Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[N:23]1([C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CCC1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 38.0 mg, 0.090 mmol) and azetidine (Aldrich; 0.018 mL, 0.269 mmol) in DMSO (0.8 mL), heating at 60° C. for 40 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(azetidin-1-yl)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (13.3 mg, 0.040 mmol, 44% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1H, br. s.), 7.91 (1H, dd, J=7.5, 1.1 Hz), 7.59 (1H, dd, J=7.8, 1.0 Hz), 7.36 (1H, t, J=7.7 Hz), 7.14 (1H, d, J=2.2 Hz), 6.96 (1H, s), 4.41 (4H, t, J=7.6 Hz), 3.42 (2H, td, J=6.6, 2.1 Hz), 2.87 (2H, t, J=7.0 Hz), 2.60 (3H, s), 2.35-2.45 (2H, m). m/z (ESI, +ve) 334.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH2:11](NC1C2N=CC=CC=2N=CN=1)C1C=CC=CC=1.C(N)C1C=CC=CC=1.C([O-])([O-])OCC.C(OC(=O)C)(=O)C.[SH-:50]>C(O)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:9](=[S:50])[NH:10][CH:11]=[N:8][C:6]=2[CH:7]=1
Reactant: N#Cc1cnc(N)cc1N
Reactant: c1ccc(CNc2ncnc3cccnc23)cc1
Reactant: [SH-]
Agent: CCOC([O-])[O-]
Solvent: NCc1ccccc1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: Nc1cc2nc[nH]c(=S)c2cn1

Procedure:
2,4-Diamino-5-cyanopyridine can be cyclized directly to many 4-benzylaminopyridopyrimidine derivatives by treatment with the benzylamine and formic acid at high temperature. For less nucleophilic amines 2,4-diamino-5-cyanopyridine is converted via ethyl orthoformate/acetic anhydride treatment, followed by cyclization with hydrosulfide ion in anhydrous conditions, to give 7-amino-4-thiono-3H-pyrido[4,3-d]pyrimidine. S-Alkylation and displacement with an appropriate amine gives the desired product. If R4 is not amino, the amine can be acylated, or reductively alkylated. Alternatively 2,4-diamino-5-cyanopyridine can be hydrolysed to the corresponding amide, and this species can be cyclized to 7-amino-4-oxo-3H-pyrido[4,3-d]pyrimidine with orthoformate. Diazotization of the 7-amine and replacement with fluorine allows for introduction of other amine and alkoxide nucleophiles at the end of the synthesis after the C4 substituent has been introduced in the usual manner. Diazotization and replacement of the amine with bromide allows for Stille couplings at the 7-position.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccnc2)cc1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C (10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:17]4[CH:16]=[CH:15][S:14][C:18]=4[CH2:19][CH2:20]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(s1)CCNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccsc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine. Yield: 56 mg (72% of theory). ESI-MS: m/z=377 (M+H)+; Rt(HPLC): 1.41 min (Method B).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([C:17]3[N:21]([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[N:20]=[N:19][N:18]=3)[C:14]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13][C:12]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:36]([O:35][C:12]1[CH:13]=[C:14]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[N:20]=[N:19][N:18]=2)=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)OC)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2′,4′-Bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid methyl ester (1 mmol) was dissolved in mixture of THF (5 ml) and water (5 ml). LiOH (72 mg, 3 mmol) was added, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete, the reaction was cooled to r.t., acidified with 1M HCl to pH=1. After extraction with ether (25 ml×3), the combined organics were washed with water (25 ml) and saturated brine (25 ml) and dried over Na2SO4. After filtration and concentration, 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid was obtained as white solid in quantitative yield. M.p.: 59-63° C.; 400 MHz 1H NMR (DMSO-d6) δ: 12.98 (br s, 1H), 8.18 (t, J=1.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.54-7.28 (m, 13H), 5.32 (s, 2H), 5.31 (s, 2H), 4.27 (t, J=7.2 Hz, 2H), 3.18 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 1.93 (pent, J=6.8 Hz, 2H); LCMS: 551 [M+H].
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=7[F:25])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6F)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(2-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (154 mg; compound B81) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (124 mg; compound C10) and HBTU (261 mg) in DCM/DMF (15 ml/1 ml) in the presence of DIPEA (324 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and by preparative HPLC as a solid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH:17]([Mg]Cl)([CH3:19])[CH3:18].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[CH2:26]([O:25][C:23]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3](=[O:2])[CH2:4][CH:5]1[CH:17]([CH3:19])[CH3:18])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nccc(OC)c2cc1OC
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
4,6,7-Trimethoxyquinoline (0.3 g, 1.4 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL). The mixture was cooled to −78° C., and isopropyl magnesium chloride (0.8 mL of a 2M solution in tetrahydrofuran, 1.6 mmol) was added. The mixture was stirred at −78° C. for 10 min, then ethyl chloroformate (0.16 mL, 1.6 mmol) was added. The reaction was warmed to room temperature and stirred overnight, then 1N HCl (6 mL) was added. After stirring for 1 h, the tetrahydrofuran was removed in vacuo, and the remaining aqueous phase was extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 0.26 g crude product. Purification by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent afforded the title product (0.23 g, 51%). 1H NMR (CDCl3) δ 0.85 (d, 3H), 0.9 (d, 3H), 1.33 (t, 3H), 1.8 (m, 1H), 2.8 (dd, 1H), 2.93 (dd, 1H), 3.9 (s, 3H), 3.95 (s, 3H), 4.3 (m, 2H), 4.5 (m, 1H), 7.3 (bs, 1H), 7.37 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]([F:23])([F:22])[F:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:17]2[CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:34])[CH:26]=[CH:25]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: Fc1ccc(C2CCN(CC3CNCC3C(F)(F)F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1

Procedure:
A solution of 0.12 g (0.36 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine, 0.069 g (0.43 mmol) of indole-7-carboxylic acid, 0.088 g (0.72 mmol) of DMAP and 0.097 g (0.5 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 10 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:5) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and 1-methylpiperazine (0.33 mL, 5 eq) was added at 0° C. The solution was stirred overnight at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.185 g, 92% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7](/[CH:19]=[CH:20]\[C:21]([O:23]C)=[O:22])[CH:6]=1.O[Li].O>CO.C1COCC1.O>[CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7](/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[CH:6]=1
Reactant: COC(=O)/C=C\c1cc(CC(=O)N(C)CCc2ccccc2)ccc1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2)c(/C=C\C(=O)O)c1
Reaction time: 12 h

Procedure:
To a solution of 160 mg (0.36 mmoles) of cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbomethoxyvinyl)phenyl]acetamide in 10 ml of a 1:1:1 MeOH/THF/H2O mixture at 0° C. is added 76 mg (1.8 mmoles) of LiOH·H2O. The reaction mixture is allowed to come to room temperature and stirred at room temperatured for 12 hours after which time the eraction mixtured is concentrated down in vacuo, taken up in H2O washed with ether (2 times) and acidified to pH 3-4 with 1N HCl. The aqueous layer extracted with ether (2 times). The ether extracts are combined and are dried with MgSO4, filtered and concentrated down in vacuo to give cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)phenyl]acetamide. (m.p. 48°-51° C.)
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1.[OH2:16]>CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:15])(=[O:1])=[O:16])=[N:12][CH:13]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Br)cn1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add a suspension of oxone®(4.97 g, 8.1 mmol) in 10 mL water to a solution of 5-bromo-2-methylsulfanyl-pyridine (1.1 g, 5.4 mmol) in 10 mL methanol, stir at r.t. for 1 h and remove methanol under vacuum. Extract the aqueous residue with dichloromethane, dry the organic extracts over sodium sulfate, filtrate and concentrate under reduced pressure to obtain 1.24 g of 5-bromo-2-methanesulfonyl-pyridine. MS (m/e): 237 (M+H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=CC=CC=2)[C:5](NS(C2SC=CC=2)(=O)=O)=[CH:4][C:3]=1SC1N(C)N=NN=1.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](/[N:39]=[C:40]2\[CH:41]=[C:42]([S:51][C:52]3[N:56]([CH3:57])[N:55]=[N:54][N:53]=3)[C:43](=[O:50])[C:44]3[C:49]\2=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([S:36]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([OH:50])=[C:42]([S:51][C:52]3[N:56]([CH3:57])[N:55]=[N:54][N:53]=3)[CH:41]=2)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35].[CH3:57][N:56]1[C:52]([S:51][C:42]2[C:43](=[O:50])[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)/[C:40](=[N:39]/[S:36]([C:31]3[CH:32]=[CH:33][C:34]([C:2]4[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:29][CH:30]=3)(=[O:38])=[O:37])/[CH:41]=2)=[N:53][N:54]=[N:55]1
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Product: Cn1nnnc1Sc1cc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ccccc2c1O
Yield: 99 %

Procedure:
3,4-dichloro-N-(4-hydroxy-3-(1-methyl-1H-tetrazol-5-ylthio)naphthalen-1-yl)benzenesulfonamide (14z) was prepared according to the procedure for 14d except using 13z, which afforded the title compound 39.8 mg (99.0%) as an off-white solid.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2=[O:17])(=O)C.Cl.N[OH:20].[N:21]1C=CC=[CH:23][CH:22]=1>>[OH:20][N:21]=[C:22]([C:5]1[CH:4]=[C:16]2[N:7]([C:8](=[O:17])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1)[CH3:23]
Reactant: NO
Reactant: CC(=O)c1cnn2c(=O)[nH]c3ccccc3c12
Reactant: c1ccncc1
Agent: Cl
Product: CC(=NO)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.5 g (0.0066 mole) of 1-acetylpyrazolo[1,5-c]quinazolin-5(6H)-one and 2.8 g of hydroxylamine hydrochloride in pyridine are stirred overnight at room temperature. The reaction mixture is poured into 450 ml ice-water and stirred for 30 minutes. The fine white precipitates that form are filtered off, washed well with water and dried in vacuo at ~90° for 20 hours. Yield: 1.4 g, m.p. 340°-342°; 87.5%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN1CCCC1=O>[CH2:10]([NH:16][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCCCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCNc1cc(C#N)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and hexylamine (1.15 ml, 8.7 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 4 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.26 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(O)=O.[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:14][C:7]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: Cc1ccccc1C#N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(Br)cc1C#N
Temperature: 50 °C
Yield: 82.8 %

Procedure:
117 g (998 mmol) of 2-methylbenzonitrile was dropped to 1000 g of a Na-X type zeolite dried powder (Zeolam type F-9 manufactured by Toyo Corp.; 100 mesh or less) while stirring under air cooling. The resulted mixed was allowed to cool, and after cooled to 50° C. or lower, to this was added 213 g (1.33 mol) of bromine, and the mixture was stirred at 80 to 85° C. for 1.5 hours, then, cooled to 15° C. or lower. This was added into mixture of 100 g of potassium carbonate, 500 ml of water and 2 L of methanol at 10° C. or lower. The mixture was stirred for 0.5 hours, then, filtrated. The filtrated residue, zeolite powder was washed with 90% methanol water (2.2L×2), the filtrate and washed solution were combined, and concentrated until the total liquid quality reached 750 ml. The resulted while crystal was filtrated, and the crystal was washed with water to obtain 162 g (826 mmol) of 5-bromo-2-methylbenzonitrile.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9](Cl)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:9]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)(=[O:22])=[O:23])=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cnc(Cl)nc1Cl
Reactant: NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cnc(Cl)nc1NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 19 h

Procedure:
A solution of 0.95 g (3.83 mmol) of 2,4-dichloro-pyrimidine-5-carboxylic acid-tert-butylamide in 6 ml of THF is mixed at room temperature while being stirred with a suspension that consists of 1.00 g (3.86 mmol) of N-(3-amino-propyl)-3-nitro-benzenesulfonamide in 9 ml of THF/0.55 ml of triethylamine. After 19 hours, the precipitate that is formed is suctioned off and washed with ethyl acetate. The filtrate is spun in, and the residue that is formed is purified by chromatography (hexane/ethyl acetate 2:1, Flashmaster II). 0.79 g (1.67 mmol, corresponding to 44% of theory) of the product is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[N+:6]([O-:8])=[O:7])=[O:4]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.9 %

Procedure:
2-Bromoacetyl bromide (173 μL, 1.99 mmol) was added dropwise to a solution of 2-nitroaniline (250 mg, 1.81 mmol) and pyridine (293 μL) in CH2Cl2 (9 mL). The reaction mixture was stirred at room temperature for 45 min. The mixture was then diluted with CH2Cl2 (10 mL), washed with aqueous 1 N HCl solution (10 mL), water (10 ml) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound (431 mg, 92% yield) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[OH:9].[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][Cl:36]>>[ClH:36].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH:11]([NH:23][CH2:22][CH2:21][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=1
Reactant: COc1cc(CC(C)=O)ccc1O
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Product: COc1cc(CC(C)NCCC(c2ccccc2)c2ccccc2)ccc1OCc1cccc(C(F)(F)F)c1
Product: Cl

Procedure:
Reacting the (3-methoxy-4-hydroxyphenyl)-acetone with the 3,3-diphenylpropylamine, reducing the resulting Schiff's base as shown above and reacting the resulting saturated compound with 3-trifluoromethylbenzyl chloride, the 1-[3-methoxy-4-(3-trifluoromethylbenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane hydrochloride is obtained, melting at 142° to 146° after recrystallization from isopropanol.