Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2c(Br)cccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Br)cccc5s4)cc3CC[C@@H]12
Yield: 78.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-bromobenzothiazole (114 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 142 mg (79%) of the title compound as an off white solid. mp 206°-210°. FDMS: m/e=474. α[D]589 =+56.25 (c=0.59, chloroform).
Reaction SMILES: Cl.[CH3:2]/[C:3](/[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]2([CH3:25])[CH3:24])=[CH:16][C:15]=1[CH3:28])=[CH:4]\[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH2:29](O)[CH3:30]>>[CH3:2]/[C:3](/[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]2([CH3:25])[CH3:24])=[CH:16][C:15]=1[CH3:28])=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:29][CH3:30])=[O:10])=[CH:12][CH:13]=1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Reaction time: 4 h

Procedure:
Gaseous hydrogen chloride was passed into a solution of 4.0 g of E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid in 300 ml of ethanol at the boiling point of the reaction mixture, until the solution was saturated. Thereafter, the mixture was kept at the boil for a further 4 hours, cooled, flushed with nitrogen and then evaporated down. The residue was digested with 30 ml of methanol, and the product was filtered off and dried. 3.6 g of ethyl E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoate of melting point 109°-110° C. were obtained (cf. Example 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>CCN(CC)CC>[Cl:8][C:4]1[N:3]=[C:2]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
A mixture of 2,6-dichloropyrazine (5.00 g, 33.6 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (6.76 g, 33.6 mmol) and K-t-BuO (1 M in tert-butanol; 35 mL, 35 mmol) in Et3N (200 mL) was stirred at room temperature for 12 h. The reaction was quenched with water (50 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous KH2PO4, dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from ethanol/water to give 9.50 g (90%) of the title compound as a white solid: mp 86-87° C.; MS m/z 313 (M)+. Anal. (C14H20ClN3O3) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CN1CCNCC1
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Product: CC(C(=O)N1CCN(C)CC1)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 103 %

Procedure:
Following the procedure of Example 6 but starting with 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (8 g.) and 1-methylpiperazine (8.2 g.), 4-[2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl]-1-methylpiperazine (10 g.) is obtained in the form of an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(#N)C>[O-:31][N+:20]1[CH:19]=[CH:18][C:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a suspension of ethyl 4-phenyl-2-pyridin-4-yl-1,3-thiazole-5-carboxylate (2.6 g, 8.5 mmol) produced above in acetonitrile (300 mL) was added m-chloroperbenzoic acid (containing water, about 70%, 3.9 g, about 16.0 mmol), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to about 100 mL, and the obtained suspension was diluted with ethyl acetate (300 mL), and washed successively with saturated aqueous sodium bisulfite solution (150 mL×2) and saturated aqueous sodium carbonate solution (150 mL×2). The combined aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate, and collected by filtration to give the title compound (2.0 g, 72%) as a yellow solid.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([F:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClCc1ccccc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Fc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 ml of dry ether was added 3.27 g (29.14 mmoles) of potassium tert-butoxide. The mixture was stirred while a solution of 3.75 g (27.75 mmoles) of 5-fluoroindole in 80 ml of ether was added. The stirring was continued for 0.5 hour. Solid was present. Then 3.69 g (29.15 mmoles) of benzyl chloride in 80 ml of ether was added. The mixture was stirred for 28 hours. Water (100 ml) was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether layers were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 6.95 g of orange oil. The oil was chromatographed on a 600 g column of silica gel. The column was eluted with 30% CH2Cl2 -Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (1×4") (30% CH2Cl1 -Skellysolve B). Fractions 11-15 were combined giving 0.88 g (14%) of 1-benzyl-5-fluoroindole as a pale yellow oil which contained a small amount of 1,3-dibenzyl-5-fluorindole.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=O)[C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12])=[C:4]([CH3:18])[CH:3]=1.[NH2:19][NH2:20]>O1CCCC1.C(O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10]([CH3:16])([CH3:15])[C:11](=[O:12])[NH:20][N:19]=2)=[C:4]([CH3:18])[CH:3]=1
Reactant: NN
Reactant: COC(=O)C(C)(C)C(=O)c1cc(C)c(Br)cc1C
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C2=NNC(=O)C2(C)C)c(C)cc1Br

Procedure:
3.5 g (11.7 mmol) of methyl 3-(4-bromo-2,5-dimethyl-phenyl)-2,2-dimethyl-3-oxo-propionate and 28 ml (28 mmol) of 1 molar hydrazine solution in tetrahydrofuran are refluxed in 50 ml of ethanol for 24 hours. The solvent is distilled off and the residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH2:33]Br)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:35][C:36]1[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=1>>[C:1]([C:9]1[C:10]([CH2:33][S:35][C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1S
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 4, 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 3-benzoyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 185°-186° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH:17]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Nitrobenzaldehyde (1 g) was dissolved in methylene chloride (20 ml), and the reaction system was cooled to 0° C. The solution was added with carboethoxymethylenetriphenylphospholan (2.56 g) and stirred at 0° C. for 1 hour. The reaction system was concentrated-under reduced pressure without any treatment, and the residue was purified by silica gel column chromatography (50 g, hexane:ethyl acetate 4:1) to obtain ethyl 3-(4-nitrophenyl)acrylate(1.27 g, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)C=1.[CH3:22][OH:23].C[O-].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of tert-butyl 4-(5-bromophenyloxy)-1-piperidinecarboxylate (12.98 g) in methanol (70 ml) was added 28% sodium methoxide methanol solution (37.8 ml) and the mixture was stirred under refluxing for 4 hours. After cooling, the reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give tert-butyl 4-(5-methoxypentyloxy)-1-piperidinecarboxylate (16.31 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH2:62])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:76])[NH:56][C@H:57]([CH2:63][NH:64][C:65]([C:67]1[C:72]([NH2:73])=[N:71][C:70]([NH2:74])=[C:69]([Cl:75])[N:68]=1)=[O:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-benzyloxy-phenyl-acetic acid (39 mg, 0.16 mmol) and HATU (61 mg, 0.16 mmol) in DMF (3 mL) is added N-methylmorpholine (64 mg, 0.64 mmol) followed by a solution of ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate C) (64 mg, 0.16 mmol) in DMF (2 mL). The resulting mixture is stirred at RT for 17 h. The solvent is removed in vacuo to afford the title compound which is used in the next step without further purification. [M+H]+ 626.
Reaction SMILES: C([N:8]1[CH2:13][C:12](=[CH2:14])[CH2:11][C@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:9]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[CH2:14]=[C:12]1[CH2:13][N:8]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C@H:9]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C@@H:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 28 h

Procedure:
A mixture of 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate from step 1d (2.3 g) and benzyl chloroformate (3 mL) was stirred at 65° C. for 28 h. The excess of the benzyl chloroformate was removed under reduced pressure. The residue was purified through Combiflash (hexane and ethyl acetate: gradient 0 to 10% during 12 min) to give the desired compound 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (1.40 g). MS (ESI): 488.1 (M+Na+); 366.1 (M+H+−COO(t-Bu)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:36][O:37][C:38]([C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH2:42])=[O:39]>CN(C=O)C>[CH3:36][O:37][C:38]([C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH:42][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:39]
Reactant: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)cc2)CC1

Procedure:
2.5 Grams of [4-(4-methoxybenzoyl)-1-piperazinyl]acetic acid was dissolved in 30 ml of DMF, then 1.2 g of triethylamine was added thereto. Under an ice-cooled condition with stirring, 1.4 g of isobutyl chloroformate was added dropwise thereto and stirred for 30 minutes. Then, the reaction mixture was stirred at a room temperature, a DMF solution of 1.6 g of o-methoxycarbonylaniline was added dropwise to the reaction mixture and stirred for 6 hours. The reaction mixture obtained was concentrated to dryness, and the residue obtained was extracted with chloroform and 1 N-sodium hydroxide. The chloroform layer was washed with water, dried and then chloroform was removed by distillation. The residue obtained was crystallized by adding ethyl acetate, the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 2.1 g of o-methoxycarbonyl-α-[4-(4-methoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [Cl-].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.[H-].[Na+]>N1C=CC=CC=1>[O:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccsc1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccsc2)cc1
Yield: 73 %

Procedure:
Couprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at reflux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with EtO (200 ml) and washed with 1N NaOH (3×100 ml), 1N HCl (2×150 ml) and 1N NaOH (150 ml). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographed using hexanes to give 3-phenoxy-thiophene as a clear oil (4.0 g, 74% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([I:16])=[CH:18][CH:19]=2)=[O:22])=[CH:8][CH:7]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)c1ccc(OCCCBr)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A solution of (3-bromopropoxy)benzene (44.4 g, 206 mmol) in DCM was added dropwise to a suspension of aluminum trichloride (27.5 g 206 mmol) and 4-iodobenzoyl chloride (50.0 g, 188 mmol) in anhydrous DCM (330 ml) at −78° C. ca. Reaction turned yellow and was allowed to warm to r.t. and stir for 4 hs. Upon completion, reaction was brought to 0° C., diluted with DCM, and quenched with 5% HCl. The organic layer was separated, washed additionally with brine, and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and re-crystallized using EtOAc to afford 60.1 g (71.8% yield) of (4-(3-bromopropoxy)phenyl)(4-iodophenyl)methanone as grey solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH3:11])[CH3:10])[N:3]=1.[CH3:12][N:13]([CH2:15][CH2:16][NH2:17])[CH3:14].[OH-].[Na+]>N1C=CC=CC=1>[CH3:12][N:13]([CH3:14])[CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH3:11])[CH3:10])[N:3]=1
Reactant: CN(C)Cc1cccc(Cl)n1
Reactant: CN(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CN(C)CCNc1cccc(CN(C)C)n1
Yield: 35.4 %

Procedure:
2-Chloro-6-dimethylaminomethylpyridine (14 g., 0.0825 mole) and unsym-dimethylethylenediamine (21.8 g, 0.248 mole) in 10 ml of pyridine are heated at 180° for 8 hours in a bomb. The dark reaction mixture is stirred over 20 g of solid sodium hydroxide for 1 hour on a steam bath. Then the mixture is filtered. Distillation of the filtrate gives 6.5 g of product, b.p. 110°-11° at 0.1 mm, nD25 1.5287.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[C:16]([CH3:24])[CH:15]=4)[CH:11]=[C:10]([C:25]([F:28])([F:26])[F:27])[N:9]=3)[CH:3]=2)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F

Procedure:
3′-[4-(3-methyl 4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.46 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.52 g), which was subsequently deprotected.
Reaction SMILES: C([C:4]1[C:5]([S:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)(O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[S:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: O=C(O)CCSc1ncccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCSc2ncccc21
Reaction time: 2 h
Yield: 27 %

Procedure:
A solution of 14 g. (61.6 mmol) 3-(3-Carboxy-2-pyridylthio)propionic acid [prepared as described in lit.: J. Heterocyclic Chem., 37.379(2000)]and 15 g.(185 mmol, 3 eqs) of anhydrous sodium acetate, in 200 mL. of acetic anhydride was refluxed (160° C.) under stirring, N2 atm, dry conditions, for 2 hours. Cooled, diluted with 300 mL of water, basified with 30% ammonium hydroxide solution to pH 8–9, extracted with 3×200 mL chloroform. Combined organics washed with 2×60 mL Sodium bicarbonate (satn.sol), water, dried, evaporated, gave 2.8 g. (27%) of the title compound, reddish solid, m.p.66–8° C., (M+H)+=166.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([CH:8]=1)[NH2:7].[CH3:15][S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:6]([NH:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=1
Reactant: CN(C)CCOc1ccc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Br)cc1NS(C)(=O)=O
Yield: 84.2 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 5-bromo-2-(2-(dimethylamino)ethoxy)aniline (1.8 g, 6.94 mmol) was mesylated with methanesulfonyl chloride (875 mg, 7.63 mol), pyridine (822 mg, 10.4 mmol), DCM (20 mL) to afford 1.97 g (83.12% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.71-7.0 (d, 1H), 7.2-7.16 (dd, 1H), 6.92-6.89 (d, 1H), 4.07-4.04 (t, 2H), 2.92 (s, 3H), 2.56-2.53 (t, 2H), 2.35 (s, 6H).