Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:24])[CH2:4][CH2:5][CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:17])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O>Cl>[ClH:1].[CH3:2][N:3]([CH3:24])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:17]1
Reactant: CN(C)CCCC(O)(CCc1ccccc1O)c1ccccc1
Agent: Cl
Product: CN(C)CCCC1(c2ccccc2)CCc2ccccc2O1
Yield: 10634.6 %

Procedure:
A sample of crude α-[3-(dimethylamino)propyl]-2-hydroxy-α-phenylbenzenepropanol, hydrochloride (1:1) (2 g, 0.017 mmoles) is heated in 100 ml of dilute HCl at 100° C. for 2 hours, cooled and extracted with ether. The aqueous is basified with 10% sodium hydroxide and extracted 4 times with chloroform. The organics are dried (carbonate) and evaporated to 1.8 g of oil which partially crystallized on standing. This is taken up in ether and converted to the hydrochloride which oiled out. Trituration with ethyl acetate gives 0.6 g of white solid (32%). This is recrystallized by dissolving in dichloromethane, adding 30 ml of ethyl acetate, and boiling down to 20 ml. Standing at 25° C. gives, after drying at 80° C., 0.4 g, 3,4-dihydro-N,N-dimethyl-2-phenyl-2H-1-benzopyran-2-propanamine, hydrochloride (1:1) mp 126°-128° C.
Reaction SMILES: CC([Mg]Cl)C.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[F:17][C:18]([F:26])([CH3:25])[C:19](N(OC)C)=[O:20]>C1COCC1>[F:17][C:18]([F:26])([CH3:25])[C:19]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:20]
Reactant: CON(C)C(=O)C(C)(F)F
Reactant: FC(F)(F)c1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)c1cccc(C(F)(F)F)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 2-propylmagnesium chloride in THF (1.3 M, 7.5 ml) was cooled to −15° C. and admixed with 1-iodo-3-(trifluoromethyl)benzene (2.80 g, 10.2 mmol). The reaction mixture was stirred at −15° C. for 1 h, warmed to room temperature and admixed dropwise with a solution of 2,2-difluoro-N-methoxy-N-methylpropanamide (1.43 g, 9.35 mmol: prepared according to Synth. Comm. 2008 (38), 1940-1945), and stirred at room temperature overnight. Then the mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% FA to 30% EA).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]([CH:32]([CH:39]2[CH2:41][CH2:40]2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=1.[H-].[Na+].Cl>C1COCC1>[CH:39]1([CH:32]([C:28]2[CH:27]=[C:26]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH:12]=3)[N:31]=[CH:30][N:29]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:41][CH2:40]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OC2CCCCO2)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OC3CCCCO3)c2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanol (189 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (174 mg) in THF (2.8 mL) was added 60% sodium hydride (25 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled to 0° C., and neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (164 mg) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>CCOCC>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[CH2:14][C:13](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:23]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.48 g, 0.024 mol) in 100 mL ether, n-BuLi (0.024 mol) was added dropwise followed by 50 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of acetophenone (2.95 g, 0.024 mol) in 25 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 25 ML Et2O was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a yellow residue. This residue was washed with hexane, filtered, and oven-dried (40° C.) to yield a pale yellow solid, 4.3 g (0.013 mol, 54%) of the title compound, mp 124°-126° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2.O.[OH-].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A solution of boron tribromide (32.5 ml, 341 mmol) in methylene chloride (60 ml) was added in portions to a solution of 5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. After stirring for 15 minutes at −30° C., the mixture was warmed up to ambient temperature and stirred for 1 hour. Methylene chloride (300 ml) was added in portions and the mixture was cooled to 0° C. Water was added in portions and the mixture was adjusted to pH6 with 4N sodium hydroxide. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g, 93%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C>[CH3:27][O:26][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:28][CH3:29])[N:4]=[C:3]([CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccccc1OC
Reactant: C1COCCN1
Solvent: CCO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(2-methoxyphenyl)quinoline-3-carboxylate (1.0 g), morpholine (1.25 g) and ethanol (13 ml) was stirred at room temperature for 3 days. The precipitated crystals were separated by filtration and recrystallized from ethyl acetate-hexane to give ethyl 6,7-dimethoxy-4-(2-methoxyphenyl)-2-morpholinomethylquinoline-3-carboxylate (0.76 g, 68%). Colorless prisms, mp. 153°-154° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H-].[Na+]>C1COCC1>[CH:8]([N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])([CH3:10])[CH3:9]
Reactant: CC(C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A 0° C. suspension of 1-(2-chloroethyl)-3-isopropylurea (6.00 g, 36.4 mmol) in THF (60 mL) was treated with NaH (60% in mineral oil, 2.50 g, 104 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 1-isopropylimidazolidin-2-one (3.21 g, 69%) as a waxy solid. MS (ESI) m/z: 129.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:30][CH2:31][O-].[Na+]>C(O)C>[CH2:30]([C:16]1[N:15]([C:11]2[C:12]([F:14])=[CH:13][C:2]([Cl:1])=[C:3]([CH:10]=2)[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5])[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:24])([F:26])[F:25])[N:17]=1)[CH3:31]
Reactant: CC[O-]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained isopropyl 5-[2-ethyl-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-2-chloro- 4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.83 ppm (d,1H), 7.39 ppm (d,1H), 6.65 ppm (s,1H), 5.72 ppm (m,1H), 4.48 ppm (m,2H), 1.38 ppm (d,3H), 1.37 ppm (d,3H), 1.29 ppm (t,3H);
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[CH2:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:38]1[C:29]2[CH2:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[CH2:33][N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:5])[C:3]4[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:43][CH:42]=3)=[O:26])[C:28]=2[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A mixture of 366 mg of 2,3,5-trichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 1.5 hours. The reaction mixture is partitioned with water and the organic layer is washed with 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.52 g of white solid residue which is purified by column chromatography on silica gel by elution with 2:1 hexane-ethyl acetate to give 120 mg of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: NC(N)=[S:3].Br[C:6]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:8])[CH3:7]>CO>[CH:9]1([C:6]([SH:3])([CH3:8])[CH3:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(Br)C1CCCCC1
Reactant: NC(N)=S
Solvent: CO
Product: CC(C)(S)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 mmol of thiourea is added to a stirred solution of 1 mmol of (1-bromo-1-methyl-ethyl)-cyclohexane [BRN 2424910] in methanol and the mixture is stirred for 12 hours at room temperature. The solvent is removed under reduced pressure and the residue is then suspended in 10 ml of 2N NaOH and heated at 60° C. for 3 hours. The reaction mixture is cooled to room temperature and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccnc(Cl)c1
Temperature: 125 °C
Yield: 62.4 %

Procedure:
To a solution of 4-bromo-2-chloro-pyridine (1.5 g, 7.8 mmol) in DME/water/EtOH 5:1:1 (20 mL) was added (2-methoxyphenyl)boronic acid (1.49 g, 9.8 mmol), Pd(PPh3)2Cl2 (112 mg, 0.16 mmol), and Na2CO3 (1.65 g, 15.6 mmol). The mixture was heated at 125° C. for 90 minutes in a microwave oven. It was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 100:0 to 80:20) to give the title compound A1 (1.07 g, 62%). MS (ES) C12H10ClNO requires: 219. found: 220 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 110 °C
Yield: 48.3 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-{[4-(methyloxy)phenyl]methyl}-3-piperidinecarboxamide (203 mg, 0.43 mmol), 5 mL of EtOH, Hunig's base (0.30 mL, 1.71 mmol), and hydrazine anhydrous (0.080 mL, 2.56 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered and washed by water, dried in vacuum, and then treated with EtOAc and CH3OH. The solid in the solvent was filtered, washed by EtOAc, and dried in vacuum to afford the title compound (101 mg) as a light yellow solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.07-1.22 (m, 3H), 1.56-1.94 (m, 4H), 2.33 (m, 1H), 2.94 (m, 1H), 3.74 (s, 3H), 4.10-4.22 (m, 1H), 4.23-4.37 (m, 1H), 5.38 (s, 2H), 6.08 (s, 2H), 6.58 (s, 1H), 6.83-6.97 (m, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.57 (dd, J=8.6, 1.26 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.98 (s, 1H) 8.36-8.48 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([OH:25])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH:23]([O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:24]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.00 mg, 2.59 mmol) (obtained as described in Reference Example 34(4)) in methylene chloride (50 ml) were added methanesulfonyl chloride (602 μl, 7.78 mmol) and triethylamine (1.09 ml, 7.78 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.02 g, yield 85%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])(=[O:25])=[O:26])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:10][CH2:9]1
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 96 %

Procedure:
2-Chlorobenzenesulfonic acid 3[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-methylphenyl ester (745 mg, 1.5 mmol), as prepared in the preceding step, was treated with 4 N HCl in 1,4-dioxane (20 mL) at room temperature for 2 H. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10% methanol in methylene chloride saturated with. NH3) to give the title compound as a colorless syrup (570 mg 95%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:11]([Cl:10])(=[O:13])=[O:12])=[C:4]2[N:3]=[CH:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2scnc2c1
Product: O=S(=O)(Cl)c1cccc2scnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Benzo[d]thiazole (1 g, 7.45 mol) was added dropwise to chlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 218 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.41 (s, 1H), 8.41 (dd, J=8.1, 1.0 Hz, 1H), 8.29 (dd, J=7.7, 1.1 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H). LC-MS: m/z 234.7 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](F)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH:32]1([SH:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:37][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: SC1CCCC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SC2CCCC2)cc(C(F)(F)F)c1
Yield: 83 %

Procedure:
Starting with {(R)-4-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (1st step intermediate of example 8-1) and cyclopentanethiol using the method analogous to the method analogous to the one described for the 1st step of example 7-1, {(R)-4-[(3-Cyclopentylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (20.2 mg, 83%) was obtained. MS cald. for C24H30F3N3O4S2 545, obsd. (ESI+) [(M+H)+] 546.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([Cl:14])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:14][C:5]1[N:4]([CH3:15])[C:3](=[O:16])[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(N)c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Cl)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.42 mmol) in dichloromethane was added diisopropylethylamine (0.51 mmol) and benzoyl chloride (0.51 mmol). The reaction was stirred overnight at room temperature. The reaction solution was washed with 5% NaHCO3, and the organic layer was purified on silica. M+1=341.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31]1(O)[CH2:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]2([CH3:30])[CH2:34][CH2:33][CH2:32]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(O)CCC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC1(OC(=O)C#C[C@H]2[C@@H](C(=O)O[C@H](C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)CCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
Using the procedure of Step A of Example 15, 3.9 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 4.3 g of 1-methylcyclobutanol were reacted with stirring at 20° C. for 18 hours. The product was chromatographed over silica gel and was eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 2.7 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-(1-methyl-cyclobutoxycarbonyl)-ethynyl]-cyclopropane-carboxylate melting at 76° C.