Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:17][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:16])OCC)[S:10][C:6]=2[CH:5]([Cl:18])[CH2:4]1)[CH3:2].[CH2:19]([NH:22][CH2:23][CH:24]=[O:25])[CH:20]=[CH2:21]>>[CH2:19]([N:22]([CH2:23][CH:24]=[O:25])[C:12]([NH:11][C:9]1[S:10][C:6]2[CH:5]([Cl:18])[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:17][C:7]=2[N:8]=1)=[O:16])[CH:20]=[CH2:21]
Reactant: CCOC(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Reactant: C=CCNCC=O
Product: C=CCN(CC=O)C(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Temperature: 125 °C

Procedure:
Ethyl N-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)-carbamate (0.08 mol) and the dimethyl acetal of 2-allylaminoacetaldehyde (30 ml.) are charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture is blanketed with nitrogen gas and is heated at 125° C. for a period of about 8 hours. After this time the reaction mixture is distilled to remove excess starting material. The residue is purified by elution chromatography using ethyl acetate as the eluant. The chromatographed solution is then stripped of solvent to yield the desired product dimethyl acetal of 2-[1-allyl-3-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[C:11]1([CH2:14][O:13][CH2:12]1)[C:10]2=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH3:21])([CH3:20])[C:11]1([CH2:14][O:13][CH2:12]1)[C:10]2=[CH2:1]
Reactant: [Li]CCCC
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C12COC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C12COC2
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (8.13 g, 22.3 mmol) in THF (44 mL) was added n-butyllithium (1.65 M in n-hexane, 13.5 mL, 22.3 mmol) in a dry ice-acetone bath under argon atmosphere. The mixture was stirred for 60 minutes in an ice bath. To the mixture was added a mixture of 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,3′-oxetan]-4-one (2.21 g, 7.44 mmol) and THF (11 mL) in an ice bath. The mixture was stirred for 1 hour at ambient temperature. The reaction was quenched by adding water in an ice-water bath. The mixture was partitioned between EtOAc-hexane (1:2) and water. The organic layer was washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated. Purification using silica gel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 20%) afforded 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,3′-oxetane] (2.02 g).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:14]1[C:21]([Cl:22])=[N:20][C:18](Cl)=[N:17][C:15]=1[Cl:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.O>[Cl:16][C:15]1[N:14]=[C:21]([Cl:22])[N:20]=[C:18]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:17]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCNCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1nc(Cl)nc(Cl)n1

Procedure:
Dihexylamine (6.3 mL, 27 mmol) was added to a mixture of cyanuric chloride (5.0 g, 27 mmol) and sodium carbonate (2.9 g, 27 mmol) in acetonitrile (50 mL). The reaction mixture was heated to reflux for 16 h and then allowed to col to ambient temperature. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography through silica gel (elution with 3:1 hexanes:chloroform) to afford 2,4-dichloro-6-dihexylamino-1,3,5-triazine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[F:14])#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[C:40]([CH2:41][NH2:42])=[CH:39][C:38]([C:43]([F:46])([F:45])[F:44])=[N:37]2)[CH:33]=[CH:34][CH:35]=1>C(#N)C.O>[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[C:40]([CH2:41][NH:42][C:10](=[O:12])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:14])[CH:5]=3)[CH3:13])=[CH:39][C:38]([C:43]([F:44])([F:45])[F:46])=[N:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(C#N)c(F)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-(4-cyano-3-fluorophenyl)propanoic acid (440 mg, 2.278 mmol) in acetonitrile was added HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (659 mg, 2.392 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-cyano-3-fluorophenyl)propanamide (870 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([I:18])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([I:18])[C:3]=1[F:10]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)c(F)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
To a solution of the 4-bromo-3,5-difluoroaniline (5 g, 20 mmol) in acetic acid (60 mL) was added NIS (5.68 g). The reaction mixture was stirred at room temperature for two hours, and poured into water (300 mL). The product was extracted with ethyl acetate (2×200 mL), and the combined organic layers were washed with 1 N aqueous NaOH (200 mL) and saturated aqueous sodium thiosulfate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was filtered through a plug of silica gel, eluting with heptane/ethyl acetate (4:1). The filtrate was concentrated in vacuo to give the title compound (7.34 g) as a white solid. 1H NMR (500 MHz, CDCl3) δ 6.44 (dd, J=10.00, 1.95 Hz, 1 H) 4.46 (br. s., 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:24])[C:10]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH2:25]([O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][Br:42])=[CH:36][CH:35]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[Br-:42].[CH2:25]([O:32][C:33]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][N+:2]2([CH3:1])[CH2:3][CH2:4][CH:5]([O:8][C:9](=[O:24])[C:10]([OH:23])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:6][CH2:7]2)=[CH:36][CH:35]=1)=[O:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)c1ccc(CCBr)cc1
Reactant: CN1CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Solvent: CN(C)C=O
Product: C[N+]1(CCc2ccc(C(=O)OCc3ccccc3)cc2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Product: [Br-]
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Hydroxy-diphenyl-acetic-acid-1-methyl-piperidin-4-yl-ester (1.56 g, 4.8 mmol) and 4-(2-bromo-ethyl)-benzoic acid benzyl ester (2.3 ml, 7.21 mmol) are dissolved in DMF (5 ml) and stirred at 50° C. for 20 hours, followed by heating at 60° C. for 5 hours. Concentration and purification twice by C-18 reverse phase chromatography (eluant: water/acetonitrile) gives the title compound as a mixture of diastereoisomers.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC(F)(F)F)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC(F)(F)F)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC(F)(F)Oc1ccc(NCC2CCCC2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC(F)(F)F)cc2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH3:23])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC([Cl:30])=O.CO>C1(C)C=CC=CC=1>[ClH:30].[CH3:24][C@@:10]12[CH2:9][NH:8][CH2:16][C@@H:15]1[C:14]1[CH:17]=[CH:18][CH:19]=[C:20](/[CH:21]=[CH:22]\[CH3:23])[C:13]=1[CH2:12][CH2:11]2
Reactant: CC(Cl)OC(=O)Cl
Reactant: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Solvent: CO
Solvent: Cc1ccccc1
Product: C/C=C\c1cccc2c1CC[C@]1(C)CNC[C@H]21
Product: Cl
Temperature: 160 °C
Yield: 86.6 %

Procedure:
cis-2-Benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.372 mmol, 118 mg) was dissolved in toluene (1 ml) and ACE-Cl (2.60 mmol, 0.286 ml, 372 mg) was added. The reaction mixture was heated to 160° C. for 15 minutes and then MeOH (1 ml) was added and the reaction mixture was heated to 160° C. for a further 5 minutes and then passed through an SCX cartridge and the resulting filtrate was purified by silica column chromatography (eluting with DCM—2, 4, 8, 16% MeOH(NH3)/DCM) The pure fractions were concentrated in vacuo and then 2 N HCl in MeOH added. The resulting solution was concentrated in vacuo to afford cis-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (85 mg): m/z: 228.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=[C:4]([CH2:14][CH3:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)CCC>[CH2:14]([C:4]1[N:3]=[C:2]([NH:17][NH2:18])[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=1)[CH3:15]
Reactant: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CCc1nc(NN)c2c(n1)N(C)C(=O)CS2
Yield: 81.2 %

Procedure:
4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4 b][1,4]thiazin-7-one from Example 119 (2.4g, 9.93 mmole) was suspended in approximately 100ml of n-butanol. Hydrazine monohydrate (0.99g, 19.9 mmole) was added and the resultant mixture was refluxed for about 20 hours. The reaction mixture was allowed to cool and the precipitate was separated by filtration, washed with water and dried, providing 1.93g (81%) of 6,7-dihydro-2-ethyl-4-hydrazino-8-methylpyrimido[5,4-b}[1,4]thiazin-7-one. Infrared and nuclear magnetic resonance spectral analyses confirmed the structural assignment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[OH:16])=[O:10].N12CCN(CC1)CC2.[C:27](Cl)(=[O:37])[C:28]1[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:30](Cl)=[O:31].[Cl:39][C:40]1[N:45]=[N:44][C:43]([O:46][C:47]2[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=2[CH:54]2[CH2:56][CH2:55]2)=[C:42]([OH:57])[CH:41]=1>C(#N)C>[C:27]([O:57][C:42]1[CH:41]=[C:40]([Cl:39])[N:45]=[N:44][C:43]=1[O:46][C:47]1[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=1[CH:54]1[CH2:56][CH2:55]1)(=[O:37])[C:28]1[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:30]([O:16][C:15]1[N:14]([CH3:17])[N:13]=[C:12]([CH3:18])[C:11]=1[C:9](=[O:10])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:31]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)c1ccccc1C(=O)Oc1c(C(=O)c2ccc(Cl)cc2Cl)c(C)nn1C
Temperature: 0 °C
Yield: 5.6 %

Procedure:
In acetonitrile (3 mL) was suspended 207 mg (0.726 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 81.6 mg (0.729 mmol) of 1,4-diazabicyclo[2.2.2]octane was added to the suspension and the resulting mixture was stirred. To the mixture was added 105 L (0.729 mmol) of phthaloyl dichloride, and after stirring at room temperature for 1 hour, 200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was further added, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate, gradient) to obtain 28.0 mg (0.0405 mmol, Yield: 5.61%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1625) and 163 mg (0.238 mmol, Yield: 33.0%) of bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] phthalate (Compound No. 2838).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1>CCOCC>[OH:15][C:16]1([C:7]2[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][CH2:21]1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52.2 %

Procedure:
n-Butyllithium (1.6M in hexanes, 6.65 mL, 10.64 mmol) was added dropwise to 5-bromo-2-methoxypyridine (2.0 g, 10.64 mmol) in ether (30 mL) cooled to −78° C. over a period of 15 minutes. The resulting solution was stirred at −78° C. for 40 minutes then a solution of benzyl 4-oxo-1-piperidinecarboxylate (2.48 g, 10.64 mmol) in ether (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature then quenched with ammonium chloride solution (50 mL) and extracted with EtOAc. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and concentrated by evaporation then purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-(6-methoxypyridin-3-yl)piperidine-1-carboxylate (1.90 g, 52%) as a pale orange oil.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)(F)C1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCC(F)(F)C3)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A mixture of 4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (64 mg, 0.20 mmole), 4-fluoro-3-methyl-benzoyl chloride (52 mg, 0.30 mmole), and triethylamine (56.5 μL, 0.40 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 29 mg, 32% yield). Exact mass calculated for C24H25F3N4O2 458.2. found 459.3 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[N:22]=[C:21]4[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]4[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:15][C:14]=3[F:31])[CH2:8]2)C=CC=CC=1.[CH3:32]S([O-])(=O)=O>>[CH3:1][CH:7]1[N:12]([CH3:32])[CH2:11][CH2:10][N:9]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]3[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:15][C:14]=2[F:31])[CH2:8]1
Reactant: CS(=O)(=O)[O-]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccccc4)C3)nc21
Product: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C(C)(C)C)CCN1C

Procedure:
7-(3-phenyl-1-piperazinyl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O1CC1C[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33]C(OC)=CC=1CC1OC1.C([OH:45])(C)C>>[CH3:27][O:26][C:24]1[CH:25]=[CH:20][C:21]([O:28][CH2:29][CH:34]([OH:45])[CH2:33][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)=[CH:22][CH:23]=1
Reactant: CC(C)O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc(Oc2ccc(OC)cc2CC2CO2)c(CC2CO2)c1
Product: COc1ccc(OCC(O)CN2CCC(c3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20 mmol) and 2,3-epoxypropyl-4-methoxyphenyl ether (3.7 g, 20.5 mmol) in isopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixture was cooled and the crystals were collected to yield 6.81 g (85%), m.p.=134-135° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>FC(F)(F)C(O)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2ccccc2o1)C1CCCCN1
Yield: 99 %

Procedure:
A solution of (RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine, D2 (0.86 g, 2.61 mmol) in trifluoroacetic acid (5 ml) and dichloromethane (20 ml) was warmed at 35° C. for 0.5 h. The reaction mixture was evaporated in vacuo and the residue partitioned between dichloromethane (30 ml) and 1N sodium hydroxide (30 ml). The aqueous layer was extracted with dichloromethane (30 ml) and the combined organic layers dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale yellow gum (0.59 g, 99%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH2:36]([NH:40][CH3:41])[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:36]([N:40]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)[CH3:41])[CH:37]([CH3:39])[CH3:38]
Reactant: CNCC(C)C
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CN(C)CC(C)C)c3)c1)=N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A stirred suspension of 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 283) (213 mg, 0.50 mmol) and thionyl chloride (0.11 ml, 1.50 mmol) in CH2Cl2 was refluxed for 45 min, evaporated to dryness and dissolved in DMF (3 ml). To the stirred solution N-isobutyl-methyl-amine (436 mg, 5.0 mmol) was added and the reaction mixture was stirred at RT for 1 h. Aqueous work-up (CH2Cl2) and further purification by column chromatography on silica gel (CH2Cl2/MeOH 15:1) yielded the title compound as a light yellow solid (142 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][O:15][C:14](=[O:18])[NH:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[CH:22]=[O:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([N:13]1[C:12]2[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]([CH:22]=[O:23])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:17]=2[CH2:16][O:15][C:14]1=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.36 g (7.5 mmol) of the compound from Example VII are dissolved in 20 ml of anhydrous dimethylformamide, and the mixture is treated with 0.28 g (9.4 mmol) of 80% strength sodium hydride under a gentle stream of argon. The mixture is stirred at room temperature for 15 min and treated with 1.54 g (9 mmol) of benzyl bromide. After 60 min, 30 ml of water are cautiously added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue which remains is chromatographed in a column (φ 3 cm) on 50 g of silica gel 230-400 mesh using petroleum ether/ethyl acetate 4:1.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:31][C:29]3[CH:28]=[CH:27][C:25]4[N:26]=[C:22]([N:21]([CH2:20][CH2:19][N:18]([CH3:17])[CH3:33])[CH3:32])[S:23][C:24]=4[CH:30]=3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(OC2CCCCC2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(OC4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following Method A, using 4-cyclohexyloxy benzoic acid (0.20 g, 0.91 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.17 g, 0.68 mmol) to afford the 0.15 g (36%). LC/MS: Retention time=5.23 min; (m/z): calcd for C25H32N4O2S: 453.6; found: 453.0.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
(±)-Heptan-1,6-diol (1.06 g, 8 mmol) and pyridine (1.36 ml, 1.33 g, 16.8 mmol) were dissolved in dichloromethane (20 ml) and the mixture was cooled in ice. Methanesulfonyl chloride (0.65 ml, 0.96 g, 8.4 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. Dichloromethane (50 ml) was added and the mixture was washed with aqueous HCl (1M, 50 ml) and brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/20% hexane, to give the alcohol as an oil (1.01 g, 60%).