Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:12][CH:13]=[C:14]([C:18]([C:23]3[N:24]=[CH:25][N:26]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:27]=3)([OH:22])[CH:19]([CH3:20])[CH3:21])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)C(O)(c1cccc(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 68.4 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 4-fluorophenylboronic acid (0.41 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), the title compound (0.71 g) was obtained as a pale-yellow solid.
Reaction SMILES: O=C(CC)CC(OCC)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][NH2:18].[CH:19]1([C:22]2N(C(C)C)N=[CH:24][C:23]=2[CH:30]=[O:31])C[CH2:20]1>>[CH2:19]([C:22]1[N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[N:18]=[CH:24][C:23]=1[CH:30]=[O:31])[CH3:20]
Reactant: NNc1ccccn1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: CCOC(=O)CC(=O)CC
Product: CCc1c(C=O)cnn1-c1ccccn1

Procedure:
5-Ethyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-pentanoate and 2-pyridyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O-:46])=[O:45])[CH2:40][CH:39]=2)O1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:10]([CH3:15])([CH3:11])[CH3:9])=[O:45])[CH2:40][CH:39]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CC1(C)OB(C2=CCN(C(=O)[O-])CC2)OC1(C)C
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 0.2 %

Procedure:
To a stirred solution of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.801 g, 1.60 mmol) in 1,4-dioxane (10 mL) and 2 M sodium carbonate solution (3.2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.65 mg, 2.10 mmol). The mixture was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.12 mg, 0.16 mmol) and heated to 100° C. After 16 h, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water (30 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (30 mL×2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (5% methanol/dichloromethane elute) to afford 0.79 mg (89%) of tert-butyl 4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[K+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
60 g of 3-fluoro-4-cyanophenol and 16 g of potassium hydroxide were dissolved in a solvent mixture of 600 ml of ethanol and 60 ml of water. To the resulting solution, was added dropwise 55.8 g of octyl bromide. After the completion of the addition, the obtained mixture was refluxed for six hours and then allowed to cool to room temperature. The solvent was distilled off and 300 ml of ethyl acetate was added to the residue. The organic layer was washed with water until the aqueous layer became neutral. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off. After purifying by distillation (main fraction: 0.5 mmHg, 157° to 160° C.), 63 g of 2-fluoro-4-octyloxybenzonitrile was obtained. Yield: 58%. 63 g of the 2-fluoro-4-octyloxybenzonitrile thus obtained was dissolved in 70 ml of absolute ether and 12.7 g of absolute ethanol was added thereto. The obtained mixture was cooled to -10° C. Then hydrogen chloride gas was bubbled therein for 30 minutes under stirring. After confirming that no hydrogen chloride was absorbed any more, the mixture was stirred at room temperature for 72 hours. 400 ml of absolute ether was added to the mixture. The crystals thus precipitated were filtered and vacuum-dried to thereby give 42 g of imino ester hydrochloride. Yield: 52%.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: CN1CCNCC1
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (80 mg), N-methylpiperazine (25 μL), 1H-1,2,3-benzotriazol-1-ol (35 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane to give the title compound (59 mg, yield: 62%) as colorless crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:12]=2[C:13]=1[CH3:14])(=O)=O.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(O)(C)C>[CH3:22][O:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[O:10][C:9](=[O:23])[C:8]([CH2:7][CH2:6][N:36]3[CH2:35][CH2:34][N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[CH2:38][CH2:37]3)=[C:13]([CH3:14])[C:12]=2[CH:15]=1
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1OC
Yield: 14 %

Procedure:
Process A; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-6,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 28) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 14%; m.p. 174°-175° C. (from isopropanol).
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH2:31][CH2:30]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1ncccc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 72 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17](O)[N:16]4[CH:20]=[CH:21][N:22]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:25]>ClCCl>[Cl:25][C:17]1[N:16]2[CH:20]=[CH:21][N:22]=[C:15]2[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)[N:18]=1
Reactant: Oc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
A suspension of 7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-ol (0.500 g, 1.69 mmol) in POCl3 (1.54 mL, 16.9 mmol) was heated to 100° C. and allowed to proceed overnight. The reaction was transferred to a flask with dichloromethane and the organics were concentrated under reduced pressure. To the crude material was added water and the mixture was stirred for 20 minutes at ambient temperature before it was neutralized with 1N NaOH to a pH of 7. The solids were collected by vacuum filtration and washed with water. The solids were purified by silica gel column chromatography eluting with 15% acetone in dichloromethane to afford 4-(4-(5-chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0400 g, 0.127 mmol, 7.53% yield). MS (apci) m/z=315.1 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]([CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]([C@H:31]6[CH2:35][CH2:34][CH2:33][O:32]6)=[O:30])[CH2:24][CH2:25]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C(=O)[C@H]2CCCO2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperazin-1-yl(tetrahydrofuran-2-yl)methanone (1.2 equiv) to give 184 (19.3 mg, M+1 480.1)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:8][CH2:9][CH3:10])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C)c([N+](=O)[O-])c1
Reaction time: 5 h

Procedure:
Potassium carbonate (13.5 g, 0.098 mol) followed by 1-iodopropane (9.56 mL, 0.098 mol) were added to a solution of 4-methyl-3-nitro-phenol (15 g, 0.098 mol) in DMF (100 mL). The mixture was stirred for 5 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil (17.5 g).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:30]2[CH:34]=[C:33]([C:35]3[C:36]4[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=4[N:38]=[CH:39][N:40]=3)[CH:32]=[N:31]2)[CH2:16][N:15]([C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[CH:19][C:18]=2[F:29])[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:30]2[CH:34]=[C:33]([C:35]3[C:36]4[CH:43]=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH:32]=[N:31]2)[CH2:16][N:15]([C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[CH:19][C:18]=2[F:29])[CH2:14]1)#[N:11]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)c(F)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Boron trifluoride etherate (2.0 mL, 16 mmol) was added to a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide (2.20 g, 3.74 mmol) in acetonitrile (30.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature overnight. The reaction was cooled to 0° C., water (5 mL) was added. After stirring at room temperature for 30 minutes, 5.0 M ammonium hydroxide in water (9 mL, 50 mmol) was added slowly at 0° C. over a period of 5 minutes. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%) to afford the desired product (1.50 g, 63%) which was further purified by re-crystallization from acetone to afford the pure product (1.25 g, purity: 99.96%). The product was then converted to TFA salt. LCMS (M+H)+: m/z=459.2. 1H NMR (300 Hz, DMSO-d6): δ 12.73 (s, 1H), 9.11 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (t, J=2.5 Hz, 1H), 7.64 (s, 1H), 7.60 (t, J=2.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 6.72 (t, J=9.0 Hz, 1H), 4.66 (d, J=7.0 Hz, 2H), 4.41 (d, J=7.0 Hz, 2H), 4.04 (m, 1H), 3.73 (s, 2H), 1.12 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@H:10]3[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:19])[N:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:30][Si:31](Cl)([CH3:38])[C:32]([CH:35]([CH3:37])[CH3:36])([CH3:34])[CH3:33]>O>[NH2:19][C:3]1[N:2]=[CH:1][N:6]=[C:5]2[C:4]=1[N:9]=[CH:8][N:7]2[C@@H:10]1[CH2:11][C@H:12]([CH2:17][O:18][Si:31]([C:32]([CH3:34])([CH:35]([CH3:37])[CH3:36])[CH3:33])([CH3:38])[CH3:30])[C@@H:13]([OH:16])[C@H:14]1[OH:15]
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of aristeromycin (50 g) and dimethylformamide (250 ml) was stirred at room temperature and imidazole (50 g) and then dimethylthexylsilyl chloride (10 ml) were added. Three further 10 ml portions of dimethylthexylsilyl chloride were added after 20 min, 1 h and 1.75 h. After 4 h the resulting mixture was poured into rapidly stirred water (2.5 L). The suspension was filtered and the residue washed with water (2×250 ml). The air dried solid was added to di-isopropyl ether (500 ml) and stirred for 20 min. The suspension was filtered and the residue collected, stirred with diethyl ether (500 ml) and filtered to give the title compound (49 g); 1H nmr (DMSO-d6) δ8.13 (1H), 8.09 (1H), 7.18 (2H), 5.03-4.93 (1H), 4.76-4.60 (2H), 4.41-4.28 (1H), 3.88-3.78 (1H), 3.72-3.57 (2H), 2.28-1.70 (3H), 1.67-1.52 (1H), 0.95-0.75 (12H), 0.1 (6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])[CH:7]=1.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 111.8 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-fluoro-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 267) (0.60 g, 1.72 mmol), SnCl2 (1.31 g, 6.91 mmol), 6N HCl (6 drops) and EtOH (7 ml) gave the title compound (610 mg) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]1([CH2:6][CH:7]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: C1COCCN1
Product: O=S(=O)(CCN1CCOCC1)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-ethenesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 92, 50 mg, 0.13 mmol) and morpholine (1.5 ml) was stirred at 25° C. for 20 min. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[4-(2-morpholin-4-yl-ethanesulfonyl)-phenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine (4 mg, 6%) as a white solid: LC/MS m/e calcd for C26H33N3O3S [M+H]+ 468.64, observed 468.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=4.3 Hz, 1H), 7.87-7.93 (m, 3H), 7.63 (d, J=8.3 Hz, 2H), 7.06 (dd, J=7.8, 5.1 Hz, 1H), 6.42 (s, 1H), 4.34 (t, J=8.0 Hz, 1H), 3.40-3.50 (m, 6H), 3.27-3.30 (m, 1H), 2.81 (t, J=6.4 Hz, 2H), 2.42 (br. s., 4H), 2.30 (dt, J=13.9, 7.2 Hz, 1H), 2.11-2.19 (m, 1H), 1.62-1.89 (m, 5H), 1.46-1.57 (m, 2H), 1.19-1.31 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:14]\[CH3:15])=[CH:4][CH:3]=1.[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:23])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[N:27]=[CH:28][N:29]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/4=[N:14]\[CH3:15])=[CH:4][CH:3]=3)[CH:30]=2)=[O:23])=[CH:19][CH:18]=1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Reactant: C/N=c1\ccccn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: C/N=c1\ccccn1-c1ccc(-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)cc1
Temperature: 130 °C
Yield: 25.3 %

Procedure:
A mixture of (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59 mg, 0.14 mmol), 5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (63 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (15 mg). MS 424.1 and 426.1 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH2:19]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[C:26]([CH3:32])[CH:25]=1)[CH3:20]>CO>[CH2:19]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=4)[CH:15]=[CH:16][C:17]=3[N:18]=2)=[C:26]([CH3:32])[CH:25]=1)[CH3:20]
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reactant: CCOC(=O)Nc1ccc(C=O)c(C)c1
Solvent: CO
Product: CCOC(=O)Nc1ccc(-c2nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.4 mL in 0.2 M DMSO solution), (4-formyl-3-methyl-phenyl)-carbamic acid ethyl ester (0.4 mL in 0.2 M toluene solution) and FeCl3 (0.2 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3-methyl-phenyl}-carbamic acid ethyl ester: MS (m/z) 449 (M+1).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:32](Br)(Br)([Br:34])[Br:33].C(C1SC(C2SC=CC=2)=CC=1)=O.ClCCl>ClCCl.CCCCCC>[Br:33][C:32]([Br:34])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
0.55 g of 5-formyl-2,2'-bithiophene was dissolved in 10 ml of dichloromethane. 1.95 g of PPh3 and 1.23 g of CBr4 were dissolved in 40 ml of dichloromethane and mixed with the 5-formyl-2,2'-bithiophene/dichloromethane solution under nitrogen gas atmosphere at 0° C. After the mixture was stirred for 1 hour and 10 ml of n-hexane was added to precipitate the triphenyl-phosphine oxide. And the reaction solution was filtered. Further, 100 ml of n-hexane was then added into the solution and the yellowish solid was obtained. The solid was further purified by column chromatography and crystallized with ethanol. The crystal product was thus obtained and the melting point thereof was 112°-113° C.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH2:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C(O)C>[CH2:16]([C:22]1[CH:23]=[CH:24][C:25]([C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:26][CH:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccccc1
Reactant: COC(=O)CCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 25 %

Procedure:
Adipic acid monomethyl ester (50 g; 0.31 mole) is converted to the acid chloride with thionyl chloride (50 g) by the manner described in Example 1. This product is reacted with hexylbenzene (100 g) and aluminum chloride (62.4 g; 0.47 mole) and the product isolated in a manner analogous to that described in Example 1. The crude product is heated under reflux in ethanol (234 ml) and 2N sodium hydroxide (234 ml) for 4 hours. The reaction mixture is then processed as described in Example 1. The product is recrystallized from aqueous ethanol to give 5-(4-n-hexylbenzoyl)pentanoic acid as colorless crystals (22.5 g), m.p. 77°-79° C.