Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][C:10](Br)=[C:9]([O:18][CH3:19])[CH:8]=2)=[O:3].[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][C:10]([CH:20]=[CH2:21])=[C:9]([O:18][CH3:19])[CH:8]=2)=[O:3]
Reactant: COc1cc2[nH]c(NC(N)=O)c(C(N)=O)c2cc1Br
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1cc2c(C(N)=O)c(NC(N)=O)[nH]c2cc1OC
Temperature: 110 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
A suspension of 2-aminocarbonylamino-5-bromo-6-methoxyindole-3-carboxamide (Compound No.7-1, 86 mg, 0.26 mmol), vinylboronic acid pinacol ester (121 μL, 0.40 mmol), tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.027 mmol) and sodium hydrogen carbonate (56 mg, 0.66 mmol) in 1,4-dioxane-water solution (3:1, 15 mL) was stirred overnight at 110° C. under argon atmosphere. After cooling, ethyl acetate (20 mL) and brine (15 mL) were added and separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4 mg) as a dark green solid (6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12](Br)=[O:13].O=C1NC2C=C(C#N)C=CC=2OC1>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Br)CBr
Agent: N#Cc1ccc2c(c1)NC(=O)CO2
Product: O=C1COc2ccc(Br)cc2N1

Procedure:
2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5 mmol) were reacted according to the procedure for Intermediate 60 to afford product as a solid, 2.1 g (85%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][N:25]([S:42]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)(=[O:44])=[O:43])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCN(S(=O)(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 6-benzenesulfonyl-1-(4-methyl-piperidine-4-yl)1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (60.0 mg, 0.15 mmol) was dissolved in DCM, triethylamine (28.0 μL, 0.20 mmol) was added followed by pyridine-3-sulfonyl chloride (32.0 mg, 0.18 mmol) and the reaction stirred at room temperature for 16 hr. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 74 mg (91%) of 6-benzenesulfonyl-1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method H, ESI): RT=3.52 min, m+H=538.3; 1H NMR (400 MHz, DMSO): δ 9.21 (s, 1H), 8.84 (m, 2H), 8.19 (m, 3H), 8.10 (m, 1H), 7.74 (d, 1H), 7.62 (m, 3H), 7.31 (d, 1H), 3.45 (d, 2H), 2.82-2.67 (m, 4H), 2.33 (m, 2H), 1.69 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](N[C@H](C(O)=O)C)[CH:5]=[CH:6][C:7]=1[OH:8].CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[NH2:30][C@H:31]([C:40]([OH:42])=[O:41])[CH2:32]C1C=CC(O)=CC=1>>[O:41]=[C:40]([C@H:31]([CH2:32][C:4]1[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=1)[NH2:30])[OH:42]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C[C@H](Nc1ccc(O)c(O)c1)C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reaction time: 6 h

Procedure:
After confirming stationary phase, DOPA (3,4-dihydroxyphenyl-L-alanine) was introduced to the concentration of 1 mM in the medium. After introducing DOPA, inducer IPTG(isopropyl-β-D-thiogalactopyranoside, 1 mM) was added to induce the expression of the above proteins. After adding IPTG, culture was conducted at 37° C. for additional 6 hours. For a positive control, tyrosine was introduced to the concentration of 1 mM instead of DOPA, and the expression of the proteins was induced with IPTG, and for a negative control, nothing was introduced. After culture, the cells were centrifuged at 4000 rpm for 10 minutes, and then, supernatant was removed, and the cells were recovered.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH:5]=[CH:6][O:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[CH:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][CH:6]=[CH:5][C:4]4[N:10]([CH:1]=[CH:2][CH:3]=4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: Nc1ccc2c(c1)-n1cccc1C=CO2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2cccc2C=CO3)ncc1Cl

Procedure:
Title compound was prepared from 6-Oxa-10b-aza-benz[e]azulen-9-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Product was obtained as a tan solid. LCMS 479.10 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 9.35 (s, 1H), 8.52 (bd, 1H), 8.20 (s, 1H), 7.46 (m, 2H), 7.39-7.32 (m, 3H), 7.26 (s, 1H), 7.03 (s, 2H), 6.88 (d, J=9.0 Hz, 1H), 6.54 (d, J=5.9 Hz, 1H), 6.29 (m, 1H), 6.21 (s, 1H), 6.06 (d, J=5.9 Hz, 1H), 2.73 (d, J=4.3 Hz, 3H).
Reaction SMILES: O[C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][C:2]1([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ccc(C2(O)c3ccccc3C(=O)c3ccccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C2(Cl)c3ccccc3C(=O)c3ccccc32)cc1
Yield: 81.1 %

Procedure:
42 g (0.14 mol) of 9,10-dihydro-9-hydroxy-9-(4-methylphenyl)-10-oxo-anthracene and 20.2 g (107 mol) of thionyl chloride in 500 ml of methylene chloride are heated under reflux for 8 hours. Thereafter, the solvent is distilled off in vacuo and the solid which remains is recrystallised from petroleum ether. 36.2 g (70.9% of theory) of 9-chloro-9,10-dihydro-9-(4-methylphenyl)-10-oxo-anthracene of melting point 136°-140° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=[C:37]4[C:41](=[CH:42][C:32]2=3)[CH2:40][CH2:39][O:38]4)C1=O.BrCC1CCOCC1.BrCC1CCCCO1>>[O:38]1[CH2:39][CH2:40][CH:41]([CH2:37][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH2:42][CH2:32]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: BrCC1CCOCC1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 129-131° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.9, 7.9, 1.3 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.87 (d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz, 1H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 4.03-3.94 (m, 2H), 3.74 (dd, J=13.8, 7.7 Hz, 1H), 3.55 (dd, J=13.8, 7.1 Hz, 1H), 3.42-3.30 (m, 2H), 2.20-2.03 (m, 1H), 1.66-1.56 (m, 2H), 1.53-1.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.7, 142.8, 138.4, 132.5, 128.9, 124.2, 123.4, 121.1, 111.5, 108.7, 99.5, 80.4, 67.6, 67.5, 64.6, 64.0, 58.1, 46.2, 34.0, 30.93, 30.86; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.15; H, 5.92; N, 3.20.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C)C=O.S(Cl)(Cl)=O.[CH2:20]([C:22](=[N:25]O)[CH2:23][CH3:24])[CH3:21]>C(Cl)(Cl)Cl.O.N1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:8]([O:10][N:25]=[C:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)=NO
Reactant: O=C(O)c1ncccc1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(CC)=NOC(=O)c1ncccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 7.0 g of 3 hydroxypicolinic acid, 10 ml of N,N-dimethylformamide was added, and then 5.9 g of thionyl chloride was dropwise added thereto at a temperature of at most 10° C. The mixture was stirred at 0° C. for 30 minutes. To the reaction solution, 30 ml of chloroform was added, and the mixture was further stirred at 0° C. for 15 minutes. Then, a solution prepared by dissolving 5.0 g of diethyl ketone oxime in 50 ml of chloroform was dropwise added thereto at 0° C., and the mixture was stirred for 30 minutes. Then, 7.9 g of pyridine was dropwise added thereto. Then, the reaction solution was stirred at 0° C. for one hour and at room temperature for one day. The reaction solution was poured into water and extracted with ethyl acetate. Then, the extract was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography by using as a developing solvent a mixture of hexane/ethyl ether to obtain 6.5 g of the above identified compound as slightly yellow transparent viscous liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24](=[O:40])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[F:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:24]([C@H:14]3[NH:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13]3)=[O:40])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Step (c) A flask was charged with (2S,4R)-tert-butyl 4-(benzyloxycarbonylamino)-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate and hydrogen chloride (4N in dioxane, 20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with saturated sodium bicarbonate (aq., 100 mL). The mixture was extracted with ethyl acetate (30 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with ethyl acetate to provide benzyl (3R,5S)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.20 g, 2.67 mmol, 30% yield over 4 steps) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=3[CH3:27])[C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>O1CCOCC1.C1COCC1.CN(C=O)C.O.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=3[CH3:27])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc([N+](=O)[O-])ccc3C)csc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-chloro-3-(2-methyl-5-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (815.2 mg, 2.00 mmol) (from Example 22 supra) in 1,4-dioxane (40 mL), THF (20 mL) and DMF (20 mL) was added NH4Cl (1.59 mg, 29.6 mmol) in water (12 mL). Zinc powder (948 mg, 14.5 mmol) was then added in several portions and the reaction was stirred at room temperature for a total of 4 hours. The resulting mixture was diluted with ethyl acetate (800 mL), washed with water (100 mL) and then brine (100 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 95/5) to give 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 584 mg, 85%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 was dissolved in N,N-dimethylformamide (3 ml). 1-Methylpiperazine (36 mg, 0.36 mmol), EDC (90 mg, 0.47 mmol) and HOBT (75 mg, 0.55 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (78 mg, Yield 64%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.S(Cl)(Cl)=O.Cl>CO>[CH2:17]([O:16][C:14]([N:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C1CN(C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: C=C1CNN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of crude 4-methylenepyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 8, (30 g) in methanol (300 mL) is added thionyl chloride dropwise at 0° C. The reaction is warmed to room temperature and stirred an additional 18 hours. Concentration of the reaction in vacuo affords a yellow oil which crystallizes upon standing to provide 23 g (97% yield) of the desired product as the HCl salt.
Reaction SMILES: C(OC(C=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=O)C.I([O-])(=O)(=O)=[O:19].[Na+].CN1CCOCC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)O)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Solvent: O
Product: O=Cc1ccc(CC(=O)O)cc1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a stirred solution of the title compound of Example 1 (46.9 g, 200 mmol) in dioxane (500 mL) and water (500 mL) was added osmium tetroxide (0.5 g, 4% in water), followed by sodium periodate (85.56 g, 400 mmol). The reaction mixture was monitored by HPLC, stirred for 1 hour and N-methylmorpholine (1.0 g) was added, followed by additional osmium tetroxide (1.0 g) after another 16 hours. After 4 hours stirring at room temperature, additional sodium periodate (40 g) was added, the reaction stirred for 21 hours, filtered, and the filter cake washed with ethyl acetate (500 mL). The phases were separated, the aqueous layer extracted with ethyl acetate (500 mL), the remaining aqueous layer acidified with hydrochloric acid (30 mL), extracted with ethyl acetate (500 mL), and the combined organic phases washed with water (500 mL), saturated sodium chloride solution (250 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The wet solid was triturated with methyl tert-butyl ether (50 mL) and to the resulting slurry was added pentane (100 mL). The slurry was filtered, the solid product was washed with pentane (2×25 mL) and dried to give the title compound (12.4 g, 38%). HPLC: 2.19 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). 1H NMR (d6-DMSO): δ 9.99 (s, 1H), 7.85-7.87 (d, 2H), 7.49-7.51 (d, 2H); 3.72 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:20])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:7][CH2:6]1.[CH2:32]([NH:35][CH3:36])[CH:33]=[CH2:34]>CN(C)C(=O)C.CCOCC>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19](=[O:20])[N:2]([CH2:3][CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][N:35]([CH2:32][CH:33]=[CH2:34])[CH3:36])[CH2:7][CH2:6]2)[CH3:1])=[CH:23][CH:24]=1
Reactant: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)CCC[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of 200 mg (0.43 mmol) trans-methanesulfonic acid 3-(4-{2-[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-ethyl}-cyclohexyl)-propyl ester and 0.204 ml (2.15 mmol) of allyl methyl amine in 2 ml of N,N-dimethylacetamide was stirred over night at 60° C. The reaction mixture was then taken up in ether and the ether phases were washed with water. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and the residue then chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and 1N ammonia in methanol as the eluent giving 124 mg (65.5%) trans-(2-{4-[3-(allyl-methyl-amino)-propyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 441 (MH+).
Reaction SMILES: CI.S([O:8][CH3:9])(OC)(=O)=O.[C:10]12[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:15][C:14](=O)[O:13][C:11]2=[O:12]>>[CH3:14][N:15]1[C:9](=[O:8])[O:13][C:11](=[O:12])[C:10]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:16]12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COS(=O)(=O)OC
Solvent: CI
Product: Cn1c(=O)oc(=O)c2ccccc21

Procedure:
N-methylation could be achieved by adding an alkylation agent. Preferably methyl iodide or dimethyl sulfate in a molar ratio, relative to isatoic anhydride, from 1 to 5, preferably 1.5, at a temperature from 10-40° C. In the case of a methylating agent, the intermediate N-methylisatoic anhydride could be isolated by filtration as a colourless crystalline compound by adding 2 parts of water to the reaction mixture. Identification was established by compare HPLC chromatograms with authentic material (supplied by Aldrich).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:37])([F:36])[CH2:24][C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([CH2:24][C:23]([F:37])([F:22])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 41 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 41%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>C(N(CC)CC)C.CN(C)C=O.O.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (6.96 g, crude from Preparation A1) in triethylamine (30 ml) and dimethylformamide (6 ml) at room temperature was added trimethylsilylacetylene (3 ml), cuprous iodide (150 mg) and bis(triphenylphosphine)palladium(II) chloride (300 mg). The mixture was heated at 50-60° C. for one hour, trimethylsilylacetylene (0.3 ml) was then added and stirring and heating continued for a further period of 30 minutes. The cooled reaction mixture was diluted with water (250 ml) extracted with ether (250 ml). The organic layer was separated (aided by the addition of brine). The aqueous layer was re-extracted with ether (250 ml). The combined ether extracts were dried (MgSO4) and evaporated to give the crude product as a gum (4.67 g).