Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34](Cl)(=[O:36])[CH3:35].C(OCC)(=O)C>O1CCCC1>[C:34]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:21])[CH3:22])[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[O:11])[C:5]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(-c2cccs2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-amino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.3 g) in tetrahydrofuran (7 mL) was added sodium carbonate (0.4 g) and the mixture cooled in an ice bath to 0° C. Acetyl chloride (0.11 mL) was added and the solution warmed to room temperature and let stir for 1 h. The mixture was poured into ethyl acetate and washed (1N HCl, a saturated solution of sodium carbonate, and H2O). The resulting solution was dried and the solvent removed by evaporation. The resulting material was purified by chromatography, eluting with methanol:dichloromethane (gradient, 5:95, 12:88) to give the title compound (0.46 g) as a light yellow powder; TLC: Rf =0.47, methanol:dichloromethane (5:95); NMR (DMSO/D2O): 8.77 (s,1), 7.81 (d,1), 7.36 (d,1), 7.09 (t,1), 4.83 (m,2), 4.09 (d,1), 2.26 (m, 1), 2.13 (s,3), 0.93 (d,3), 0.80 (d,3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(Cl)c2)c1CO
Temperature: -10 °C
Yield: 78 %

Procedure:
To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (4.8 g, 20 mmol in THF (50 mL) at −10° C. was added triethylamine (2.9 mL, 21 mmol) and then a solution of ethylchloroformate (1.96 mL, 20 mmol) in THF (10 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (2.0 g, 50 mmol) in water (10 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature over 2 h and diluted with sodium hydroxide (2 N, 30 mL) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (3.5 g, 78%) which was obtained as a clear oil which solidified with time as a white solid. Mp: 66-68° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1cc(OCc2ccccc2)ccn1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(OCc3ccccc3)ccn2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-amino-4-methylthiazole (43.8 mL, 17.5 mmol), 4-(benzyloxy)-2-chloropyridine (4.23 g, 19.3 mmol), potassium phosphate (4.09 g, 19.3 mmol), and toluene (44 mL), and the reaction mixture was degassed with nitrogen. Tris(dibenzylideneacetone)-dipalladium (0) (0.401 g, 0.438 mmol) and 9,9-dimethyl-4,5-bis(diphenyl-phosphino)-xanthene (0.279 g, 0.482 mmol) were added, and the reaction mixture was degassed with nitrogen. The reaction mixture was warmed to 90° C., degassed water (15 mL) was added, and reaction mixture was stirred at 90° C. overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered through a small plug of silica gel, and the filtrate was concentrated down to 50 mL of ethyl acetate and filtered to afford 4-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (2.50 g, 47.5% yield) as a white solid. 1H NMR (CDCl3) δ 9.29 (bs, 1H), 8.15 (d, 1H), 7.39 (m, 4H), 7.35 (m, 1H), 6.53 (dd, 1H), 6.41 (d, 1H), 6.36 (d, 1H), 5.07 (s, 2H), 2.33 (s, 3H). Mass spectrum (esi) m/z=298 (M
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1([C:15]2[C:16]([O:18][C:19](=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:19]1([OH:27])[O:18][C:16](=[O:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1Br
Reactant: O=C1OC(=O)C(c2ccccc2)=C1c1ccccc1
Solvent: ClCCl
Product: O=C1OC(O)(Nc2ccccc2Br)C(c2ccccc2)C1c1ccccc1
Temperature: 200 °C
Yield: 40 %

Procedure:
A mixture of 2-bromoaniline (2.18 g, 12.7 mmol) and 2,3-diphenylmaleic anhydride (3.17 g, (12.7 mmol) were stirred and heated under argon to 200° C. for 6 h. The mixture was cooled to room temperature, dissolved in CH2Cl2 (50 mL), dried (MgSO4) and evaporated. Purification of the crude product by flash chromatography on silica gel (5×25 cm column, 2 L of 3:7 hexanes/CH2Cl2, then CH2Cl2) gave first 4-(2-bromoanilino)-2,3-diphenyl-4-hydroxybutyrolactone (2.16 g, 40% yield) as a yellow solid, mp 162-164° C. and then the title compound as a bright yellow solid, mp 178-180° C., 2.00 g, 39% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13](O)=[O:14].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:20].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:19]([CH3:20])[CH3:18])=[O:14]
Reactant: COc1c(Br)cc(F)c2[nH]cc(CC(=O)O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(Br)cc(F)c2[nH]cc(CC(=O)N(C)C)c12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To the solution of 8-9 (11.5 g, 38.0 mmol) in THF (300 mL) was added HATU (22.0 g, 58.0 mmol) Me2NH.HCl (3.1 g, 38.0 mmol) at 0° C. After the mixture was stirred for 5 minutes, DIPEA (12.3 g, 95.3 mmol) was added. The mixture was stirred overnight at room temperature. The volatile was removed and the residue was purified by flash chromatography (Silica gel, DCM/MeOH=50:1) to afford 8-10 (9.0 g, 72%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:18][S:19]([CH2:22][CH2:23][NH2:24])(=[O:21])=[O:20].Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:24][CH2:23][CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCNc1cc(Cl)nc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30 %

Procedure:
In a 250 mL round-bottom flask was placed 4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 500 mg, 1.85 mmol) in dichloromethane (20 mL) to give a colorless solution. 2-(methylsulfonyl)ethanamine.HCl (325 mg, 2.04 mmol) was added followed by addition of triethylamine (0.77 mL, 5.55 mmol). The mixture was stirred at room temperature for 19 hours and was then refluxed for 21 hour. Excess potassium carbonate was added and heating under reflux was continued for 6 hours. The mixture was cooled to room temperature and stirred at room temperature for 2 weeks. The mixture was diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (20-100% ethyl acetate in hexanes) to give the title compound as a yellow solid (196 mg, 30%). HRMS: 357.0417 [M+H]+. For [M+H]+ mass error=−0.2 mDa or −0.60 ppm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=1
Reactant: Cc1cccc(Cl)n1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-4,6-dimethylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C13H19N3, 217.2; m/z found, 218.1 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[NH3:28]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([NH2:28])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(N)=O
Yield: 80 %

Procedure:
The title compound (0.2 g, 80%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4 mL) by an analogous procedure to that described in example 31. mp: 107-109° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O:9][C:10](=O)[O:11]C(C)(C)C)([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>O1CCOCC1>[C:10]([NH:4][CH2:3][CH2:1][OH:2])([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethanolamine (0.1 mol), di-tert-butylcarbonate (0.15 mol), dioxane (50 mL) and aq. 2 N NaOH (25 mL) is stirred at RT for 24 hr. The dioxane is removed by evaporation under reduced pressure. Water (50 mL) is added to the aqueous mixture and the mixture is extracted with CH2Cl2 (4×25 mL). The combined organic layers are dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Pure N-BOC-ethanolamine is obtained by purification of the crude product with the use of flash chromatography over silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[OH:12]O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-:12])[CH:8]=[CH:7]2
Reactant: Brc1cccc2ccncc12
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccc2cccc(Br)c2c1
Temperature: 75 °C

Procedure:
A solution of 8-bromo-isoquinoline (prepared by the method of F. T. Tyson, J.A.C.S., 1939, 61, 183) (1.25 g, 6 mmol) in acetic acid (5 ml) was treated with 27% aqueous hydrogen peroxide solution (1.8 ml) and heated at 75° C. overnight. The mixture was evaporated and the residue partitioned between aqueous sodium carbonate solution and dichloromethane, re-extracting with dichloromethane twice more. The combined organic extracts were dried and evaporated. The residue was triturated with ether/petrol and isolated by filtration (1.14 g, 85%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[C:1]([O:9][CH2:15][CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1

Procedure:
0.20 mol of benzoic acid was mixed with 260 ml of ethanol, and 30 ml of con. sulfuric acid was added. The reaction mixture was reacted completely and crystallized from ether. Ethyl benzoate was obtained (71.1%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][N:12]1[CH2:17][C:16](=O)[NH:15][C:14]2([CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[C:13]1=O.[OH-].[K+]>CCOCC>[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][C:14]2([CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH2:13]1
Reactant: CN1CC(=O)NC2(CCc3ccccc3C2)C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CN1CCNC2(CCc3ccccc3C2)C1
Yield: 70 %

Procedure:
To a suspension of lithium aluminum hydride (114 mg, 3 mmol) and aluminum chloride (400 mg, 3 mmol) in ether (5 ml), a suspension of 1'-methylspiro[tetralin-2,3'-piperazine]-2',5'-dione (80 mg, 0.33 mmol) in ether (2 ml) was added, while the former was stirred under ice cooling conditions, followed by further stirring at room temperature for 10 minutes. After a 1N aqueous potassium hydroxide solution was added, the precipitate was filtered off. The filtrate was washed by sequential additions of a 1 N aqueous potassium hydroxide solution and chloroform. After the mother liquor was eluted with saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (50 mg, 70%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])C(OC(C)(C)C)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1

Procedure:
A solution of 2.9 g (5 mmol) of ethyl 8-[N-(p-chloro- phenylsulfonyl)-N-(t-butoxycarbonyl)amino]-4-[2-(3-pyridyl- oxy)-ethyl]octanoate in 30 ml trifluoroacetic acid is stirred at room temperature. After 18 hours the reaction mixture is evaporated to dryness. The residue is dissolved in methylene chloride and the solution is washed with saturated NaHCO3 solution, dried and evaporated. The residue is chromatographed on silica gel using 1:1 ethyl acetate/methylene chloride as eluent to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoate.
Reaction SMILES: [Br:1]Br.Cl[C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1>C(O)(=O)C>[Br:1][C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1
Reactant: BrBr
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Solvent: CC(=O)O
Product: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Temperature: 100 °C
Reaction time: 48 h
Yield: 20.2 %

Procedure:
Bromine (1.26 ml, 25 mmol) was added dropwise to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (2.3 g, 8.2 mmol) in 25 ml of acetic acid and the mixture was stirred for 48 h at 100° C. in a sealed flask. The cooled mixture was evaporated to dryness and the residue which consisted of two major products was triturated with water to give a solid, which was recrystallised from ethyl acetate/methanol with decolorising charcoal to afford 538 mg (20%) of the title compound. An analytically pure sample was obtained by preparative hplc on a Source RPC 15 column using acetonitrile/water (20:80) with 0.1% TFA as eluent; mp 282-283° C.; 1H-NMR (DMSO-d6): δ1.16 (d, 6H), 3.86 (m, 1H), 7.14 (s, 1H), 7.18 (br, 1H), 10.74 (s, 1H); MS: m/e 323/325 (M+); (C8H10N3Br1O2S2); calc C, 29.64; H, 3.11; N, 12.96; found C, 29.49; H, 3.04; N, 12.59.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C(O[CH:8]=[CH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C.FC(F)(F)C(Cl)=O.C(OCC)=C.Cl>CO>[F:12][C:11]([F:14])([F:13])[C:10]1[NH:4][C:2](=[O:3])[N:1]=[CH:8][CH:9]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NC(N)=O
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: O=c1nccc(C(F)(F)F)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8.74 moles of urea in 2.2L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel was added dropwise over about 3 hours under N2 atmosphere an equimolar amount of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether. The temperature of the reaction mixture was kept below 15° C. After 15 min, 1.35 L of a concentrated HCl solution (32%) was added to the cooled suspension obtained and a clear solution was obtained. The solution was slowly heated to 60° C. and after 2 hours stirring, a suspension was formed. After overnight stirring at 60° C. and subsequently 1 h stirring at 0 to 5° C., the precipitate was filtered off. The residue was washed with water until neutral pH and subsequently with hexane (ca. 500 ml). After overnight drying on a rotary evaporator under reduced pressure in a 2-L flask, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained as colorless crystals. The yield was 1.2 kg (85% of the theoretical yield).
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].F[C:22](F)(F)[C:23](O)=[O:24].C(Cl)(=O)C.[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C.O>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([O:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:18][C:17]([O:19][CH3:20])=[C:16]([C:23](=[O:24])[CH3:22])[CH:15]=2)=[CH:12][N:11]=1
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Reactant: O=C(O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)Cl
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine in anhydrous dichloroethane (20 mL) was added to trifluoroacetic acid (0.06 mL, 0.77 mmol), acetyl chloride (0.31 mL, 4.37 mmol), and aluminum trichloride (583 mg, 4.37 mmol). After stirring for 22 hours at room temperature, water (1.2 mL) was added to the reaction at 0° C. The mixture was dried using anhydrous sodium sulfate and concentrated in vacuo. Aqueous sodium hydroxide (0.2M, 10 mL) was added to the residue and the mixture was heated at 100° C. for 1 hour. After cooling, the reaction was extracted with dichloromethane. The dichloromethane layer was dried using anhydrous magnesium sulfate, concentrated, and purified with silica gel column chromatography eluting with 96/4/0.1 dichloromethane/methanol/ammonium hydroxide to yield 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (72 mg, 31%) as off-white solid, MS (M+H)=317. Also recovered was 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-2-hydroxy-4-isopropyl-phenyl]-ethanone (43 mg, 20%) as pale yellow solid, MS (M+H)=303.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:34]([CH3:48])[CH2:35][CH2:36][N:37]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([C:14]2([CH:11]3[CH2:10][CH2:9][N:8]([CH:34]([CH3:48])[CH2:35][CH2:36][NH2:37])[CH2:13][CH2:12]3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure C with the above carbamate (170 mg, 0.37 mmol), then using general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) followed by general procedure D gave 3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (46 mg, 68% over 3 steps).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:42]([CH3:41])(=[O:44])=[O:43])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCO)cc32)nc1-c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOS(C)(=O)=O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 0.266 g (0.583 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-hydroxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41d), 0.152 mL (0.875 mmole) of ethyldiisopropylamine and 5 mL of dichloromethane at 0 degrees was added 0.054 mL (0.7 mmole) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 1 hour and then diluted with 30 mL of dichloromethane. The mixture was washed with 10 mL of saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 0.248 g of 4-(3-chloro-phenyl)-2-[6-(4-methanesulfonyloxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41e) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1cc2cccnc2[nH]1
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by f-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)