.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:21])[C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(=O)C>[CH3:21][N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:10]=2[C:9]1=[O:20]
Reactant: CN(C(=O)c1ccccc1C(F)(F)F)c1cccnc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c2c(C(F)(F)F)cccc2c2ncccc21
Temperature: 25 °C
Yield: 94 %

Procedure:
4.5 g N-(2-chloro-pyridin-3-yl)-N-methyl-2-trifluoromethyl-benzamide (14.3 mmol), 2.2 g tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) (1.4 mmol), 9.7 g sodium carbonate (Na2CO3) (71.5 mmol), and 50 mL N,N-dimethyl acetamide (DMA) were added in a flask and reacted for 18 hr under nitrogen. After cooling to room temperature, the reaction was quenched by water. After filtration, concentration, and purification by column, 3.73 light yellow solid was obtained, with a yield of 94%.
Reaction SMILES: [CH2:1]1[C:5]2(CCCC3(CCCC3)[C:6]2=[O:15])[CH2:4]CC1.C1C2(CCCCC2=O)CCC1.C[Mg]Cl.[Cl-].[NH4+].[CH3:32][C:33]1([OH:47])[C:42]2([CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][C:34]21[CH2:38][CH2:37][CH2:36][CH2:35]2>O1CCCC1>[C:6]([O:47][C:33]1([CH3:32])[C:34]2([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:39][CH2:40][CH2:41][C:42]21[CH2:43][CH2:44][CH2:45][CH2:46]2)(=[O:15])[C:5]([CH3:1])=[CH2:4]
Reactant: O=C1C2(CCCC2)CCCC12CCCC2
Reactant: CC1(O)C2(CCCC2)CCCC12CCCC2
Agent: C[Mg]Cl
Agent: O=C1CCCCC12CCCC2
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)C2(CCCC2)CCCC12CCCC2
Temperature: 50 °C
Yield: 97 %

Procedure:
With stirring under nitrogen atmosphere at 50° C., a mixture of 44.3 g of dispiro[4.1.4.3]tetradecan-6-one (which had been synthesized from spiro[4.5]decan-6-one by a method as described in A. P. Krapcho, Synthesis, 1974, p 383 and references cited therein) and 50 ml of tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 0.43 mol methylmagnesium chloride (which had been prepared from 10.45 g of metallic magnesium, 150 ml of tetrahydrofuran and chloromethane), during which time the temperature was kept below 60° C. The reaction mixture was cooled to room temperature, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent vacuum distillation, there was obtained 46.3 g (yield 97%) of the target compound, 6-methyldispiro[4.1.4.3]-tetradecan-6-ol.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (4.50 g, 27.3 mmol) and triethylamine (11 mL, 81 mmol) in 200 mL dichloromethane at 0° C. was added dropwise a solution of 4-chlorobenzenesulfonyl chloride (5.69 g, 27.1 mmol) in 25 mL dichloromethane. The reaction was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate and water. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 0 to 100% ethyl acetate in hexane to give 4-chloro-N-(trans-2-hydroxymethylcyclohexyl)benzenesulfonamide (6.5 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (m, 2H), 7.48 (m, 2H), 5.21 (d, J=7.81 Hz, 1H), 3.76-3.95 (m, 1H), 3.37 (ddd, J=11.14, 7.11, 3.40 Hz, 1H), 2.87-3.10 (m, 1H), 2.34-2.55 (m, 1 H), 1.47-1.70 (m, 4H), 1.19-1.40 (m, 2H), 0.94-1.19 (m, 3H). LC/MS R.T.=2.73 min; [M+H]+=304. HRMS [M+H]+ calc'd 304.0774, found 304.0768.