Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(NC(C)C)(C)C>CN(C=O)C.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>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:20])=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:11]=3)[C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]2=3)[CH2:14][CH2:13]1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Reactant: C#Cc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]sc2c1c(=O)c1cc(F)c(C#Cc3ccccn3)cc1n2C1CC1
Temperature: 90 °C

Procedure:
Pd (PPh3)4 (4.5 mg) is added to a stirred solution of 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (23 mg, 0.065 mmole) in DMF (1 mL), followed by the addition of 2-ethynylpyridine (2 equivalents, 0.13 mmole) and diisopropyl amine (0.15 mL.) under argon at room temperature. The reaction tube is sealed and then stirred in a microwave (100 W, 90° C.) until complete as monitored by LC/MS. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is dissolved in a mixture of DMF: CHCl3: MeOH (1:8:1) and precipitated by adding diethyl ether (1-2 ml). This process is repeated three to five times. The resulting solid, 9-cyclopropyl-6-fluoro-7-(2-(pyridin-2-yl)ethynyl) isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione, is washed with water to remove salt. The product is dried and analyzed. HPLC may be needed to obtain adequately pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8](Br)[CH2:7]1)=[O:5])[CH3:2].[C:14]([NH2:20])([NH2:19])=[N:15][C:16]([NH2:18])=[S:17]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[N:18]=[C:16]([NH:15][C:14]([NH2:20])=[NH:19])[S:17][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: NC(=S)N=C(N)N
Product: CCOC(=O)C1CCc2nc(NC(=N)N)sc2C1

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-4-oxo-cyclohexane carboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to form the title compound.
Reaction SMILES: [NH:1]1[CH:5]([C:6](O)=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]1[CH:16]=C[CH:14]=[CH:13][C:12]=1[O:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>C(Cl)Cl.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:6]([CH:5]2[NH:1][C:2](=[O:9])[CH2:3][CH2:4]2)=[CH:10][C:11]=1[CH3:16]
Reactant: COc1ccccc1C
Reactant: O=C1CCC(C(=O)O)N1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CCC(=O)N2)cc1C
Temperature: 100 °C
Yield: 55.9 %

Procedure:
2-Pyrrolidone-5-carboxylic acid (2.0 g, 15.5 mmol) and 2-methylanisole (2.1 mL, 17.0 mmol) were added to a mixture of 1.0 g (3.52 mmol) of phosphorous pentoxide and 6.7 mL methanesulfonic acid. The mixture was heated at 100° C. for 2 hr, cooled down to rt, and poured into a mixture of H2O and CH2Cl2. The aqueous layer was separated, and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, washed with sat'd NaHCO3, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 4:1 v/v EtOAc/hexanes as the eluant afforded 1.78 g (56%) of the title compound: 1H NMR δ 1.88-1.97 (m, 1H), 2.21 (s, 3H), 2.35-2.54 (m, 3H), 3.81 (s, 3H), 4.66 (t, J=7.1, 1H), 6.53 (br. s, 1H), 6.79 (d, J=8.6, 1H), 7.05-7.09 (m, 2H).
Reaction SMILES: Cl.C(=[N:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[O:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:21]=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[NH2:15][C:16]1[CH:17]=[C:18]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[O:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:21]=1
Reactant: Cc1cc(N=C(c2ccccc2)c2ccccc2)cc(Oc2cc(NC(=O)C3CC3)ncn2)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(N)cc(Oc2cc(NC(=O)C3CC3)ncn2)c1
Yield: 80.9 %

Procedure:
Add 1M HCl aqueous solution (10 mL) to a solution of the imine obtained in Step 3 (450 mg, 1.0 mmol) in THF (10 mL), stir the reaction at room temperature for 1 hr. Basicify with saturated NaHCO3 solution, extract with EtOAc (30 mL×2). Combine the organic layers, dry over anhydrous Na2SO4. Concentration and purification by chromatography (silica gel, EtOAc:PE=1:1) afford the title compound (230 mg, 80.8%). MS: (M+1): 285.2.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@@H:31]([CH2:36][OH:37])[CH2:32][CH:33]([CH3:35])[CH3:34]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:36][OH:37])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CN[C@@H](CO)CC(C)C
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)C[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (1.5 g, 4.86 mmol), DIPEA (691 mg, 5.35 mmol) and (R)—N-methylleucinol (956 mg, 7.29 mmol) were mixed in NMP (7.5 mL). The resulting solution was stirred at 110° C. under a nitrogen atmosphere for 2 days. After cooling to room temperature the reaction mixture was poured onto ice. The resulting yellow precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash column chromatography on silica (DCM:EtOAc 50:50 to 0:100) to give 1.42 g (72% yield) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[O:5][C:6]=1[Br:7].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:8]([C:4]1[O:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Br)c(Br)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of the product of Step 1 (0.1 mol) in dichloromethane (300 ml) was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (11.7 g, 0.12 mol) followed by triethylamine (36 ml, 0.36 mol). The mixture was allowed to warm to room temperature and stirred for 30 minutes The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. After separation of the layers, the organic phase was washed sequentially with 2M hydrochloric acid, water and brine, dried and concentrated in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1:1) to give the title compound (30.1 g, 96%); 1H NMR (CDCl3) 7.12 (1H, s), 3.78 (3H, s), 3.31 (3H, s).
Reaction SMILES: [Br:1][C:2](Br)(Br)[F:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=O)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]>COCCOC.O1CCCC1>[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=[C:2]([F:3])[Br:1])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: FC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=C(F)Br)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tribromofluoromethane and triphenyl phosphine in ethylene glycol dimethyl ether was stirred at 70° C. for 1 hour. The reaction solution was cooled with ice, and a solution of trans-4-(trans-4-ethylcyclohexyl)cyclohexane carboaldehyde in tetrahydrofuran was added thereto. After the reaction solution was further stirred for 1 hour, the temperature of the solution was gradually raised up to room temperature, and insoluble substances were removed by filtration. Dilute hydrochloric acid was added to the filtrate, and it was extracted with toluene. After the organic layer was washed with water, it was dried by using anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain a brown oily product. After this product was purified by using a silica gel column chromatography, it was recrystallized from heptane to obtain trans-4-(trans-4-ethylcyclohexyl)cyclohexyl-2-fluoro-2-bromoethene.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=O)=O.[Na+].[I-:26].O>C1COCC1.CC(C)=O>[Cl:16][C:11]1[CH:10]=[C:9]([C@H:8]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][CH2:6][I:26])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 364 (750 mg, 1.88 mmol) in THF (25 mL) and acetone (5 mL) at RT was added NaI (1411 mg, 9.41 mmol) and stirring was continued overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated to afford 810 mgs (100%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-iodopropylcarbamate (366).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:14])[C:11]([O-:13])=O)=[CH:2]1.[K+].[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:19]1[CH2:20][CH2:21][N:22]([C:11](=[O:13])[C:10]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[C@H:17]([CH3:16])[CH2:18]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2ncccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium 7-azaindole 3-glyoxylate 3a (25.4 g, 0.111 mol), (R)-3-methyl-N-benzoylpiperazine 4a (22.7 g, 0.111 mol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (33.3 g, 0.111 mol) and Hunig's Base (28.6 g, 0.222 mol) were combined in 500 ml of DMF. The mixture was stirred at room temperature for 8 hours.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH2:37][C:36]5[CH:35]=[C:34]([Cl:33])[CH:41]=[C:40]([Cl:42])[CH:39]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCc2cc(Cl)cc(Cl)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.059 g (0.33 mmole) of 3,5-dichloro-benzylamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.078 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3,5-dichloro-benzyl)-3-methoxy-benzamide (I-42) as a white solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[C:24]=4C)=[O:19])=[CH:13][C:12]=3[CH3:36])=[CH:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O>O>[CH3:36][C:12]1[CH:13]=[C:14]([NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[CH:24]=2)=[O:19])[CH:15]=[N:16][C:11]=1[C:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2)cnc1C1=CCC(=O)CC1
Yield: 28.9 %

Procedure:
N-[6-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)-5-methylpyridin-3-yl]-5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (823 mg), trifluoroacetic acid (9 ml) and water (catalytic amounts) was stirred at room temperature overnight. After the reaction, water was added, extracted with chloroform, the aqueous layer was neutralized under cooling by the addition of a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and saturated brine respectively and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with ethanol and the resulting solid was dried at 60° C. in vacuo to give N-[5-methyl-6-(4-oxocyclohex-1-en-1-yl)pyridin-3-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (210 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([S:19]([C:21]([F:24])([F:23])[F:22])=[O:20])[C:15]([C:25]([NH2:27])=O)=[N:14]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([S:19]([C:21]([F:24])([F:22])[F:23])=[O:20])[C:15]([C:25]#[N:27])=[N:14]1
Reactant: Cc1c(S(=O)C(F)(F)F)c(C(N)=O)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid amide (0.98 g) in dichloromethane (5 mL) was added triethylamine (0.63 g, 6.2 mmol) followed by trifluoroacetic anhydride (0.89 g, 4.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and quenched by addition of water (2.0 mL) at 0° C. The resulting mixture was extracted with dichloromethane after it was warmed to room temperature. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography, elution with heptanes/EtOAc, to provide 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carbonitrile as a white solid (0.85 g, 2.0 mmol, 99% in three steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.45 (s, 3H), 7.55-7.63 (m, 1H), 7.76 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.3 (d, J=7.9 Hz, 0.5F), −113.0 (d, J=7.9 Hz, 0.5F), −73.9 (s, 1.5F), −73.8 (s, 1.5F), −63.9 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[O:24][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc(OC)cc2)C1c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate with 4-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-(4-methoxy-benzyloxy)-5-propyl-piperidine-1-carboxylate as a colourless solid, MS: 416 (M-C4H9)+.
Reaction SMILES: COC(Cl)=O.ClC1C=NC(OC2CCCCC2)=C(C=1)C(O)=O.NCC[C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1.Cl>O1CCCC1.C(N(CC)CC)C>[CH3:36][O:35][C:28]1[CH:27]=[CH:26][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: COc1cc(CCN)ccc1C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: O=C(O)c1cc(Cl)cnc1OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)O
Reaction time: 0.5 h

Procedure:
6 g of triethylamine and 1.9 g of chloroformic acid methyl ester are added, while stirring and cooling with ice, to 5 g of 5-chloro-2-cyclohexyloxy-nicotinic acid in 150 ml of tetrahydrofuran. Stirring is continued for 30 minutes at 0° C. and, while stirring, 4.6 g of 4-(2-aminoethyl)-2-methoxybenzoic acid are added in the form of its hydrochloride. The mixture is further stirred for 4 hours at room temperature, the solvent removed under reduced pressure, the residue reprecipitated from ammonia and recrystallized from ethanol or ethyl acetate. The 4-(2-<5-chloro-2-cyclohexyloxy-nicotinamido>-ethyl)-2-methoxy-benzoic acid obtained melts at 170°-172° C.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].NO[CH2:10][C:11](O)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH2:20][C:21](=O)[CH:22]=2)[CH:17]=[CH:16][N:15]=1>O.C(O)C.N1C=CC=CC=1>[C:5]([CH2:4][O:3][N:2]=[C:20]1[C:16]2[C:10]3[C:11]([CH:23]=[CH:14][N:15]=2)=[CH:21][CH:22]=[CH:23][C:14]=3[N:15]2[C:19]1=[CH:18][CH:17]=[CH:16]2)([OH:7])=[O:6]
Reactant: NOCC(=O)O
Reactant: O=C1C=c2cnccc2=CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 111.5 %

Procedure:
A solution of aminooxyacetic acid hemihydrochloride (60.0 g.) in water (180 cc.) is added to a stirred boiling solution of 7H-indolizino 5,6,7-ij]isoquinolin-7-one (60.0 g.) in ethanol (1,800 cc.) and pyridine (27.3 cc.). Boiling is maintained for 2 hours 30 minutes. After cooling, the yellow crystals obtained are filtered off, washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-carboxymethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (67.6 g.), melting at 212° C. with decomposition, is obtained.
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[S:9][CH:10]=[C:11](CC(O)=O)[N:12]=1)=O)C.[NH:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:12]=1
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Product: CCOC(=O)CN(CC(=O)OCC)c1csc(N)n1

Procedure:
The subtitle compound was prepared from 2-[[1,1-dimethylethoxy]carbonylamino]4-thiazoleacetic acid (0.75 g) (Chem. Pharm. Bull. 1993, 41, 758) and diethyl iminodiacetate (0.83 g) according to the method of example 15 step (i) followed by step (ii). Yield 0.91 g.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[CH:28]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(C(C)C)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(c2ccc(C(C)C)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
1.5 g (5.3 mmol) of ethyl 5-[4-(1-methylethyl)phenyl]piperidine-3-carboxylate were dissolved in 18 ml of dichloromethane, and 0.81 g (7.9 mmol) of triethylamine was added at 0° C. 1.43 g (10.5 mmol) of cyclopentanecarbonyl chloride were then added dropwise.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[C:3]1=[O:21]
Reactant: Cc1cccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(N2CC(C(=O)O)N(C)C2=O)n1

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.5 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-6-methylpyridine (258 mg, 1.5 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (733 mg, 2.25 mmol), Xantphos™ (65.1 mg, 0.113 mmol) and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.038 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 56%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 0.84 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was dried to give 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.84 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccncc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)O

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 319.2 (M+1).