Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].B.CSC.CO>O1CCCC1>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(NC=O)cc1)NC(C)=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(C[C@H](NC(C)=O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100.0 g of methyl (2S)-2-ethanamido-3-(4-methanamidophenyl)propanoate in 3000 cm3 of tetrahydrofuran at 20° C. with stirring are added, under nitrogen, 378 cm3 of a 2 M solution of borane/methyl sulphide in tetrahydrofuran such that the temperature of the reaction mixture is maintained below 25° C. At the end of the addition, the reaction mixture is kept stirring for 1 hour at 25° C. and 1000 cm3 of methanol are then added dropwise. At the end of the addition of the methanol, the mixture is stirred at 25° C. under nitrogen for 16 hours and then concentrated under reduced pressure (20 kPa) at a temperature of 40° C. At the end of the concentration, the mixture is allowed to return to 25° C. under nitrogen and 1000 cm3 of dichloromethane and 1000 cm3 of saturated aqueous sodium chloride solution are then added. The mixture is stirred for 30 minutes at 25° C. and is then separated by settling of the phases. The lower organic phase is removed and dried over anhydrous sodium sulphate. After filtration of the sodium sulphate, the solution is concentrated at 30° C. under reduced pressure (20 kPa).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:36]2[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=2)=[CH:8][C:7]=1[CH3:21]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (5.6 g) obtained in Example 1, step F, 2-chloro-5-(trifluoromethyl)pyrimidine (2.36 g), tetrakistriphenylphosphinepalladium (0.678 g), 2M aqueous sodium carbonate solution (17.6 mL) and dimethoxyethane (52.8 mL) was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.93 g).
Reaction SMILES: NC1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1.O1[C:22]2([CH2:27][CH2:26][CH2:25][CH:24]([C:28]3[CH:33]=[C:32]([NH2:34])[N:31]4[N:35]=[CH:36][CH:37]=[C:30]4[N:29]=3)[CH2:23]2)[O:21]CC1.O1C2(CCC(C3C=C(N)N4N=CC=C4N=3)CC2)OCC1>>[NH2:34][C:32]1[N:31]2[N:35]=[CH:36][CH:37]=[C:30]2[N:29]=[C:28]([CH:24]2[CH2:25][CH2:26][CH2:27][C:22](=[O:21])[CH2:23]2)[CH:33]=1
Reactant: Nc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12
Agent: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Nc1cc(C2CCCC(=O)C2)nc2ccnn12

Procedure:
3-(7-Aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone was synthesized in a manner similar to the synthesis of 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but 5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH3:33])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][CH2:32][CH3:33])([O-:29])=[O:28]
Reactant: CCCC[N+](=O)[O-]
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitrobutane (0.080 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.084 g (59%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.20 (m, 3H), 5.17 (dd, J=4.4, 10.0 Hz, 1H), 2.63 (m, 4H), 1.65 (m, 6H), 1.36 (m, 4H) 1.00 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.6, 128.7, 128.6, 126.0, 94.3, 39.5, 35.9, 31.8, 31.4, 28.7, 23.3, 19.5, 13.6 ppm; IR νmax (cm−1) 3027, 2935, 2858, 1730, 1560, 1454, 1373, 1031, 749, 700; HRMS (FAB) calcd for C16H23NO3 (MNa+) 300.1570, found 300.1575.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:21][C:20]3[C:19](=[O:22])[NH:18][C:17]([CH:23]4[CH2:27][CH2:26][CH2:25][NH:24]4)=[N:16][C:15]=3[CH:14]=2)[C:10]([CH3:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(C(C)C)C(C)C)C.CN(C)C=O>O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:21][C:20]3[C:19](=[O:22])[NH:18][C:17]([CH:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:16][C:15]=3[CH:14]=2)[C:10]([CH3:28])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nn(Cc2ccccc2)cc1-c1cc2nc(C3CCCN3)[nH]c(=O)c2s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCCC1c1nc2cc(-c3cn(Cc4ccccc4)nc3C)sc2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 6-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one (391 mg) produced in Example 124, step C, ethyl 2-bromoacetate (184 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (258 mg) and N,N-dimethylformamide (5 ml) was stirred at 60° C. for 2 hr. Ethyl acetate (50 mL) and water (50 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (140 mg) as a colorless solid.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.C(O)(=O)C.[Br:15]Br>>[Br:15][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)csc12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Thieno[3,2-d]pyrimidin-4(3H)-one (38.0 g, 0.25 mol) was dissolved in acetic acid (143 mL, 2.5 mol), and bromine (40.4 mL, 0.78 mol) diluted with acetic acid (122 mL, 2.1 mol) was slowly added to the solution prepared. The reaction solution was stirred in a sealed reactor for 18 hours at 120° C. The reaction solution was cooled to room temperature and acetic acid was removed by distillation under reduced pressure. The reaction mixture was poured into an ice water to generate a solid compound, and the resulting solid compound was filtered and dried. The title compound was obtained without purification (37.5 g, 65%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[F:21])=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NCc1ccccc1F
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccccc1CNCCCOc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 2-fluorobenzylamine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=100%, [M+H]+=392.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:6]1)([CH3:26])[CH3:25]
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)nc2)cc1
Reactant: CC(C)I
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(=O)n(C(C)C)c2)cc1

Procedure:
N-{3-[4-(6-Hydroxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (168 mg, 1.49 mmol) was reacted with 2-iodopropane in analogy to example 36f. Yield: 26 mg (15%), M+H+: 343.20. N-{3-[4-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yloxy)phenyl]1-methylpropyl}acetamide was obtained as by-product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:25]([O:27][CH2:28][CH3:29])=[O:26])#N>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:6]2
Reactant: CCOC(=O)C#N
Reactant: COc1ccc2c(c1)CCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cc(OC)ccc2C1=O
Reaction time: 0.67 h

Procedure:
To a solution of 5-methoxyindan-1-one (15.0 g, 92.5 mmol) in THF (370 mL) at −78° C. was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (200 mL, 200 mmol) via an addition funnel during 15 minutes. After 40 minutes, ethyl cyanoformate (14.0 mL, 142 mmol) was added during several minutes and the reaction mixture was allowed to warm gradually. After 30 minutes, the reaction mixture was partitioned between EtOAc and dilute aqueous HCl and the organic phase was washed with water and brine and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure gave ethyl 5-methoxy-1-oxoindane-2-carboxylate as a brown solid which was used in the next step without purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1COC1C=CC(CO)=CC=1.C[O:20][C:21](=[O:49])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])=[CH:34][CH:33]=2)=[CH:26][C:25]=1[CH3:48]>>[Cl:47][C:41]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=1[CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][S:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]([OH:49])=[O:20])=[C:25]([CH3:48])[CH:26]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)cc1C
Agent: OCc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 32A. MS m/z 265 (M-Cl). Step 3. Preparation of {4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (Compound 32C)
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)(=[O:11])=[O:10])[C:5](O)=[O:6].CCO.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.[Pd]>[CH2:3]([CH:4]1[C:5](=[O:6])[NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9](=[O:11])(=[O:10])[NH:8]1)[CH:2]([CH3:21])[CH3:1]
Reactant: CC(C)CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CC1NS(=O)(=O)c2ccccc2NC1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A stirred suspension of N-(3′-methyl-1′-carboxybutyl)-2-nitrobenzenesulfonamide (6.7 g; 21.2 mmol) and 10% Pd/C (200 mg) in abs. EtOH was hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. A solution of the crude product in dry THF (50 ml) at 0° C. was added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warmed to rt. and left with stirring over night. The reaction mixture was filtered and the solid material was washed with THF. The combined organic fractions were evaporated to dryness and the remanense added H2O and extracted with EtOAc. The combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 3 g (53%) product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][N:6]=[C:5]([CH2:8]O)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(OCC)C>[Br:32][CH2:8][C:5]1[CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[O:7][N:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)c1cc(CBr)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
2.47 g of (5-trifluoromethyl-isoxazol-3-yl)methanol was dissolved in 80 ml of diethyl ether, and 6.56 g of triphenylphosphine and 8.9 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.14 g of 3-(bromomethyl)-5-trifluoromethylisoxazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[C:50]2[CH2:49][CH2:48][CH2:47][C@@H:46]([OH:51])[C:45]=2[CH:44]=[CH:43][CH:42]=1)=[NH:40]>CN(C=O)C.CC(=O)OCC>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][C:50]2[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:42][CH:43]=[CH:44][C:45]1=2
Reactant: N=C(NO)c1cccc2c1CCC[C@H]2O
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4O)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, chromatographed (EA/hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O3: 375.4; found 376.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.3 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.91-4.83 (m, 1H), 4.79 (dq, J=12.0, 6.0 Hz, 1H), 3.20 (dt, J=17.8, 5.4 Hz, 1H), 3.01 (dt, J=13.3, 6.4 Hz, 1H), 2.13-1.81 (m, 4H), 1.79 (d, J=7.2 Hz, 1H), 1.47 (d, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 10% IPA/hexane: 99.4% ee, tR=40.85 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:5][C:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(C)(OCC)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(CCl)(OCC)OCC
Temperature: 40 °C
Yield: 77.1 %

Procedure:
A mixture of 1,1,1-triethoxyethane (97.3 g) and N-chlorosuccinimide (88.1 g) in carbon tetrachloride (600 ml) was warmed to 40° C. and then irradiated with an ultraviolet lamp. The reaction became exothermic and then subsided upon completion of the reaction. The precipitated succinimide byproduct was filtered off and the filtrate was concentrated to remove carbon tetrachloride. The residual liquid was distilled to obtain pure 2-chloro-1,1,1-triethoxyethane (91.0 g; b.p. 91° C./25 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-bromobiphenyl (18.6 g, 79.8 mmol) in chloroform (150 mL) is added dropwise chlorosulfonic acid (11.2 g, 96 mmol). A white solid precipitate forms during the addition. The reaction is stirred at room temperature for 6 hr, at which time the precipitate is collected by filtration and the precipitate is then washed with cold chloroform. The product is dried under vacuum to give a white solid product. The product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:21]=4[N:22]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1

Procedure:
To 3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile (prepared as described in example 43, 0.29 g, 0.56 mmol), methanol saturated with hydrogen chloride gas (15 mL) is added at 0° C. with stirring. The reaction mixture is allowed to reach rt and stirred there for 12 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (15 mL) and ammonium carbonate (0.520 g, 3.37 mmol) is added. After stirring at rt for 24 h, the reaction mixture is concentrated and the residue obtained is purified by column chromatography to afford 3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.96-8.03 (m, 3H), 7.77 (d, 2H), 7.69 (m, 1H), 7.63 (m, 2H), 7.34-7.43 (m, 5H), 6.96 (br, 1H), 5.60 (br, 2H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 534.2.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])([O-:33])=[O:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N+:31]([O-:33])=[O:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 35.1 mg (0.21 mmol) of 2-nitrophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 6 mg (11.2% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.ClC1[CH:13]=[C:14](C=CC=1)[NH2:15].O1CCNC1=O.C(=O)=O>CCOCC.O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:6][CH2:13][CH2:14][NH2:15])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: O=C1NCCO1
Agent: O=C=O
Solvent: CCOCC
Solvent: O
Product: NCCNc1cccc(Cl)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
Gaseous hydrogen chloride was reacted with m-chloroaniline in ether at 0° C. to prepare the m-chloroaniline hydrochloride. This reactant (65.6 g, 0.4 mole) was then intimately mixed with 2-oxazolidinone by grinding with a mortar and pestle. The ground mixture was then added to a 250 ml flask equipped with a mechanical stirrer and gas vent. The flask was heated in an oil bath to 160° C. with stirring. The solid mixture melted and CO2 evolution commenced in about 15 minutes. Heating was continued for about six hours whereupon the flask was cooled and the contents dissolved in water and filtered. The filtrate was then basified with aqueous caustic causing a yellow oil to separate. Extraction with methylene chloride, drying and distillation under vacuum gave 55 g (80 percent yield) of N-(3-chlorophenyl)-1,2-ethanediamine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2nccs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
N-Boc-piperazine (1.42 g, 7.6 mmol, 1.1 eq) was dissolved in 1,2-DCE (20 mL). To this solution, 2-thiazolecarboxaldehyde (0.780 g, 6.91 mmol, 1 eq) in 1,2-DCE (4 mL) was added followed by the portionwise addition of sodium triacetoxyborohydride (2.05 g, 9.68 mmol, 1.4 eq). The mixture was stirred at room temperature for 3 h and then washed with an aqueous saturated solution of NaHCO3. The organic layer was dried (MgSO4), the solvent removed in vacuo and the crude product was purified by column chromatography on a Biotage SP1 system (hexanes/EtOAc; v/v 6:4) to give the title compound (1.95 g, 100%); 1H-NMR (500 MHz, CDCl3): δ 1.47 (s, 9H, C(CH3)3), 2.54 (t, 4H, J=4.7 Hz, piperazine N(CH2)2), 3.48 (t, 4H, J=5.0 Hz, piperazine N(CH2)2), 3.89 (s, 2H, NCH2), 7.30 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.72 (d, J=3.5 Hz, 1H, thiazole 4-H); LC (Method B)-MS (ESI, m/z): Rt=2.84 min—306 [(M+Na)+, 100%].