Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1N(C)N=CC=1[C:8](O)=[O:9].[NH:11]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[N:11]1([CH:8]=[O:9])[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13][CH2:12]1
Reactant: Cn1ncc(C(=O)O)c1Br
Reactant: C1CCC2NCCCC2C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=CN1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 159.6 %

Procedure:
5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid (29.6 mmol), decahydro-quinoline (Aldrich Chemical Company, Inc., Milwaukee, Wis.; 4.9 g, 35.5 mmol), diisopropylethylamine (11 mL, 59.2 mmol), and PyBrop (bromo-tris-pyrrolidino-phophonium hexafluorophosphate) (Chem-Impex International, Inc., Wood Dale, Ill.; 16.6 g, 35.5 mmol) were mixed together in dry dichloromethane (70 mL) and dry dimethylformamide (20 mL). The mixture was stirred overnight at room temperature. At this time, the mixture was diluted with dichloromethane and extracted three times with water. The combined dichloromethane extracts were evaporated, and the residue was purified by flash chromatography, eluting with 0-10% ethyl acetate/hexanes to give 5-bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)-methanone (7.9 g, 82% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 656.1 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH:6]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(Br)C=C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:17]1([C:19]([OH:21])=[O:20])[C:18]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH2:1]
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCC1(C(=O)O)c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.50 mol/l, n-hexane solution) was slowly added dropwise to a solution of fluorene-9-carboxylic acid (3.0 g) in THF in an argon atmosphere at −78° C. The mixture was stirred at −78° C. for 30 min and then at 0° C. for 30 min. The stirred mixture was again cooled to −78° C. Allyl bromide (2.5 ml) was slowly added dropwise thereto at −78° C., and the mixture was stirred at −78° C. for 30 min and then at room temperature overnight. After the disappearance of fluorene-9-carboxylic acid was confirmed by TLC, a saturated aqueous ammonium chloride solution was slowly added to the reaction solution. Ethyl acetate was then added thereto to perform extraction. The organic layer was washed with a saturated aqueous sodium chloride solution and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 9-allyl-9H-fluorene-9-carboxylic acid (3.58 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:32][CH2:31][C:30](=[O:33])[N:29]1[CH2:34][C:35](O)=[O:36]>>[O:27]=[C:28]1[NH:32][CH2:31][C:30](=[O:33])[N:29]1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:6][CH:7]=1)=[O:36]
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reactant: O=C(O)CN1C(=O)CNC1=O
Product: O=C(CN1C(=O)CNC1=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2-(2,5-dioxo-imidazolidin-1-yl acetic acid as described in example 217. The product with the molecular weight of 483.49 (C26H21N5O5); MS (ESI): 484 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pd].C(O)C>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[O:13][CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1coc(-c2ccc([N+](=O)[O-])c(OC)c2)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1coc(-c2ccc(N)c(OC)c2)n1
Yield: 67.5 %

Procedure:
The same operation as in Example (95b) was performed using methyl 2-(3-methoxy-4-nitrophenyl)-1,3-oxazole-4-carboxylate obtained in Example (102c) (1.46 g, 5.25 mmol), 10% Pd/C (0.3 g) and ethanol (20 mL). The resulting solid was washed with dichloromethane/hexane to obtain 0.88 g of the title compound as a colorless solid (67%).
Reaction SMILES: [O:1]1[CH:4]([CH2:5][CH2:6][CH3:7])[CH:2]1[CH3:3].[N-:8]=[N+:9]=[N-:10].[Li+].CCOCC.ClCCl>CN(C)C=O.C(OCC)(=O)C.CCCCCC.O>[OH:1][CH:2]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:3][N:8]=[N+:9]=[N-:10]
Reactant: CCCC1OC1C
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCCCC(O)CN=[N+]=[N-]
Reaction time: 48 h
Yield: 99.3 %

Procedure:
To a solution of 2,3-epoxyhexane 33 (4.155 g, 41.48 mmol) in N,N-dimethylformamide (DMF) was added lithium azide (3.8 g, 77.6 mmol) and the resulting mixture was stirred for 48 hours. The reaction mixture was poured into a solvent mixture of ether, dichloromethane and water, and stirred for a few minutes. The organic layer was separated from the aqueous layer and then the aqueous phase was extracted three times with ether-dichloromethane mixture. The combined organic extracts were washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated on rotory evaporator to give an oil. Flash column chromatography of the oil using 10% ethyl acetate in hexane as eluent afforded 34 (5.9 g, 99.3%): 1H NMR (300 MHz, CDCl3) δ3.775 (m, 1H, CHOH), 3.38 (dd, 1H, CHN3), 3.25 (dd, 1H, CHN3), 2.2 (d, 1H, OH), 1.6-1.2 (m, 6H, CH2 's), 0.95 (t, 3H, CH3).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]3([OH:45])[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]3)=[CH:30][C:29]=2[CH3:46])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2>O1CCCC1.C(OCC)(=O)C.Cl.[Na+].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]3([OH:45])[CH2:42][CH2:41][S:40](=[O:43])(=[O:44])[CH2:39][CH2:38]3)=[CH:30][C:29]=2[CH3:46])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(O)CCS(=O)(=O)CC6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 M aqueous NaOH solution (250 μL) is added to a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-((1,1-dioxo-4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (85 mg) in tetrahydrofurane (4 mL). The mixture is stirred at room temperature for 12 hours. Then the mixture is diluted with ethyl acetate and neutralized with 1 M aqueous HCl solution. The resulting mixture is diluted with saturated aqueous NaCl solution and the phases are separated. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 80 mg; LC (method 7): tR=1.04 min; Mass spectrum (ESI+): m/z=611 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26]>CN(C)C=O.O>[CH3:23][NH:24][C:25]([N:12]1[C:13](=[O:14])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10](=[O:15])[NH:11]1)=[O:26]
Reactant: CN=C=O
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O

Procedure:
To a solution of 2.5 g of 4-(3',5'-dichlorophenyl) urazole in 10 ml of N,N-dimethylformamide were added a drop of triethylamine and, in turn, 0.8 g of methyl isocyanate dropwise at room temperature with agitation. The reaction was continued for one additional hour under the same conditions and the reaction mixture was poured in water to precipitate crystals which were filtered and recrystallized from acetoneethanol to obtain 1-methylcarbamoyl-4-(3',5'-dichlorophenyl) urazole in an amount of 2.1 g (yield being 68%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C.[OH-].[Na+]>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:9]=1[CH3:10]
Reactant: Sc1ccccn1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccco2)ccnc1CSc1ccccn1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
One equivalent (2.92 g) of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 min. to a solution of 2-mercaptopyridine (1.12 g/10 mmol) in 40 ml of ethanol and 21 ml of 1 N sodium hydroxide solution. The mixture is then stirred for 2-3 h at 50-60° C. and for a further 3-4 h at RT.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10](=S(C)(C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH:10]([Br:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 20 %

Procedure:
To a stirred solution of 2.73 grams (0.01 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate prepared in Example XLVII (Compound 205) in 35 milliliters of chloroform was added a solution of 1.37 grams (0.01 mole) of bromine in 35 milliliters of chloroform, dropwise, at ambient temperature. The mixture became dark orange and showed a slight exothermic effect during the feed period. Stirring was continued for 20 minutes, at which time the solution was a clear light yellow in color. It was then evaporated free of solvent and stored at 5° C. for a period of about 64 hours causing the residue to crystallize. Two recrystallizations from hexane-ethyl acetate (10:1) gave 0.58 gram (0.002 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-bromo-3-oxopropanoate having a melting point of 117° C.-119° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17]1)=[O:15])C1C=CC=CC=1.[OH-].[Li+].OO.S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>O1CCCC1.O>[C@H:16]1([C:14]([OH:15])=[O:30])[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17]1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CC12CCOCC2
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CC12CCOCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3.700 g of (R)-4-benzyl-3-((R)-6-oxaspiro[2.5]-octane-1-carbonyl)oxazolidin-2-one in 20 ml of tetrahydrofuran/water 3:1 is cooled to 0° C. 0.608 g of lithium hydroxide and 1.95 ml of hydrogen peroxide (30% in water) are added to the solution, which is stirred at room temperature for 6 hours. Saturated aqueous sodium thiosulphate solution is added to the reaction mixture, which is then extracted with tert-butyl methyl ether. The aqueous phase is adjusted to pH 2 with 4M HCl and extracted with dichloromethane. The combined extracts are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a colourless liquid and is employed without further purification for the next stage. Rf=0.55 (dichloromethane-methanol-water-acetic acid 150:54:10:1); Rt=2.10 (Gradient I).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[CH:14][CH:13]=2)=[N:8][CH:9]=1)[CH3:2].[NH2:30]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:30]=[C:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=2)[CH:9]=1)[CH3:2]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CCOc1ccc(C#Cc2ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2)nc1
Solvent: C1CCOC1
Product: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of tert-butyl [(1S)-2-{4-[(5-ethoxypyridin-2-yl)ethynyl]phenoxy}-1-methylethyl]carbamate (2.25 g) in THF (30 mL) was added 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (1.75 g, containing water) at room temperature, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. To the residue were added DMF (20 mL) and potassium carbonate (1.18 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (1.18 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]([CH3:25])[CH3:24])[C:11]=2[N:10]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(O)(C(F)(F)F)=O>>[CH2:21]([C@H:13]1[N:12]([CH:23]([CH3:24])[CH3:25])[C:11]2[N:10]=[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[N:18]=[CH:17][C:16]=2[N:15]([CH3:19])[C:14]1=[O:20])[CH3:22]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNS(C)(=O)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 126) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with methane sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 419.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 8.87 (s, 1H), 8.81 (d, 1H, J=5.0 Hz), 8.27 (d, 1H, J=5.0 Hz), 8.22 (s, 1H), 4.75 (d, 2H, J=5.0 Hz), 4.60 (m, 1H), 4.44 (m, 1H), 3.33 (s, 3H), 2.93 (s, 3H), 1.84 (m, 1H), 1.73 (m, 1H), 1.36 (t, 6H, J=7.5 Hz), 0.76 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH:10]=[O:11])[CH2:7][CH2:6][C:5]([CH3:8])=[CH:4][CH:3]1[CH3:9].[CH:12]([Mg]Br)([CH3:14])[CH3:13]>>[CH3:13][CH:12]([CH3:14])[CH:10]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([CH3:8])=[CH:4][CH:3]1[CH3:9])[OH:11]
Reactant: CC(C)[Mg]Br
Reactant: CC1=CC(C)C(C)(C=O)CC1
Product: CC1=CC(C)C(C)(C(O)C(C)C)CC1

Procedure:
2-methyl-1-(1,2,4-trimethyl-3-cyclohexen-1-yl)-1-propanol (compound 1) was prepared from 1,2,4-trimethyl-3-cyclohexene-1-carboxaldehyde and isopropylmagnesium bromide (reaction 1 above).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([S:20]([C:23]2[C:24]([CH:28]=[O:29])=[CH:25][S:26][CH:27]=2)(=[O:22])=[O:21])[CH:14]=[CH:13]3)=[CH:6][CH:5]=1>CO.C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([S:20]([C:23]2[C:24]([CH2:28][OH:29])=[CH:25][S:26][CH:27]=2)(=[O:22])=[O:21])[CH:14]=[CH:13]3)=[CH:8][CH:9]=1
Reactant: O=Cc1cscc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1cscc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.3 %

Procedure:
Sodium borohydride (21 mg, 0.53 mmol) was added to a solution of 4-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}thiophene-3-carbaldehyde (42 mg, 0.11 mmol) in MeOH (5 mL) and CH2Cl2 (2 mL) and the mixture stirred at ambient temperature. After 40 minutes, the mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL) and the organic fraction washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford solid material which was washed with Et2O and further dried in vacuo to yield (4-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}-3-thienyl)methanol as a white solid (40 mg). 1H NMR (400 MHz, d6-DMSO): δ 8.70 (1H, s), 8.59 (1H, d, J=3.4 Hz), 8.34 (2H, t, J=6.2 Hz), 8.19 (1H, d, J=8.8 Hz), 8.03 (1H, dd, J=1.7, 8.6 Hz), 7.93-7.85 (3H, m), 7.53 (1H, d, J=3.4 Hz), 7.38 (2H, t, J=8.9 Hz), 5.31 (1H, t, J=5.6 Hz), 4.53 (2H, d, J=5.7 Hz). m/z (ES+) 384 [(M-OH)+].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[CH3:14]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Agent: B
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CO)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended in THF (50 mL) and borane-THF complex (1M in THF, 26 mL, 26 mmol) added drop-wise over ˜15 minutes. The reaction mixture was stirred under argon at room temperature overnight then quenched with water (52 mL) and extracted with ethyl acetate (×3). The combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% ethyl acetate/petroleum ether yielded the title compound as a cream solid (0.379 g). δH (MeOD, 400 MHz) 7.36 (2H, m), 7.25 (1H, d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H, s). MS (ES): MH+ 180.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:19][C:18](=O)[N:17]4[CH:21]=[CH:22][N:23]=[C:16]4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C1C=CC=CC=1)C.C(=O)(O)[O-].[Na+]>>[Cl:26][C:18]1[N:17]2[CH:21]=[CH:22][N:23]=[C:16]2[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(=O)[nH]3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: CN1CCC(c2ccc(-c3cc4nccn4c(Cl)n3)cc2)CC1
Temperature: 50 °C
Yield: 71.2 %

Procedure:
To a suspension of 7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (0.728 g, 2.361 mmol) in phosphoryl trichloride (12 mL, 131.1 mmol) under nitrogen was added N,N-diethylaniline (0.9390 mL, 5.902 mmol). The reaction was then heated to 50° C. for 4 hours. The reaction was concentrated, and the residue obtained was treated with 15 mL of a 1:1 mixture of ice and saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (4×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated with diethyl ether and the solid was collected by means of vacuum filtration. The solid was saved. The filtrate was concentrated and the resulting residue purified by silica gel column chromatography, eluting with 20% methanol in dichloromethane. The product-containing fractions were concentrated under reduced pressure and the material was combined with the triturated solid to afford 5-chloro-7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidine (550 mg, 1.68 mmol, 63% yield). MS (apci) m/z=327.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].C1C=CC=CC=1.[H-].[Na+].C[O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17](=O)[CH:16]=1>CCOCC>[CH3:1][S:2]([CH2:4][C:17]1[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[C:15](=[O:14])[CH:16]=1)=[O:3]
Reactant: CS(C)=O
Reactant: COc1cc(=O)oc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CS(=O)Cc1cc(=O)c2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A mixture of dimethyl sulfoxide (500 ml), benzene (375 ml) and sodium hydride (52 g of a 57% oil dispersion, 1.24 mole), was heated at 75° under nitrogen until all the solid dissolved giving a clear gray-green solution. The solution was cooled in an icebath and 4-methoxycoumarin (75 g, 0.425 mole) was added. The reaction mixture was stirred at room temperature for one hour and poured into excess anhydrous ether. Th ether was decanted from the insoluble salts, which were washed several times with fresh ether. The salts were dissolved in a minimum of cold water and acidified with ice-cold 5 N hydrochloric acid. The acidified solution was extracted with chloroform (5×40 ml). The extracts were combined, dried over Na2SO4, and evaporated at reduced pressure to give a solid product. Recrystallization from absolute ethanol gave white crystals (57.3 g, 61%), m.p. 142°-146°.