Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:3]=1)=[O:38]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(NC(=O)c3cccc(Br)c3)c2)nc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a mixture of 2-(3-amino-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (§) (20.0 mg, 0.06 mmol) in THF (2 mL), triethylamine (13 μL, 0.09 mmol) and 3-bromobenzoylchloride (10 μL, 0.07 mmol) was added and stirred at 50° C. for 2 hrs. The mixture was quenched with concentrated HCl and purified on BondElut® SCX (Varian Incorporated). Formed solid was washed with CH2Cl2 to give the title compound (25.3 mg, 81%). 1H-NMR (400 MHz, d6-DMSO) δ 10.43 (s, 1H), 9.68 (s, 1H), 8.15 (t, 1H), 8.08 (s, 1H), 7.97 (dt, 1H), 7.81 (ddd, 1H), 7.75 (brd, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.36 (dt, 1H), 7.31 (t, 1H), 7.05-6.98 (2H), 6.42 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 517, 519.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH3:35])[C:20]2[NH:21][C:22](=O)[C:23]3[CH:33]=[CH:32][CH:31]=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26]=2[N:27]=1.C(Cl)Cl.[CH:39]([N:42](C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[C:39]([C:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[N:30][C:24]=2[N:25]([CH2:28][CH3:29])[C:26]2[N:27]=[C:17]([CH3:16])[CH:18]=[C:19]([CH3:35])[C:20]=2[N:21]=1)#[N:42]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Agent: CC[N+](CC)(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [C-]#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(C#N)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluorornethanesulfonic anhydride (0.24 mL, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one in 15 mL of methylene chloride containing 0.25 mL (14 mmol) of diisopropylethylamine. The resulting mixture was refluxed under Ar for 3 hr. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 mL of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate, and the solution washed with water and brine, and then dried (magnesium sulfate). The solution was concentrated in vacuo and the residue was chromatographed over silica (eluted with 5% ethyl acetate/hexane). The resulting solid was crystallized from heptane to provide 33 mg of the title compound as red crystals, m.p. 154°-155° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:29][C:30]1[CH:57]=[CH:56][C:33]([C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH:40]=[C:39]3[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]=[CH2:55])[CH:49]=2)=[O:35])=[CH:32][CH:31]=1>C1COCC1.COCCOC>[Cl:29][C:30]1[CH:57]=[CH:56][C:33]([C:34]([OH:35])([C:21]2[N:17]([CH3:16])[C:18]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:19][CH:20]=2)[C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH:40]=[C:39]3[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]=[CH2:55])[CH:49]=2)=[CH:32][CH:31]=1
Reactant: Cn1ccnc1Sc1ccccc1
Reactant: C=Cc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COCCOC
Product: C=Cc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4ccc(Cl)cc4)c4cnc(Sc5ccccc5)n4C)cc23)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
2,2,6,6-tetramethylpiperdine (4.5 mL, 26.5 mMol) was dissolved in a solution of anhydrous THF (100 mL) and anhydrous 1,2-dimethoxyethane (50 mL) under an atmosphere of dry N2 and the solution was then cooled to −78° C. To this solution was added 2.5 M n-butyllithium in hexanes (9.6 mL, 24.1 mMol) and the mixture was stirred for 20 minutes. To this solution was added 1-methyl-2-phenylthio-1-H-imidazole (4.58 g, 24.1 mMol) and the solution was stirred at −78° C. for 45 minutes. 6-(4-Chloro-benzoyl)-1-methyl-4-(3-vinyl-phenyl)-1H-quinolin-2-one (9.64 g, 24.1 mMol) was then added and the solution was slowly warmed to ambient temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the solution was partitioned between water and EtOAc. The aqueous layer was washed 2 more times with EtOAc. The EtOAc extracts were combined and dried over Na2SO4, filtered and concentrated under vacuum to give a yellow oil. The oil was chromatographed on flash silica gel eluting with a gradient from EtOAc/hexanes (1:1) to EtOAc/hexanes (4:1) to give 8.66 g of the titled compound as a foam.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][C@@H:10]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:14][CH2:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1.[OH-].[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:23]([N:12]1[CH2:13][CH2:14][C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C@@H:10]([CH2:9][NH:8][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CNS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were added to chloroform (1 mL) solution of 41 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 2.5 hours. 39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were further added to the reaction liquid, and stirred at room temperature for 1 hour. Still further, 39 μL of triethylamine and 18 μL of dimethylsulfamoyl chloride were added to the reaction liquid, and stirred at room temperature for 1 hour. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 27 mg of the entitled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>C(O)C>[CH:17]1([CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:19][CH2:18]1
Reactant: NCC1CC1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c([N+](=O)[O-])c1
Yield: 54.6 %

Procedure:
A mixture of 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C, 849 mg, 3.2 mmol), and cyclopropylmethylamine (333 μL, 3.8 mmol) in ethanol (15 mL) was stirred under reflux for 16 h. After removal of solvent, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1 as eluent) to afford the title compound (521 mg, 55%) as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1.CN(C)C(=O)C.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([OH:50])[CH:48]=3)[N:43]=[CH:42][N:41]=2)=[N:37][CH:38]=1>O>[Cl:7][C:8]1[C:9]([O:50][C:47]2[CH:48]=[C:49]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][N:41]=[C:40]3[NH:39][C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][N:37]=2)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1
Reactant: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCCCOC5CCCCO5)cc4Cl)cc23)cn1
Temperature: 180 °C
Reaction time: 14 h
Yield: 70.7 %

Procedure:
Potassium tert-butoxide (0.89 g, 7.90 mmol) and 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (2.52 g, 8.69 mmol) were added to an N,N-dimethylacetamide solution (2.5 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (1.0 g, 3.95 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform/methanol (10:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=3:1 to 3:2) to obtain 6-({3-chloro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (1.46 g, yield: 71%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[O:11][CH:8]1[CH2:9][CH3:10]>O>[OH:11][CH:8]([CH2:9][CH3:10])[CH2:7][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4]
Reactant: CCC1CO1
Reactant: CC(C)(N)CO
Solvent: O
Product: CCC(O)CNC(C)(C)CO
Yield: 82 %

Procedure:
In this example, 1780 g (20 mol) of 2-amino-2-methyl-1-propanol and 10 g water were added to a 5-liter three-necked flask equipped with a thermometer, condenser, magnetic stirrer, dropping funnel, and nitrogen inlet. 1,2-butylene oxide (1584 g, 22 mol) was added into the flask slowly at 90° C.-100° C. with stirring and under a nitrogen atmosphere. The resulting crude product was N-(2'-hydroxybutyl)-2-amino-2-methyl-1-propanol (82% yield with 90% alkanolamine conversion as determined by GLC).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl.O>CCO>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([F:17])([F:18])[F:16])[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Yield: 73.6 %

Procedure:
A mixture of 5-chloro-6-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (230 mg, 0.743 mmol), SnCl2.2 H2O (1.90 g, 7.43 mmol) and EtOH (300 mL) was refluxed for 24 h, then rota-evaporated to dryness. The residual solid was washed on a Bursch funnel with water (6×15 mL), and dried to give 153 mg (74%) of the title compound as a yellow powder. Mp >360° C. 1H NMR (DMSO-d6) 11.777 (s, IH), 11.360 (s, 1H), 7.140 (s, 1H), 5.499 (s, 2H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)=[O:18].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:18])=[O:5]
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCCCCBr)CC2)CC1
Reactant: C=C(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.6 g, 41.8 mmol) in dimethylformamide (30 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.5 g, 37.5 mmol) in dimethylformamide (50 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 6-bromo-hexyl ester (15.0 g, 33.8 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. over night. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from acetonitrile to afford a white waxy solid. Further purification is achieved by preparative HPLC using water/acetonitrile as eluant.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9](=[O:26])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[N:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:35].[ClH:35].[ClH:35].[NH2:7][C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[N:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
[1-benzyl-2-oxo-2-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-yl)-ethyl-carbamic acid tert-butyl ester (0.046 mg) was dissolved in DCM (5 mL) and HCl/dioxane (0.5 mL) was added. The suspension was stirred at room temperature for 3 hours, after which it was concentrated to give (2R)-2-amino-3-phenyl-1-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-1-yl)-propan-1-one trihydrochloride (0.031 g, 86%). Rt 1.55 min. MS (ESI+) [M+H]+363.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[N:12]=[C:13]=[S:14])[CH3:2].[CH2:15]([NH:17][CH2:18][C:19](O)=[O:20])[CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:15]([N:17]1[CH2:18][C:19](=[O:20])[N:12]([C:4]2[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:13]1=[S:14])[CH3:16]
Reactant: CCNCC(=O)O
Reactant: CCc1cccc(C(C)C)c1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(C(C)C)c1N1C(=O)CN(CC)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 28 using 20.5 g of 2-ethyl-6-isopropylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane). Crystallization from diethyl ether/hexane afforded pure title compound (7.5 g) as a white solid, m.p. 77°-79° C. Anal. Calcd. for. C16H22N2O S: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12; H, 7.77; N, 9.69. Mass spectrum i2EI, M.+) m/z 290.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 2-fluoro-5-formylbenzonitrile (5.0 g, 33.5 mmol), 4-chloro-3-(trifluoromethyl)phenol (6.59 g, 33.5 mmol) and potassium carbonate (13.9 g, 101 mmol) in N,N-dimethyl formamide (DMF) (10 mL) was stirred at 60° C. overnight and filtered. Purification via Biotage-C18 system afforded the title product (6 g) as a pale solid. LC-MS (ESI): m/z 326 [M+H]+; 3.51 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30].O>O1CCCC1>[Cl:20][C:10]1[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:12][C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)CCl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 2-amino-5-chloro-6-[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 1, METHOD A, Step 2, 5 g, 16.7 mmol) in tetrahydrofuran (150 mL) were added potassium carbonate (5.1 g, 36.6 mmol) and chloroacetyl chloride (2.7 mL, 33.3 mmol) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 h and at room temperature for 15 h. After addition of water, the mixture was extracted with ethyl acetate and washed with brine. The combined organic layer was dried over sodium sulfite and concentrated to give the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=3)[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:37][CH3:38].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:37][CH3:38]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(Oc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)C(=O)O)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (6.6 g, 11.9 mmol) in methanol (30 ml) was added 2N aqueous sodium hydroxide solution (11.9 ml, 23.8 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from hexane to give (2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionic acid (5.28 g, 84%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([CH2:31][CH3:32])[C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(I)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:11])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: IC1CCCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCC3)c2n1
Yield: 41 %

Procedure:
2,6-Dichloropurine (1 mmol), powdered potassium carbonate (4 mmol) and cyclohexyliodide were vigorously stirred in 5 mL DMSO overnight. After evaporation of the solvent the product was extracted (water/diethylether) and purified by column chromatography (silicagel/1% MeOH in CHCl3). Crystallization from diethylether gave product in 41% yield, mp 116-121° C.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Product: CC(C)NS(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N-isopropyl-2,4-dichlorothiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with 65% strength aqueous isopropylamine solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[CH:5]2.O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+:27].[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([O-:14])=[O:13])[CH:6]=[CH:5]2.[Na+:27]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc2cc(Cl)ccc2c1
Temperature: 70 °C
Yield: 96.6 %

Procedure:
6-Chloronaphth-2-ylsulphonyl chloride (2.61 g) was added in one portion to a stirred mixture of sodium sulphite heptahydrate (4.71 g), sodium bicarbonate (1.64 g) and water (25 ml) which had been heated to 70° C. The resultant mixture was heated to that temperature for 3 hours and then allowed to cool slowly to ambient temperature. The crystalline precipitate was isolated giving sodium 6-chloronaphth-2-ylsulphinate (2.4 g) which was used without further purification.