Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([OH:16])([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)[C:12]([F:14])([F:13])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2cccc3cnccc23)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-isoquinolin-5-yl-butan-2-ol (Example 182, 50 mg) in dichloromethane (1.3 ml) was cooled to −70° C. A 1M solution of boron tribromide in dichloromethane (0.505 ml) was added and the mixture was stirred at −70° C. for 30 min and at 0° C. for 1 h. A mixture of ice water and saturated aqueous NaHCO3 solution was added and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (45 mg) as a colorless solid. MS (m/e)=382.1 [M+H+].
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:22])([CH3:21])[CH2:5]1.[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[CH2:25]([O:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:21])([CH3:22])[CH2:5]1)[CH:24]=[CH2:23]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Temperature: 35 °C
Yield: 69.9 %

Procedure:
Sodium hydride (2.65 grams, 110 mmol) is added to a solution of 30.0 grams (105 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (as prepared in Example 5) in 150 ml of tetrahydrofuran under nitrogen. The reaction mixture is heated at reflux for three hours, cooled to 35° C., and treated with 12.7 grams (110 mmol) of allyl bromide. The reaction mixture is heated at reflux for one hour, then partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer is washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in heptane (50 ml) and passed through a pad of silica gel (eluent 5:1 heptane:ethyl acetate). The crude product is purified by flash chromatography (silica gel; 9:1 heptane:ethyl acetate) to afford 23.9 grams (70% yield) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[F:30][C:31]1([F:36])[CH2:34][CH:33]([OH:35])[CH2:32]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:33]2[CH2:34][C:31]([F:36])([F:30])[CH2:32]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:6]=2[N:7]=1
Reactant: OC1CC(F)(F)C1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(F)(F)C4)c23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A solution of 4-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 3,3-difluorocyclobutan-1-ol (1.1 equiv), and sodium tert-butoxide (1.2 equiv) in 1,4-dioxane (0.22 M) were combined in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed, and the mixture was stirred at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and purified using silica gel chromatography (0-50% ethyl acetate in hexane) to afford the title product (64.1% yield) as a clear oil. MS (ESI) m/z 523.4 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][CH:8]=2)=[N:3]1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Cl:19][CH2:20][C:21]([N:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:22]
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)cc2)n1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of 4-[4-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine 6BH (13.7 g, 44 mmol) in dichloromethane (450 ml) was added TEA (37 ml, 264 mmol) dropwise. After stirred at 0° C. for 10 min, chloroacetyl chloride (10.5 ml, 132 mmols) was added to the reaction mixture. The resulting mixture was stirred at 0° C. for 1 hr., and quenched with water (165 ml). The reaction mixture was diluted with dichloromethane (600 ml). The organic layer was separated and washed with brine, dried over MgSO4. Reaction mixture was concentrated to ˜50 ml, ether was added and the solid was filtered out to get the desired product 7BH (8.74 g).
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.N[C:10]1[N:15]=[CH:14][N:13](Cl)[C:12]2=[CH:17][NH:18][S:19][C:11]=12>>[N:18]1[S:19][CH:11]=[C:12]2[C:17]=1[CH:10]=[N:15][CH:14]=[N:13]2
Reactant: NC1=C2SNC=C2N(Cl)C=N1
Agent: O=C1CCC(=O)N1Br
Product: c1ncc2nscc2n1

Procedure:
Reaction of 4,6-dichloro-5-nitropyrimidine with CuCN/NMP gives the 4-nitrile. Reduction of the nitro group to the amine is followed by diazotization/thiation to give the corresponding 5-mercapto compound. Reaction of this with Me3Al/NH4Cl gives the amidine which is oxidatively cyclized with NBS to 7-amino-4-chloroisothiazolo[4,5-d]pyrimidine. Removal of the amino functionality by diazotization/hypophosphorus acid is followed by displacement of the 4-chlorine with an appropriate amine to give the desired isothiazolo[4,3-d]pyrimidine derivatives as shown above.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H:8]1[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][C@H:9]1[CH2:17][OH:18].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@H:8]1[CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CC2(C[C@@H]1CO)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CC2(C[C@@H]1COS(C)(=O)=O)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (1.93 ml, 24.9 mmol) is added to a cooled (0° C.) solution of ((7R,8S)-8-hydroxymethyl-1,4-dioxa-spiro[4.4]non-7-yl)-methanol (Tet. Lett., 2002,43, 4947; 1.17 g, 6.22 mmol) and triethylamine (3.50 ml, 24.9 mmol) in dichloromethane (30 ml). The reaction is stirred for 2 hours at 0° C. and then partitioned between dichloromethane and iced water. The organic phase is washed with 1M aqueous HCl, saturated aqueous NaHCO3, brine, dried (MgSO4) and evaporated to afford methanesulfonic acid (7R,8S)-8-methane-sulfonyloxymethyl-1,4-dioxaspiro[4.4]non-7-ylmethyl ester, MH+345.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:27])[N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:27][C:4]1[N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[N:8]=2)[CH:6]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nc(Br)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Cc1nc(-c2ccc(N)nc2)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.60) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.11 g, 47%). MS (ISP) 465.3 [(M+H)+]; mp 285° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To 4-hydroxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.45 mmol) and pyridine (0.661 mL, 8.18 mmol) in dichloromethane (10 mL) at 0° C. is added methanesulfonyl chloride (0.593 mL, 7.63 mmol). After 3 hours, one additional equivalent of methanesulfonylchloride and pyridine are added. After 1 hour the reaction mixture is concentrated, then EtOAc and water are added. The organic layer is concentrated and chromatographed on silica gel eluting with MeOH in dichloromethane 0-3% to give the title compound as a yellow oil (1.60 g, 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:19]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C(NCCc1ccccc1)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CCNC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of 4-bromo-N-(2-phenylethyl)benzamide (10.0 g, 32.9 mmol) and acetyl chloride (3.04 ml, 42.7 mmol) in dichloromethane (80 ml) was added aluminum chloride (11.0 g, 82.2 mmol), and the mixture was stirred at room temperature for one day. The reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was powderized with isopropyl ether to give the title compound (9.79 g).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[N:31]1[CH:32]=[CH:33][C:28]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=2)=[CH:29][CH:30]=1
Reactant: CCCc1cc(C(=O)O)ccc1OCC1CCCCC1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)Nc2ccncc2)ccc1OCC1CCCCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 22-6 (770 mg, 2.78 mmol) in 10 mL of (CH2Cl)2 and 0.05 mL of DMF was added 0.26 mL (3.05 mmol) of oxalyl chloride. The resulting solution was heated at 50° C. for 30 min, cooled to 0° C. and treated with 1.20 g (13.8 mmol) of 4-aminopyridine. Stirring was continued for 2 h before the heterogeneous mixture was diluted with 50 mL of EtOAc and quenched with 25 mL of 5% Na2CO3. The organic extract was washed with sat'd NH4Cl (3×50 mL), water (2×25 mL), brine (25 mL) and dried over MgSO4. Evaporation of the solvent and column chromatography (EtOAc) afforded product 22-7.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([N:13]=[C:14]=[S:15])([CH3:12])[CH3:11].[H-].[Na+].CCOCC>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]2[S:15][C:14]([NH:13][CH:10]([CH3:12])[CH3:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 2,6-dichloropyridin-3-amine (3.71 g, 22.8 mmol, 1.0 eq.) and isopropyl isothiocyanate (2.5 mL, 23.5 mmol, 1.0 eq.) in DMF (57 mL) under nitrogen at 0° C. was added NaH (95% in mineral oil, 0.77 g, 30.5 mmol, 1.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 68° C. overnight. After cooling to 0° C., isopropyl isothiocyanate (1.5 mL) and NaH (0.44 g) were added, and heating was resumed. After 7.25 h, the reaction was cooled to room temperature. At 0° C., aqueous HCl (1 N), water and EtOAc were added, and the reaction mixture was stirred. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Trituration with Et2O afforded 5-chloro-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a white solid (3.43 g, 66% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:20])[NH:16][NH:17][C:18]=2[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC[CH2:22]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]([O:20][CH3:22])=[N:16][NH:17][C:18]=2[CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1[nH][nH]c(=O)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNCC1
Product: COc1n[nH]c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-4-(5-methyl-3-oxo-(1H)-pyrazol-4-yl)piperidine (Step C) using a procedure analogous to that described for Piperidine 15, Step D. RF: 0.34 (7:3 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.47 (s, 9H), 1.57–1.59 (m, 2H), 1.75–1.83 (m, 2H), 2.16 (s, 3H), 2.44–2.50 (m, 1H), 2.70 (m, 2H), 3.86 (s, 3H), 4.17 (m, 2H); 13C-NMR (125 MHz) δ 55.8 (O—CH3).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CCCCCCl
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCCN1C(=O)C(CCO)Oc2ccccc21
Yield: 32 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloropentane in 32% yield and isolated as a colorless oil; IR (KBr) 3424, 2956, 2932, 1680, 1500, 1272, 1062, 749 cm-1 ; 1H NMR (CDCl3) δ0.91 (t, J=6.8 Hz, 3H), 1.31-1.38 (m, 4H), 1.66 (br t, J=5.5 Hz, 2H), 2.08-2.29 (m, 2H), 2.59 (br s, 1H), 3.87-3.94 (m, 2H), 4.69 (dd, J=7.3, 5.8 Hz, 1H), 6.92-7.08 (m, 4H); Anal. Calc'd for C15H21NO3 : C, 68.42; H, 8.04; N, 5.32. Found: C, 68.10; H, 7.88; N, 5.32.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.ClCCl>[N:28]1([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[CH2:11]2)=[O:27])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 93 μl of cyclopentanecarbonyl chloride (0.762 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 133 mg (57% of theory)
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[C:7]([O:20]CC2C=CC=CC=2)[CH:6]=[C:5]([CH2:28][CH3:29])[N:4]=1)[CH3:2]>N1C=CC=CC=1>[CH2:1]([C:3]1[NH:4][C:5]([CH2:28][CH3:29])=[CH:6][C:7](=[O:20])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2c(OCc3ccccc3)cc(CC)nc2CC)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(-c2c(CC)[nH]c(CC)cc2=O)cc1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 9, part (iii), but starting from compound I, there was obtained in 84% yield 2,6-diethyl-1,4-dihydro-3-(4-ethoxycarbonylphenyl)-4-oxopyridine as a solid, NMR (d6 -DMSO): 0.87,1.07(two t, 3H), 1.21(t, 3H), 1.33(t, 3H), 2.34(t, 3H), 2.53(q, 2H), 4.32(q, 2H), 6.03,6.25(two s, 1H), 7.29(d, 2H), 7.95(d, 2H); mass spectrum (chemical ionisation, ammonia): 300(M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:17]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:17])[NH2:15])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCSc1nsc(NC(=O)NC)c1C#N
Product: CCSc1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4.0 g of 1-methyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea in 6 ml of concentrated sulfuric acid was heated at 160° for 1.5 hours. After this time the reaction mixture was poured into 120 ml of ice-water, and this mixture was stirred for 45 minutes. The white precipitate was collected by filtration. The solid was recrystallized from ethanol to give 4.0 grams of 1-methyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, m.p. 205°. The nmr spectra was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17](OC)=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[NH2:21]/[C:22](/[C:29]([F:32])([F:31])[F:30])=[CH:23]\[C:24]([O:26]CC)=O.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:24](=[O:26])[CH:23]=[C:22]([C:29]([F:30])([F:31])[F:32])[NH:21][C:17]2=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21

Procedure:
A mixture of 7-fluoro-6-methoxycarbonylamino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (1.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate was dissolved in dimethylformamide (5 g), and sodium hydride (0.2 g) was added thereto. The resultant mixture was stirred for 30 minutes while cooling with ice and heated under reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give 1-[7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.2 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:23]([S:24]([CH3:33])(=[N:26]C(=O)C(F)(F)F)=[O:25])=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=[CH:20][C:10]=1[C:11]([NH:13][C:14]1[N:18]([CH3:19])[N:17]=[N:16][N:15]=1)=[O:12]>CO>[CH3:7][O:8][C:9]1[C:23]([S:24]([CH3:33])(=[NH:26])=[O:25])=[C:22]([C:34]([F:36])([F:35])[F:37])[CH:21]=[CH:20][C:10]=1[C:11]([NH:13][C:14]1[N:18]([CH3:19])[N:17]=[N:16][N:15]=1)=[O:12]
Reactant: COc1c(C(=O)Nc2nnnn2C)ccc(C(F)(F)F)c1S(C)(=O)=NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(C(=O)Nc2nnnn2C)ccc(C(F)(F)F)c1S(C)(=N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
31.5 mg (0.228 mmol) of potassium carbonate were added to 36.0 mg (0.076 mmol) of 2-methoxy-N-(1-methyl-1H-tetrazol-5-yl)-3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]-4-(trifluoromethyl)benzamide in 5 ml of methanol. The mixture was stirred at RT for 30 minutes. For work-up, the solvent was removed at a temperature of at most 30° C. on a rotary evaporator. The residue was taken up in water and the mixture was extracted with dichloromethane. A drop of glacial acetic acid was then added to the aqueous phase, and the mixture was extracted twice with dichloromethane. On a rotary evaporator, the aqueous phase was then freed from the solvent at a temperature of at most 30° C. The residue was stirred with dichloromethane and then combined with the organic phases isolated above. The solvent was removed on a rotary evaporator, and 20 mg of product were isolated as residue.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[CH3:39]>CN(C)C=O>[Cl:38][C:34]1[C:33]([CH3:39])=[C:32]([CH2:31][N:13]2[C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=3[N:11]=[C:12]2[C:14]([F:17])([F:15])[F:16])[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)-3-chloro-2-methylbenzene (1.500 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). Purification on a silica gel column (10-50% EtOAc in hexane) failed to produce pure material. The fractions containing product were combined and the solvent was removed under reduced pressure to afford methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (2.03 g, 4.34 mmol, 95% yield) (only 87% pure). A portion of this material (165 mg) was purified by RP-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give pure desired product (92.3 mg, 0.193 mmol, 4.24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J=2.27 Hz, 1H), 7.28-7.43 (m, 2H), 7.04 (t, J=7.96 Hz, 1H), 5.97 (d, J=7.83 Hz, 1H), 5.71 (s, 2H), 3.93 (s, 3H), 3.66-3.80 (m, 4H), 3.06-3.25 (m, 4H), 2.46 (s, 3H). MS (ES+) m/e 468 [M+H]+