Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:28]=1)=[O:6]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2cccnc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
2-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dichloromethane and added with oxalylchloride and a catalytic amount of N,N-dimethylformamide at 0° C. The resulting mixture was refluxed for 3 hours and concentrated under reduced pressure. And then, the obtained acid chloride was dissolved in dichloromethane and cooled to 0° C. Ethyl 3-(4-nitrophenyl)acrylate (1.35 g, 7 mmol) prepared in step 1 and triethylamine were added, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue then was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (2.1 g, yield: 92%, colorless liquid).
Reaction SMILES: ON[C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28]C3C=CC=CC=3)=[CH:23][CH:22]=2)(=O)=O)CCN(CC2C=CC=CC=2)CC1)=[O:4].C[O:36][C:37]1C=CC(S)=C[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:37]([O:36][C:3](=[O:4])[CH2:5][S:18][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:38]
Reactant: O=C(NO)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OC)cc1

Procedure:
1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous K2CO3 (10 gm, excess) in dry acetone (100 ml), α-bromo ethyl acetate (3.3 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O and 0.5N NaOH solution. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. (4-methoxy- phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32](O)[CH3:33])=[N:30][CH:31]=1.CCCCC>C(Cl)Cl>[Cl:21][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=1)[CH3:33]
Reactant: CC(O)c1ccc(F)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: CC(Cl)c1ccc(F)cn1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
A mixture of triphenylphospine (0.92 g, 3.5 mmol) and CCl4 (4 mL) was stirred for 10 min. and then a solution of 1-(5-fluoropyridin-2-yl)ethanol (0.25 g, 1.7 mmol) in DCM (2 mL) was added. After 18 h, pentane (20 mL) was added, the solid material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent heptane:ethyl acetate 3:1) affording the title compound (8 mg, 3% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:9](=[O:27])[C:8]=3[CH:7]=[CH:6][N:5]2[C:28]=1[CH3:29].[C:30](Cl)(=[O:32])[CH3:31]>C1(C)C=CC=CC=1>[C:30]([N:12]1[C:13]2[C:4]3=[N:3][C:2]([CH3:1])=[C:28]([CH3:29])[N:5]3[CH:6]=[CH:7][C:8]=2[C:9](=[O:27])[C@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:32])[CH3:31]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](OC(=O)C(C)(C)C)[C@@H](c1ccccc1)N3
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
175 g of (8R,9R)-2,3-dimethyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are dissolved in 2200 ml of toluene under argon and with exclusion of moisture with mechanical stirring. Half the amount of acetyl chloride (130 ml in total) is then added dropwise with ice cooling in the course of 30 min. After removing the ice bath, half the amount of triethylamine (250 ml in total) is then added dropwise at 10° C. in the course of 40 min (warming to 30° C.). After 15 min at this temperature, the procedure is repeated as described with the second half of the reagents indicated. The mixture is then added to 1 l of ice water with stirring. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2×200 ml). The combined organic phases are washed with water (3×400 ml), dried over sodium sulfate and evaporated. The yellow-brown residue is crystallized using 300 ml of tert-butyl methyl ether. After stirring in the cold for 1 h, it is filtered off, washed with 200 ml of tert-butyl methyl ether and the filter residue is dried to constant weight in a vacuum drying oven. 186 g (95%) of the title compound are isolated as a yellowish solid of m.p. 168-170° C.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:10])[CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:11]([O-:14])(O)=[O:12].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C2C(=O)N(C([O-])=O)C=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1COCC1>[OH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[C@H:2]([NH:1][C:11]([O:14][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: CC(C)[C@@H](O)[C@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 41.3 %

Procedure:
To a stirred mixture of (2S*,3R*)-2-amino-3-hydroxy-4-methyl-pentanoic acid (0.152 g, 1.04 mmol) and NaHCO3 (0.088 g, 1.05 mmol) in H2O (6.0 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (0.96 g, 1.21 mmol) [prepared as for example 32, step 1] in THF (6.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.145 g, 41%), as a yellowish solid, which was used in the next step without further purification. MS (ESI) m/z: 338 [M−H]+; (ESI) m/z: 336 [M−H]−. 1H NMR (DMSO-d6) δ 0.80 (d, J=6.63 Hz, 3H), 0.93 (d, J=6.49 Hz, 3H), 1.28-1.41 (m, 2H), 1.50-1.69 (m, 4H), 1.81-1.91 (m, 1H), 2.57 (d, J=7.67 Hz, 2H), 3.47 (d, J=8.36 Hz, 1H), 3.89-3.99 (m, 2H), 4.15 (dd, J=2.83, 9.47 Hz, 1H), 4.58 (s, 1H), 6.64 (d, J=9.43 Hz, 1H), 7.10-7.32 (m, 5H), 12.43 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(N(C(C)C)CC)(C)C>>[NH2:9][C:3]1[NH:4][C:5](=[O:8])[N:6]=[CH:7][C:2]=1[N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([F:10])[CH2:12]1
Reactant: FC1CCCNC1
Reactant: Nc1nc(=O)[nH]cc1Br
Solvent: CCN(C(C)C)C(C)C
Product: Nc1[nH]c(=O)ncc1N1CCCC(F)C1

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine, 1.25 eq. of 3-fluoropiperidine and 2.5 eq. of diisopropylethylamine at 120° C. for 2 days yielding 6-amino-5-(3-fluoropiperidin-1-yl)pyrimidin-2(1H)-one as an orange crunchy solid (24%). LCMS (m/z): 213.0 (MH+); LC Rt=1.07 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:18])/[CH:14]=[C:15](\[NH2:17])/[CH3:16])[CH3:11].[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)[CH3:20]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:31])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:17][C:15]=1[CH3:16])=[O:18])[CH3:11]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(F)c1
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(F)c2)C(C(=O)OCC)=C(C)N1

Procedure:
6.2 g of 3-fluorobenzaldehyde, 6.5 g of β-aminocrotonic acid ethyl ester and 9.5 g of oxalacetic acid diethyl ester in 40 ccs of ethanol are heated to the boil overnight, the mixture is evaporated in vacuo and a light yellow oil is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.N1CCCCC1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#Cc3ccccc3)c2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.52 g, 1.5 mmoles), prepared as described in example 45, in dry DMF (10 ml) under N2 was added with piperidine (1 ml, 10 mmoles), phenylacetylene (0.15 g, 1.5 mmoles), PdCl2 (0.013 g, 0.075 mmole), triphenylphosphine (0.039 g, 0.15 mmole) and CuI (0.014 g, 0.075 mmole). The mixture was stirred for 20 hours, poured into saturated NHCl (10 volumes) and extracted twice with CH2Cl2, then washed with 5% HCl, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: CH2Cl2/ethyl ether 9:1). The resultant solid was triturated in ethyl ether to give 0.41 g of the title compound (yield: 52%). m.p.: 213.4-214.4° C. (dec.).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]1[O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1>>[CH2:12]1[O:21][C:20]2[CH:19]=[CH:18][C:16]([NH:17][C:2]3[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=3[N+:8]([O-:10])=[O:9])=[CH:15][C:14]=2[O:13]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccc2c(c1)OCO2
Temperature: 120 °C
Reaction time: 5 h

Procedure:
0.86 g of 3-fluoro-4-nitrophenol and 2.25 g of 3,4-methylenedioxyaniline were mixed and stirred for 5 hours at 120° C. The raw mixture was chromatographed on silica gel.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (194 mg, 0.54 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (101 mg, 0.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (189 mg, 66%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]=[O:31])=[C:19]([CH3:32])[CH:18]=1>C1COCC1.CCCCCC>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:19]([CH3:32])[CH:18]=1
Reactant: Cc1cc(Cl)c2ccc(Cl)cc2c1CCC=O
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (0.292 g, 2.64 mmoles) dissolved in dry THF (2 ml) is added dropwise via a syringe through a septum to a stirred suspension of sodium hydride (0.127 g of a 50% NaH in mineral oil, 2.64 mmoles) in dry THF (7 ml) which had been chilled in an ice-water bath. The reaction was stirred in the cold for 15 minutes at which time a clear solution was obtained. To this solution in the cold was added n-butyl lithium (1.80 ml of a 1.47M solution in hexane; 2.64 mmoles) via syringe through the septum dropwise in about 5 minutes. The orange solution is stirred with ice-water bath for 15 minutes and then cooled to -78° C. in a dry ice-acetone bath. To this cold stirred reaction was added dropwise via syringe, 3-(4,7-dichloro-2-methylnaphthalen-1-yl)propanal (0.6715 g, 2.513 mmoles) dissolved in dry THF (5 ml). The reaction is allowed to stir at -78° for 15 minutes, then allowed to warm to 0° by emersing the reaction flask in an ice-water bath. When ice separated from the flask, the reaction was worked up by partitioning it between ether (150 ml) and water containing 0.6 ml of 12N HCl. Extracted the water layer with ether. The combined ether extracts are washed with water twice then with saturated solution of NaHCO3. The ether was dried (MgSO4) and the solvent removed in vacuo to leave 0.96 g of crude title Rf =0.45 (silica, 5% acetone/CH2Cl2) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:3]=1[CH2:4][NH:5][C:6](=[O:40])[N:7]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:39])[CH2:29][O:30][P:31]([O:36]CC)([O:33]CC)=[O:32])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[Si](I)(C)(C)C>C(#N)C>[Cl:1][C:2]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:3]=1[CH2:4][NH:5][C:6](=[O:40])[N:7]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:39])[CH2:29][O:30][P:31]([OH:36])([OH:33])=[O:32])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8]
Reactant: CCOP(=O)(OCC)OCC(O)COCC(COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(COCC(O)COP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 72 %

Procedure:
To a solution of Isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-[3-(diethoxy-phosphoryloxy)-2-hydroxy-propoxy]-propyl ester (0.60 g, 0.895 mmol) in acetonitrile (30 mL) was added TMSI (1.43 g, 7.16 mmol) dropwise at 0° C. After stirring at 0° C. for 4.5 h, the reaction was quenched with EtOH. The solvent was removed, and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (0.1% TFA buffer) to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2-hydroxy-3-phosphonooxy-propoxy)-propyl ester (396 mg, 73%). LRMS [M−H]+ m/z 613.5
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1>>[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c(O)n1
Product: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a 500 ml single-necked round-bottomed flask, 230 ml of a 65% ageous HNO3 solution is added and stirred under cooling (ice/water cooling bath). 7.00 g of 3-bromo-6-methyl-pyridin-2-ol 2 at ambient temperature is introduced portion-wise. Stirring is continued for 3.5 hours at ambient temperature. After pouring the mixture into 200 ml of an ice/water mixture (pH 1), the water phase is extracted with AcOEt. The organic phase is washed twice with water brought to pH 4 by adding ageous NaOH solution (pH meter), then dried over sodium sulfate, filtered and concentrated in vacuo to give 7.52 g of a yellow solid. This crude material is suspended in diethyl ether and stirred for 1 hour at ambient temperature, filtered, washed with the same solvent and dried to give 3.89 g of the compound as a yellow-orange solid (m.p. >220° C.).
Reaction SMILES: FC(F)(F)[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.OC[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[Na].[ClH:35]>C(OC(C)C)(C)C.C1(C)C=CC=CC=1>[Cl:35][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH2:19][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cl
Reactant: OCC1CCCCO1
Reactant: COC(=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Agent: [Na]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: O=C(OCC1CCCCO1)c1ccccc1Nc1ccnc2cc(Cl)ccc12
Yield: 67 %

Procedure:
By treating 15.4 g of methyl 2-(7-chloro-4-quinolyl)aminobenzoate (II, R=Cl, R"=CH3), 8.46 g of 2-hydroxymethyltetrahydropyran, 125 ml of toluene and in the presence of sodium, as described in Example 1, 19.8 g of a crude material are isolated. This material is dissolved in 250 ml of diisopropyl ether and 7 ml of hydrochloric acid (g) 10N ethanolic solution are added under cooling in water-ice bath. After 15 minutes the precipitated hydrochloride is filtered off, dried (19.45 g; 91%) and recrystallized in acetonitrile. 14.34 g (yield: 67%) of the hydrochloride--yellow solid--are obtained with m.p. 187°-187.5° C. and elemental analysis C, H, N, Cl correct.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:20]=1)(=[O:10])[CH3:9].Br[CH:38]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])[C:39]([CH:41]1[CH2:43][CH2:42]1)=[O:40]>>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[C:39]([CH:41]2[CH2:42][CH2:43]2)=[O:40])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[N:20]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: CCOC(=O)Cc1cc(/C=C2\CNCCC2SC(C)=O)nn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1C(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 132-(g), (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-5-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrogen trifluoroacetate (1.23 g) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone. The product was purified by silica gel chromatography to afford the title compound (1.11 g, yield: 81%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2cccc(Cl)c2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3-chloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (2.44 g, 8.88 mmol) and phosphoroxychloride (25 mL) according to the general procedure I. Obtained as a white solid (1.62 g, 62%). MS (EI) 292.0 [(M)+]; mp 89.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[N:14]O)[CH2:12][CH2:13][C:3]1=2.C(=O)([O-])[O-:17].[Na+].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:17])[NH:14][CH2:12][CH2:13][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)C(=NO)CC2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime (1.53 g), polyphosphoric acid (40 g) and dioxan (15 ml) were heated at 110°-120° for 2.2h under nitrogen. The reaction mixture was cooled, and treated with 2N sodium carbonate solution (`l). The suspension was extracted with ethyl acetate (4×400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallised from ethyl acetate/cyclohexane. This solid was purified by FCC, eluting with System A (200:10:1) to give a solid (1.26 g) which was recrystallised from ethanol to provide the title compound (960 mg), m.p. 234°-238°.
Reaction SMILES: ClC(O[C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23]CC[CH2:20]1>>[CH3:20][O:19][CH2:23][C:6]([O:7][CH2:8][CH2:14][NH:13][CH3:18])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: c1ccncc1
Product: CNCCOC(=O)COC

Procedure:
To a solution (15 mL) of bis(trichloromethyl)carbonate (0.652 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.55 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., 2-(methylamino)ethyl methoxyacetate (0.99 g) obtained in Reference Example 13 was added. The mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue and the mixture was stirred. The ethyl acetate layer was separated and taken, washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (15 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.13 g), triethylamine (0.86 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60° C. for 4 days. After concentration under reduced pressure, ethyl acetate (80 mL) and water (30 mL) were added to the residue, and the mixture was stirred. The ethyl acetate layer was separated and taken, and the ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and water (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate, then acetone:ethyl acetate=1:3), and further by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then 3:1) to give the title compound (0.588 g) as colorless syrup.