Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]([NH:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])=[O:30])=[CH:24][C:23]=2[CH3:32])=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1cc(CC(=O)Cl)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A 22.6 ml (0.16 mole) sample of triethylamine was added to a suspension of 6.78 g (0.054 mole) of glycine methyl ester hydrochloride in 200 ml of spectral grade chloroform. The mixture was cooled to 0° C. and a solution of 16.8 g (0.54 mole) of [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 80 ml of chloroform was added slowly. The mixture was stirred at room temperature overnight. The solution was washed successively with dilute hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized successively from methanol and acetonitrile to give 9.2 g (47% yield) of crystalline methyl N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}-glycinate, m.p. 198°-201° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:32]2[S:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)S1

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 0.7 g of 2,4-thiazolidinedione, 1 g of piperidine and 20 ml of ethanol. The resulting product was a pale brown powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>O1CCOCC1>[CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[N:3]=1
Reactant: O=C(O)CCBr
Reactant: CC1=CC(=O)N=N1
Solvent: C1COCCO1
Product: CC1=NN(CCC(=O)O)C(=O)C1
Yield: 22 %

Procedure:
To a solution of 3-methyl-pyrazol-5-one (5.7 g, 58.0 mmol) in anhydrous 1,4-dioxane was added 3-bromopropionic acid, and the resulting mixture was heated to reflux for 48 h.12 The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromotography using 5-10% MeOH/DCM as an eluent to give 3j (22%) as a solid.13 mp: 210-215° C. (Lit. mp 178-180° C.); 1H NMR (400 MHz, CDCl3): δ 2.21 (s, 3H), 2.76 (m, 2H), 3.14 (s, 2H), 4.14 (m, 2H), 8.01 (brs, 1H); HRMS (m/z): [M−H]− calcd for C7H4N2O3, 169.0619; found, 169.0622.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]2)[CH2:31]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:33]4[NH:30][CH2:31][CH:32]4[N:34]4[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3NCC3N3CCNC(=O)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-ylpiperazin-2-one (44 mg, 0.28 mmol) and 4 Å powdered molecular sieves (250 mg) in MeOH (2 mL) and DCE (5 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-7%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 514 as a yellow foam (42 mg, 31%). LCMS (Method I): RT 2.28 min [M+H]+ 531.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.74 (m, 1 H); 7.31-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.94-3.80 (m, 7 H); 3.66 (bs, 2 H); 3.43-3.33 (m, 4 H); 3.21 (s, 3 H); 3.06 (s, 2 H); 2.58 (t, J=5.37 Hz, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH:1]1([N:6]2[C:15](OS(C(F)(F)F)(=O)=O)=[C:14]3[C:8]([CH2:9][C:10]([CH3:27])([CH3:26])[NH:11][C:12]([CH3:25])([CH3:24])[CH2:13]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]1([N:6]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:14]3[C:8]([CH2:9][C:10]([CH3:27])([CH3:26])[NH:11][C:12]([CH3:25])([CH3:24])[CH2:13]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)Cc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC(C)(C)N1
Product: CC1(C)Cc2nn(C3CCCC3)c(-c3ccccc3)c2CC(C)(C)N1
Yield: 59.5 %

Procedure:
The title compound (129 mg) was prepared as in Example 294, using 263 mg of trifluoro-methanesulfonic acid 2-cyclopentyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 110 mg of phenylboronic acid. MS (ESI): exact mass calculated for C22H31N3, 337.25; found, m/z 338.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.56-7.49 (m, 3H), 7.32-7.30 (m, 2H), 4.51-4.44 (m, 1H), 3.12 (s, 2H), 2.72 (s, 2H), 2.03-1.88 (m, 6H), 1.61-1.57 (m, 2H), 1.45 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:35]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[CH:38][CH:37]=3)[N:34]=[C:33]([CH2:45][OH:46])[CH:32]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:35]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH3:44])=[CH:40][CH:41]=3)[N:34]=[C:33]([CH:45]=[O:46])[CH:32]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CCOc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1ccc(-n2nc(C=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of Dess-Martin periodinane (2.0 g, 4.6 mmol, 2.0 equiv) in CH2Cl2 (10 mL) was added a solution of [5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-methanol (prepared by the method of Example 1, Steps A-C; 0.84 g, 2.3 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. Then the reaction was quenched with 1 M NaOH (10 mL), and the resulting mixture was stirred until the layers separated. The aqueous layer was back-extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 1 M NaOH (20 mL) then H2O (20 mL), dried (MgSO4), and concentrated to provide the pure aldehyde as a dark brown oil (0.59 g, 1.6 mmol, 70%). TLC (silica gel, 1:1 EtOAc/hexanes): Rf=0.62. MS (ESI): mass calculated for C18H14Cl2N2O2, 360.04; m/z found, 361 [M+H]+. 1H NMR (400 mHz, CDCl3): 10.05 (s, 1H), 7.38-7.36 (m, 2H), 7.25-7.21 (m, 2H), 7.0 (s, 1H), 7.0-6.97 (m, 1H), 6.93-6.91 (m, 2H), 4.06 (q, J=7.0 Hz), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:18][C:19](=[O:32])[C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)([CH3:22])[CH3:21])=[N+:15]([O-:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:18][CH:19]([OH:32])[C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)([CH3:22])[CH3:21])=[N+:15]([O-:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(=O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Yield: 80.6 %

Procedure:
0.46 g of sodium borohydride was added to a stirred solution of 4.53 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]pyridine N-oxide in 60 ml of ethanol. After 2 hours the solution was diluted with 200 ml of water and extracted with diethyl ether. The organic phase was evaporated to give 3.67 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyridine N-oxide of melting point 125° C. after recrystallization from ethanol
Reaction SMILES: C(O[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14](=[O:16])[CH3:15])[CH:6]=1)(=O)C.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:6]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)n1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 150 mL sealed tube was placed a solution of 1-acetyl-1H-indol-3-yl acetate (2.5 g, 11.51 mmol) in toluene (80 mL). To this was added tert-butyl piperazine-1-carboxylate (10.71 g, 57.55 mmol). To the mixture was added p-toluenesulfonic acid (400 mg, 2.33 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed 3 times with 200 mL of NaCl(aq.). The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 10:1 petroleum ether/ethyl acetate solvent system. This resulted in 2.9 g (72%) of tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate as a purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([Br:17])=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc(C)n(C)n2)cc1C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nn(C)c(C)c2Br)cc1C
Yield: 49.7 %

Procedure:
At room temperature, a mixture of 3-(4-methoxy-3-methyl-phenyl)-1,5-dimethyl-1H-pyrazole (described in Reference Preparation example 43) 5.9 g, N-bromosuccinimide 5.8 g and chloroform 100 ml was stirred for seventeen hours. To the reaction mixture was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-4-bromo-1,5-dimethyl-1H-pyrazole 4.0 g.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:13][C:14]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:15]=1[O:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:14]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-n3cncn3)cc2)c(Cl)c1

Procedure:
125 mg of 4-[1,2,4]triazol-1-yl-phenol, 212 mg of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester and 207 mg of potassium carbonate are stirred for 24 hours at 50° C. in 4 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.9).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH3:43])[CH:35]=2)=[CH:21]1.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(Cl)Cl.C1COCC1>[CH:46]1([NH:49][CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]3[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=3[C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([CH3:43])[CH:35]=3)=[CH:21]2)[CH2:48][CH2:47]1
Reactant: NC1CC1
Reactant: Cn1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCNC4CC4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a 0° C. solution of trifluoromethanesulfonic acid anhydride (188 mg, 0.67 mmol) in dry methylene chloride (15 mL) was added a solution of 3-[1-(3-hydroxy-propyl)-1H-indol-3-yl)-4(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (100 mg, 0.25 mmol) in THF (10 mL). After 2 hours, cyclopropylamine (200 μl, 5 mmol) was added and stirring continued over night. The reaction mixture was quenched with water. The organic phase was separated, washed with water (3×), dried, and evaporated. The residual red oil was purified by flash chromatography on silica gel eluting with a methylene chloride/ethanol gradient (98:2-95:5). Evaporation of the eluting solvent gave the title compound (70 mg, 64% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[OH:14][C:15]1[CH:16]=[C:17]([NH:18][S:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])(=[O:12])=[O:11])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-hydroxy-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.55 (1H, m), 7.00 (1H, m), 6.70 (2H, m), 6.60 (2H, m), 5.61 (1H, s), 3.83 (3H, s). Anal. Calcd. for C13H10F3NO4S: C, 46.85; H, 3.02; N, 4.20; S, 9.62. Found: C, 46.79; H, 3.03; N, 4.24; S, 9.53.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[O:18][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (6.48 g, 20 mmol; Example D-28 a), benzyl bromide (3.6 ml, 30 mmol), K2CO3 (12.44 g, 90 mmol) and acetone (300 ml) was refluxed with stirring for 2.5 d. The solvent was then evaporated in vacuo. To the residue was added water (100 ml) and the mixture was extracted with EtOAc (100 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give the title compound as a yellowish solid; MS-(+)-ion: M+1=414.1.
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:12]=2)/[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Temperature: 47.5 °C
Yield: 99.4 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-methanesulfonyl4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (273 mg, 0.7 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in a, vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[3-methanesulfonyl4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (262 mg, 100%) as a yellow solid: EI-HRMS m/e calcd for C17H20N4O4S (M+) 376.1205, found 376.1204.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([O:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][O:38][C:33]1[CH:34]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:36]=[C:31]([NH2:30])[N:32]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: COc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Yield: 40.5 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 2-amino-4-chloro-6-methoxypyrimidine (55.0 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 15 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as an off-white solid (55.6 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:25][CH2:26]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)CC1

Procedure:
A solution of 12 ml (0.0718 mol) of diethyl azodicarboxylate (93%) in 80 ml of benzene is added dropwise to a mixture of 14.62 g (0.06791 mol) of cis-4-(N-BOC-amino)-cyclohexanol, 11.1 g (0.068 mol) of N-hydroxyphthalimide, 17.84 g (0.068 mol) of triphenylphosphine and 600 ml of benzene at 20°-30° C., while stirring. The reaction mixture is further stirred at room temperature for 15 hours and then evaporated in vacuo. The residue is purified by flash chromatography on silica gel of particle size 0.04-0.063 mm using methylene chloride. After evaporation of the product-containing fractions, the title compound is obtained as a crystalline residue, m.p. 207°-208° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]3[C:15]4[C:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:21]([C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[S:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH:32]([NH:31][C:29]([C:21]1[S:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([N:13]3[CH:11]4[CH2:10][CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:12]4)[C:15]=2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCN)C4)c2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCNS(C)(=O)=O)C4)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
4-[3-(2-aminoethoxymethyl)-8-azabicyclo[3.2.1]octan-8-yl]-N-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (0.1 g, 0.2 mmol) and was stirred in DCM (10 mL) at 0° C. Triethylamine (0.04 g, 0.06 mL, 0.4 mmol) was added followed by methanesulfonyl chloride (0.04 g, 0.02 mL, 0.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed at reduced pressure. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by acidic prep HPLC (method 1). Desired fractions were combined and concentrated at reduced pressure. The residue was taken up in DCM, washed with sat. NaHCO3 solution, the organic dried over Na2SO4 and concentrated at reduced pressure to afford N-isopropyl-4-[3-[2-(methanesulfonamido)ethoxymethyl]-8-azabicyclo[3.2.1]octan-8-yl]-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (41 mg).