Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:23][CH:24]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])[CH3:25]>>[CH3:35][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:26]([CH:24]([CH3:25])[CH3:23])[C:27]=1[NH:28][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[CH3:34]
Reactant: CCCCCCCCCCCCn1nnc(CCC(=O)O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CCCCCCCCCCCCn1nnc(CCC(=O)Nc2c(C(C)C)cccc2C(C)C)n1

Procedure:
In a manner similar to Example 34, 2-dodecyl-2H-tetrazole-5-propanoic acid was condensed with 2,6-bis(1-methylethyl)aniline to give the title compound, mp 41°-43° C.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=O)=O.C([Li])CCC.[Si](Cl)(C(C)(C)C)(C)C.[C:25]1(=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>O1CCCC1.CCCCCC>[C:27]1([C:10]2[N:6]=[CH:7][NH:8][CH:9]=2)[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH:26]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: O=C1CCc2ccccc21
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=C(c2c[nH]cn2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole (1.9 g, prepared according to Chadwick, D. J. and Ngochindo, R. I., J. Chem. Soc., Perkin Trans. I 1984, 481) in dry tetrahydrofuran (90 ml) at −70° C. under nitrogen, is added dropwise 2.5 M butyllithium in hexane (5.1 ml). After 30 minutes tert-butyldimethylsilyl chloride (2.0 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to 25° C. After 1.5 hours the mixture is again cooled to −70° C. and treated with 2.5 M butyllithium in hexane (5.3 ml). After 30 minutes, 1-indanone (2.1 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to room temperature. The reaction mixture is then quenched with saturated Na2CO3 solution (2 ml), and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with water, dried with sodium sufate and evaporated to dryness under reduced pressure. The bis-protected intermediate is refluxed with 2 N hydrochloric acid (200 ml) for 2 hours. The cooled solution is made basic by ammonium hydroxide solution, and extracted with methylene chloride. The organic layer is washed with water, dried with sodium sulfate and the solvent removed under reduced pressure. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent. The product is converted to the hydrochloride salt in ethyl acetate-ethanol solution, m.p. 232-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:27])[N:7]([CH2:28][CH2:29][CH2:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]=2[CH:42]=1.CN>C(O)C.ClCCl>[NH2:31][CH2:30][CH2:29][CH2:28][N:7]1[C:8](=[O:27])[CH2:9][C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:12][C:11]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:42][C:6]1=2
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN2C(=O)c4ccccc4C2=O)C(=O)C3)cc1OC
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN)C(=O)C3)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring solution of 2-{3-[9-chloro-2-(3,4-dimethoxy-phenylamino)-6-oxo-5,6-dihydrobenzo[b]pyrimido[4,5-d]azepin-7-yl]-propyl}-isoindole-1,3-dione (I-40-c) (51 mg, 0.09 mmol) in ethanol (1.5 mL) was added methylamine (40% by wt in H2O, 0.5 mL). After stirring for 2.5 h at room temperature, the solution was diluted with dichloromethane and washed with water. The organics were dried over magnesium sulfate and concentrated. Preparative HPLC gave I-40: MS Rt═1.32 min. m/z═454 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:30][N:31]([CH2:22][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:6]2[CH2:5][CH2:4][S:3](=[O:27])(=[O:28])[C:2]([CH3:29])([CH3:1])[CH2:7]2)[CH:21]=1)[CH3:32]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)cs1
Yield: 37.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid was added, dimethylamine (0.348 mL, 0.697 mmol) was added. The mixture was stirred 2 hours at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The sodium triacetoxyborohydride polymer bound was removed by filtration (syringe filter 45 um). The product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:47]([F:50])([F:49])[F:48])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:42])(=[O:41])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][CH:21]=3)[C:15]([CH2:43][CH2:44][CH2:45][CH3:46])=[N:14]2)[CH:12]=1>>[C:37]([O:36][C:34]([NH:33][S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[C:15]([CH2:43][CH2:44][CH2:45][CH3:46])=[N:14][N:13]([C:11]3[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=3[C:47]([F:49])([F:48])[F:50])[C:17]2=[O:18])=[CH:21][CH:22]=1)(=[O:41])=[O:42])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Yield: 52 %

Procedure:
Propionyl bromide was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step F) according to the method of Example 26. Purification by silica gel flash chromatography (gradient elution with 0.5-5% MeOH in CH2Cl2) followed by semi-preparative HPLC (Zorbax C8 reverse phase column, elution with 60:40 and then 65:35 MeCN--H2O) gave 13 mg (52%) of the title compound as a solid, mp 158°-161° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 714 (M+2Li)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11]2)=[CH:7][C:6]([C:22]([F:25])([F:24])[F:23])=[CH:5][N:4]=1.Cl.[F:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[F:27][CH2:28][CH2:29][NH:30][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:22]([F:23])([F:25])[F:24])[CH:7]=2)[CH:11]=1)=[O:20]
Reactant: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)O)c2ncccc21
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
See FIG. 19(a). To a stirred solution of 1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (60 mg, 0.177 mmol) in dichloromethane (5 mL) were added 2-fluoroethan-1-amine hydrochloride (26 mg, 0.26 mmol), triethylamine (0.053 g, 0.531 mmol) and T3P (0.33 g, 0.531 mmol) and reaction mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured in to water and extracted with dichloromethane. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed with water,brine and solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using silica gel column chromatography to afford N-(2-fluoroethyl)-1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide as a white solid. Yield: 15 mg. (22.3%). ES+MS m/z: 397. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.66-3.70 (m, 2H), 3.72-3.76 (m, 2H), 4.00 (s, 3H), 4.50-4.52 (m, 2H), 4.62-4.64 (m, 2H), 5.76 (s, 2H), 7.30-7.33 (m, 1H), 7.92 (s, 1H), 8.11 (d, 1H, J=8.3 Hz), 8.32 (s, 1H), 8.50-8.52 (m, 1H), 8.66-8.67 (m, 1H), 8.94 (t, 1H, J=5.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:3]=1
Reactant: CC#CCO
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.4 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 401 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 152 mg of 2-butyn-1-ol, to which 87 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 11 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 395 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (162)).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:38][C:39]1([CH3:50])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41](=[O:49])(=[O:48])[NH:40]1>CN(C=O)C>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][N:40]1[C:39]([CH3:50])([CH3:38])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41]1(=[O:48])=[O:49]
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Reactant: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2S(=O)(=O)N1CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
(S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine (mixture obtained as described in Example 5, Step 1, 100 mg, 0.18 mmol) is dissolved in DMF (2 ml), then K2CO3 (30 mg, 0.22 mmol) and 2,3-dihydro-3,3-dimethyl-1,2-benzisothiazole 1,1-dioxide (71 mg, 0.36 mmol) are added. The mixture is stirred at RT for 5 hours. The reaction is quenched with water (10 ml), and the product extracted with Ethyl Acetate. The organic layer is washed with H2O (3×15 ml), dried over Na2SO4 and evaporated under vacuum. The crude is purified by preparative HPLC (Method 2), to yield 100 mg of the title compound (85% yield). MS/ESI+ 657.51 [MH]+; 1H NMR (400 MHz, acetone) ppm 8.40 (s, 2H), 7.38 (m, 2H), 7.36 (m, 3H), 7.03 (m, 1H), 6.81 (m, 2H), 5.63 (m, 1H), 4.14 (s, 2H), 3.90 (d, 2H), 3.54-3.29 (2H), 3.25-3.00 (2m, 2H), 1.27 (s, 6H), 0.72 (m, 1H), 0.30-0.05 (2 m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[CH3:27]COCC>>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH3:27])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Product: COC(=O)/C(=C(\COC(C)=O)c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
To a suspension of the acid from Example 4 (100 mg) in Et2O (20 mL) was added dropwise excess CH2N2 solution in Et2O. The solution was concentrated and the solid was swished with 2:1 hexane/EtOAc to give 90 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.BrCC1C=C2C(=CC=1)N=CC=N2.CC1C=C2C(=CC=1)N=CC=N2>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(C)nc2ccccc12
Agent: BrCc1ccc2nccnc2c1
Agent: Cc1ccc2nccnc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(CBr)nc2ccccc12

Procedure:
By brominating 2-methyl-4-methoxy-quinazoline [Recl. Trav. Chim. Pays-Bas 76, 401 (1957)] with N-bromosuccinimide in carbon tetrachloride in an analogous manner to the procedure described for the preparation of 6-bromomethylquinoxaline [J. Het. Chem. 11, 595(1974)] from 6-methylquinoxaline there was obtained 2-bromomethyl-4-methoxy-quinazoline as a light yellow solid; MS: 252, 254 (M)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:16][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH2:9])=[N:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
Benzyl bromide (0.86 ml, 7.9 mmol) was added to a mixture of 6-aminonicotinic acid (1.0 g, 7.2 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 16 hr and diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (1×). The EtOAc layer was washed with brine, dried over MgSO4 and concentrated to provide crude solid product. Recrystallization from diethyl ether provided the title compound as a pale yellow solid (0.88 g, 53%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)[CH2:2][CH3:3]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CCCOc1ccc(CCCCCC(=O)O)cc1
Yield: 91.9 %

Procedure:
This compound was synthesized from 6-(p-propoxyphenyl)-5-hexenoic acid (1.49 g, 6 mmol) and Pd/BaSO4 (150 mg) by a hydrogenation reaction. Crystallization (petroleum ether) yielded the product (1.38 g, 92%) as white crystals (mp 42°-43° C.), IR: 3400-2500, 1715 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.55 (m, 8H), 2.40 (m, 4H), 3.90 (t, 2H), 6.95 (q, 4H), 7.90 (bs, 1H). Anal. Calcd. for C15H22 O3 : C, 71.97, H, 8.86%; Found: C, 72.04, H, 8.88%.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30]Br>C(#N)C>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][N:11]1[C:10](=[O:13])[NH:9][C:8](=[O:14])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12]1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=c1[nH]nc(-c2ccccc2)c(=O)[nH]1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: O=c1[nH]c(=O)n(Cc2c(F)cccc2F)nc1-c1ccccc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
To a stirring suspension of 6-phenyl-1,2,4-triazine-3,5-(2H,4H)-dione (6.00 g, 31.7 mmol) in dry acetonitrile (50 mL) under nitrogen was added bis(trimethylsilyl)acetamide (15.7 mL, 63.4 mmol). The resulting yellow solution was heated at 80° C. for 3 hours. The solution was cooled and 2,6-difluorobenzyl bromide (8.20 g, 39.6 mmol) was added in one portion. The mixture was heated at 80° C. under nitrogen for an additional 15 hours. The resulting solution was cooled to room temperature, quenched with methanol (20 mL), and diluted with dichloromethane (175 mL). The mixture was washed with water (75 mL) and brine (70 mL), and dried over magnesium sulfate. Evaporation gave a tan solid that was triturated with cold diethyl ether (5×5 mL). After drying in vacuo, the compound was isolated as a flocculent, off-white solid (8.80 g, 88%).
Reaction SMILES: [CH3:1][N:2]([O:19][CH3:20])[C:3]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[NH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[O:4].[CH:21]([O-])([O-])[O:22]C.[CH3:26]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1>[CH3:1][N:2]([O:19][CH3:20])[C:3]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[NH:9][C:10](=[O:15])[CH2:11][C:12]([O:22][CH3:21])([O:14][CH3:26])[CH3:13])=[O:4]
Reactant: CO
Reactant: CON(C)C(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Product: CON(C)C(=O)Oc1cccc(NC(=O)CC(C)(OC)OC)c1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture of 32.5 g of m-(N-methyl-N-methoxy-carbamoyloxy)-acetylacetanilide, 0.4 g of p-toluene sulfonic acid, 32.5 g of methyl orthoformate and 60 ml of methanol was stirred for 24 hours at 20°C and after the addition of 0.4 g of quinoline, the mixture was evaporated to dryness to obtain 40 g of m-(N-methyl-N-methoxy-carbamoyloxy)-3,3-dimethoxy-butyranilide. The product was dissolved in 175 ml of toluene and the solution was heated at 140°C. for 5 hours while distilling off a toluene-methanol azeotrope. The mixture was then evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 methylene chloride-acetone mixture yielded 11.5 g of m-(N-methoxy-carbamoyloxy)-3-methoxy-crotonanilide with a refractive index nD20 = 1.544.
Reaction SMILES: [CH3:1]S(C1C=C(C=C(OCC)N=1)C(O)=O)(=O)=O.[ClH:17].[CH3:18][S:19]([C:22]1[CH:27]=[C:26]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[C:24]([O:31][CH3:32])[N:23]=1)(=[O:21])=[O:20].C[Mg]Br>CC(C)=O>[ClH:17].[CH3:18][S:19]([C:22]1[CH:27]=[C:26]([C@@H:28]([NH2:30])[CH2:29][CH3:1])[CH:25]=[C:24]([O:31][CH3:32])[N:23]=1)(=[O:21])=[O:20]
Reactant: COc1cc([C@H](C)N)cc(S(C)(=O)=O)n1
Reactant: CCOc1cc(C(=O)O)cc(S(C)(=O)=O)n1
Agent: C[Mg]Br
Agent: Cl
Solvent: CC(C)=O
Product: CC[C@H](N)c1cc(OC)nc(S(C)(=O)=O)c1

Procedure:
The Weinreb amide of 2-methanesulfonyl-6-ethoxy-isonicotinic acid was also converted to (S)-1-(2-methanesulfonyl-6-methoxy-pyridin-4-yl)-ethylamine hydrochloride according to methods described in Example 43 except during the Grignard addition methyl magnesium bromide was added to the Weinreb amide instead of ethyl magnesium chloride to afford the corresponding methyl ketone.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Br:49]C1C=CC(N)=CC=1>C(O)(=O)C>[Br:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(Br)cc1
Yield: 4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 4-bromoaniline (280 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 13 mg (0.034 mmol, 4% yield) of the title compound.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34](O)[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(Cl)c1)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1cccc(Cl)c1)O2

Procedure:
2-(3-Chlorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 635 mg of 2-(3-chloro-phenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.79 (s, 1H), 7.48 (d, 1H, J 0.7 Hz), 7.42-7.37 (m, 3H), 6.71-6.49 (m, 3H), 5.04 (m, 1H), 2.91 (m, 1H), 2.65 (m, 1H), 2.12 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[CH3:34][C:31]1([CH3:35])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1
Reactant: C[C@@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To cis-4-[2-(4,4-dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (648 mg, 1.33 mmol) produced in Example (61a) was added a mixed solvent of ethyl acetate (5 mL)-dichloromethane (1 mL), followed by stirring at room temperature under a nitrogen atmosphere. A 4N solution of hydrogen chloride in ethyl acetate (5 mL, 20 mmol) was added dropwise thereto, followed by stirring for 17 hours under the same conditions. Saturated aqueous solution of sodium carbonate was added to the reaction mixture to make the mixture basic. Dichloromethane and water were added thereto and extraction was performed with dichloromethane. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 451 mg of the title compound as light yellow crystals.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=1)#[N:2].[CH2:14]([N:17]=[C:18]=S)[CH2:15][CH3:16].[N:20]1C=CC=CC=1>>[CH2:14]([N:17]=[C:18]([NH2:20])[NH:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:12]=1)[CH2:15][CH3:16]
Reactant: N#CCCCCc1nccc(N)n1
Reactant: c1ccncc1
Reactant: CCCN=C=S
Product: CCCN=C(N)Nc1ccnc(CCCCC#N)n1

Procedure:
A mixture of 2-(4-cyanobutyl)-4-aminopyrimidine (1.0 g.), n-propylisothiocyanate (0.57 g.) and pyridine (25 ml.) was heated under reflux for 3 hours. The solvent was removed by evaporation in vacuo and the residue was purified by medium pressure chromatography on silica gel using CHCl3 /MeOH 9.75:0.25 v/v as eluant. The purified product (0.85 g.) in EtOH (10 ml.) was added to EtOH saturated with ammonia (30 ml.) and mercuric oxide (0.6 g.). After 15 minutes the reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give 5-(4-[2-propylguanidino]pyrimid-2-yl)valeronitrile (0.85 g.) which was used without further purification.