Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][O:25][C:26]([NH:28][C:29](=NC(OC)=O)SC)=[O:27]>C(O)(=O)C.CO>[CH3:24][O:25][C:26]([NH:28][C:29]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH:21]4[CH2:22][CH2:23]4)=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:3][C:2]=2[N:1]=1)=[O:27]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(NCC4CC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.7 %

Procedure:
To a solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 3,4-diamino-phenyl ester (648 mg) in acetic acid (4.5 ml) and methanol (40 ml) at 80° C. was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg). The reaction mixture was refluxed for 4 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 4-(cyclopropylmethyl-amino)-benzene sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (378 mg) as a beige solid. Mass spectrum: 417 [M+H]+; retention time=13.16 minutes.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14](Cl)(=[O:16])=[O:15]>[NH4+].[Cl-]>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14]([NH2:2])(=[O:16])=[O:15]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])ccc1S(N)(=O)=O
Yield: 68.9 %

Procedure:
To a concentrated solution of ammonium hydroxide (28%, 2.5 mL, 20 mmol) was added cautiously 2-methoxy-4-nitrobenzenesulfonyl chloride (0.25 g, 1.0 mmol). After stirring 24h the reaction mixture was added to satd NH4Cl (50 mL) and extracted with DCM (2×50 mL). The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure. The crude residue was chromatographed (silica, MeOH/DCM, 0:100 to 10:90) to yield 2-methoxy-4-nitrobenzenesulfonamide (0.16 g, 68%) as a pale brown solid. 1H-NMR (DMSO-d6) δ 7.99 (1H, d), 7.90-7.95 (2H, m), 7.47 (2H, br s), 4.04 (3H, s).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[S:23][CH2:22]1)[C:17]([OH:19])=[O:18])=O)C1C=CC=CC=1.[BrH:37].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[BrH:37].[BrH:37].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[S:23][CH2:22]1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)CSc2ccccc21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCCCCC(N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (40 mg) obtained in Example 52-(2) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (1 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and diluted with a mixture ethyl ether (80 ml) and petroleum ether (20 ml), followed by stirring. The supernatant layer is removed by decantation, and precipitate is collected and dried to provide 3(R)-(5-amino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide (33 mg) as colorless powder.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(OC1CCCCO1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 7 g. 4-(8-cyclohexyloctylamino)benzoic acid, 2 g. 2,3-dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and condensed. The residue is crystallized from methylcyclohexane to white crystals.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([NH2:7])=[S:6].C([O:10][C:11](=O)[CH:12]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[C:13](OCC)=[O:14])C>C(O)C>[OH:14][C:13]1[C:12]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[C:11]([OH:10])[N:7]=[C:5]([SH:6])[N:4]=1
Reactant: CCOC(=O)C(NC(=O)c1cccc(C)c1)C(=O)OCC
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(=O)Nc2c(O)nc(S)nc2O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
1.5 equivalents of sodium methoxide (30% in methanol) were added to 7.79 g of thiourea in 150 ml of absolute ethanol. A solution of 30 g of 2-(3-methyl-benzoylamino)malonic acid diethyl ester in 100 ml of absolute ethanol was added dropwise, and the mixture was stirred at 60° C. for 2 h. Then the mixture was cooled to 0° C. for 30 min, and the precipitate was filtered off with suction, washed and dried. 28.6 g of the crude title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:31](=[O:33])[N:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:29][CH2:28][C:27]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[C:3]([N:37]2[CH2:36][CH2:35][CH:34]([N:30]3[CH2:29][CH2:28][C:27]4[CH:40]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=4[NH:32][C:31]3=[O:33])[CH2:39][CH2:38]2)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3Br)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.38 g (1.1 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.29 g (1.1 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.22 g (1.6 mmol) potassium carbonate and 3.0 mL NMP were combined and stirred for 10 h at 130° C. Then the reaction mixture was combined with water and the precipitate formed was suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNS(=O)(=O)c1cccs1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNS(=O)(=O)c3cccs3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.105 g, 0.379 mmol) was reacted with N-(2-azidoethyl)thiophene-2-sulfonamide (0.099 g, 0.379 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(thiophene-2-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.49 (s, 3H), δ 7.39 (s, 1H), δ 6.99 (s, 1H), δ 6.41 (bm, 3H), δ 4.43 (s, 2H), δ 3.42 (s, 2H), δ 2.54 (s, 2H), δ 2.09 (s, 2H), δ 1.51 (m, 13H), δ 1.19 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 150.8, 149.4, 148.1, 141.1, 138.3, 132.2, 132.1, 127.7, 122.6, 85.2, 53.8, 50.2, 43.2, 31.2, 29.9, 29.2, 28.8, 28.1, 25.5 ppm; HRMS (ESI) calcd for C21H31N7O4S2(M+) 509.1879. found 509.1879, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)thiophene-2-sulfonamide hydrochloride (0.098 g, 58% yield). 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), δ 7.76 (s, 1H), δ 7.57 (s, 1H), δ 7.11 (s, 1H), δ 6.46 (s, 1H), δ 4.79 (s, 2H), δ 3.55 (s, 2H), δ 2.50 (s, 2H), δ 1.66-1.18 (bm, 8H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 155.6, 147.2, 140.9, 132.7, 132.3, 127.8, 127.7, 108.8, 53.1, 42.2, 36.8, 28.1, 27.8, 27.5, 24.9, 24.3, 23.8 ppm; HRMS (ESI) calcd for C16H23N7O2S2(M+) 409.1355. found 409.1354.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccc(Cl)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-chloro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][CH:17]([CH3:19])[CH3:18])[CH:3]=3)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: CC(C)Oc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CC(C)Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[2-(4-iodo-2-isopropoxyphenoxy)ethyl]pyrrolidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 7 mg (8% of theoretical); C28H29ClN2O2 (M=460.995); calc.: molpeak (M+H)+:461/463 (Cl); found: molpeak (M+H)+: 461/463 (Cl); HPLC-MS: 10.50 minutes (method A).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:25])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A mixture of tert-butyl (S)-2-(4-trifluoromethoxyphenoxymethyl)pyrrolidine-1-carboxylate (2.31 g, 6.39 mmol) prepared in Reference Example 62, trifluoroacetic acid (20 ml), and methylene chloride (20 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with 10% sodium hydroxide aqueous solution and the mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-2-(4-trifluoromethoxyphenoxymethyl)-pyrrolidine (1.65 g, yield 99%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:18])[C:3]=12
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1cnc2[nH]cnc(Cl)c1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1 g, 6.5 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Alfa Aesar) was dissolved in DCM (30 ml) and then NCS (1.04 g, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, and then heated at 60° C. for 22 hours. After cooling a light yellow solid was obtained by filtration of the desired product in 1.2 g. LCMS [MH+] 188.0@1.42 min (5 min run)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][O:36][CH3:37])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][O:36][CH3:37])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: C#CC(C)(C)N(CC)CCOC
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCOC)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine were converted to yield {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-(2-methoxy-ethyl)-amine as brown oil, MS: 447 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.[NH4+].[OH-]>O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cccnc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1cncc(-c2nc3ncccc3[nH]2)c1
Yield: 66.3 %

Procedure:
A solution of 2,3-diaminopyridine (1.1 g, 10 mmol) and nicotinic acid (1.23 g, 10 mmol) in polyphosphoric acid (15 mL) was heated at 160° C. for 4 hours and poured into 150 mLs of water. The pH was adjusted to pH 8 with NH4OH with cooling. The precipitate was filtered and air dried. Recrystallization from EtOH to give 1.3 g of product (66%), m.p.=133°-135° C. Anal. Calcd. for: C, 67.34; H, 4.11, N, 28.36. Found: C, 67.21; H, 4.04; N, 28.11.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][C@H:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.O>CN(C=O)C>[CH3:12][N:9]1[CH2:8][C@H:7]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[CH:19]=[C:2]([O:1][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[N:26][N:25]=3)[C:3]([CH3:20])=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: Cc1cc2c(cc1O)[C@@H](c1ccccc1)CN(C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1Oc1nnnn1-c1ccccc1)[C@@H](c1ccccc1)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-8-Hydroxy-3,7-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (13.35g, 0.0499 mol) was dissolved in DMF (70 ml) and 50% sodium hydride in mineral oil (2.4 g, 0.0499 mol) was added with stirring under nitrogen. The solution was stirred at room temperature for one hour longer. A solution of 5-chloro-1-phenyl-1H-tetrazole (9.90 g) in DMF (40 ml) was added dropwise to the solution with stirring. The solution was stirred for two hours longer and then at 45° C. for another 0.5 hour. The solution was chilled and poured into 900 ml of ice and H2O. The solution was extracted with 2× 250 ml of ether. The combined ethyl layers were washed with 300 ml of water. The ether solution was dried and reduced to about 125 ml. The solid was filtered off, m.p. 140°-142° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)(=O)=O.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:10]1[C:11]2[C:16](=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH:17]=[C:9]1[CH2:8][CH2:7][CH2:6][N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]([CH3:24])[C:11]3[C:16]([CH:17]=2)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=3)[CH2:27][CH2:26]1
Reactant: C1CNCCNC1
Reactant: COc1cc2c(cc(CCCOS(C)(=O)=O)n2C)c(OC)c1OC
Product: COc1cc2c(cc(CCCN3CCCN(CCCc4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-1-methyl-4,5,6-trimethoxyindole (130 mg) and homopiperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=O)[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1)[C:5](OCC)=[O:6].O.[NH2:25][NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[CH2:10][CH:4]1[C:3]([C:2]([F:23])([F:22])[F:1])=[N:26][NH:25][C:5]1=[O:6]
Reactant: NN
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])c(C)c1)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC2C(=O)NN=C2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 55.3 %

Procedure:
Ethyl 4,4,4-trifluoro-2-(3-methyl-4-nitro-benzyl)-3-oxo-butyrate (2.0 g), hydrazine monohydrate (0.5 g) and a small amount of p-toluenesulfonic acid were dissolved in toluene, and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 4-(3-methyl-4-nitro-benzyl)-5-trifluoromethyl-2,4-dihydro-pyrazol-3-one (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Yield: 66.9 %

Procedure:
To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (747 g, 2.31 mol) in dichloromethane was added boron tribromide (1.15 kg, 4.62 mol) slowly at −78° C. The reaction mixture was allowed to rise to room temperature. When the reaction was complete as measure by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine, dried over Na2SO4, and concentrated. The residue was recrystallized in petroleum ether to give the title compound as a white solid (460 g, yield 68%). 1H NMR (CDCl3, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of sodium hydride (60% oily suspension) (8.0 g) in 200 ml of dimethylsulfoxide was added dropwise 27.2 g of p-methylphenethyl alcohol at a temperature below 20° C. under ice-cooling, followed by stirring at room temperature for 1 hour. To the resultant mixture, was added dropwise a solution of 31.7 g of 2-chloro-5-nitropyridine in 100 ml of dimethylsulfoxide, and the resulting mixture was heated at 60° C. for 1 hour. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were washed with water and dried over magnesium sulfate. After removal of the solvent, the oily products were purified by column chromatography on silica gel using benzene as an eluent to give 28.9 g of 2-(4-methylphenethyloxy)-5-nitropyridine as yellow crystals. Yield, 56%. M.P., 85°-85.5° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:31][CH:32]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-bromo-4-fluorobenzene
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([CH:17]([Cl:22])[CH2:18][N:19]=[C:20]=[O:21])C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:20]([NH:19][CH2:18][CH2:17][Cl:22])=[O:21])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(Cl)CN=C=O
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Product: COc1c(I)cc(NC(=O)NCCCl)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 2-chloroethyl isocyanate (0.085 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+]>CC(C)=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (28 g) in acetone (250 mL) is treated portionwise with sodium thiomethoxide (10 g) and the mixture is stirred overnight at room temperature. After filtration, the solution is concentrated and water (300 mL) is added to the residue. The yellow solid is filtered off and subjected to flash chromatography eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give methyl 4-methylthio-3-nitrobenzoate (18.5 g), in the form of a yellow solid, m.p. 118°-120° C.