Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([NH:14][C:15]([CH3:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[I-].[Na+].[C:20]([NH:23][CH2:24][C:25]#[C:26][CH2:27]Cl)(=[O:22])[CH3:21]>O1CCOCC1.C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:8]([NH:14][C:15](=[O:16])[CH3:17])([CH2:27][C:26]#[C:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:13]
Reactant: CC(=O)NCC#CCCl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC#CCNC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of sodium hydride (60% dispersion in mineral oil, 3.48 g) in dioxane (70 ml) was added dropwise absolute ethanol (70 ml). The mixture was allowed to warm to room temperature and a solution of diethyl acetamido malonate (20.5 g) in dioxane (70 ml) was added dropwise. Sodium iodide (9.07 g) was added and a solution of 1-acetylamino-4-chloro-2-butyne (11 g) in dioxane (140 ml) was added dropwise at room temperature. After addition of another 100 ml of ethanol the mixture was refluxed for 2.5 h. The reaction mixture was cooled and the precipitate formed was filtered off. Purification using chromatography on silica (eluent: ethyl acetate/methanol 9/1 v/v) yielded acetamido(4-acetamido-2-butynyl)-malonic acid diethyl ester. (15.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:25][CH:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])=[O:23]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[S:12][CH2:28][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[NH:25][S:22]([C:15]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH3:13])(=[O:23])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(Cl)c2ccccc2)c(C)c1
Reactant: Sc1nccn1-c1ccccn1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Yield: 87 %

Procedure:
1-(2-pyridyl)-2-mercaptoimidazole and (2,4,6-trimethylphenyl)sulfonylaminobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(2-pyridyl)-2-[2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio]imidazole.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10]([Cl:22])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)F)c(OC2CCCC2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g; that is prepared as described in Reference Example 42) and thionyl chloride (4 mL) in toluene (10 mL) is heated at 80° C. for 2 hours, and then evaporated under reduced pressure, to give 3-cyclopentyloxy-4-difluoromethoxybenzoyl chloride (0.48 g), in the form of a pale yellow low melting solid, which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)([O:8][CH2:9][CH3:10])[CH:5]([CH3:7])[CH3:6])[CH3:2].CC(C)([O-])C.[Al+3].CC(C)([O-])C.CC(C)([O-])C>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([O:8][CH2:9][CH3:10])=[C:5]([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(OCC)(OCC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Solvent: CC(C)(C)O
Product: CCOC(OCC)=C(C)C
Yield: 59.9 %

Procedure:
A mixture of 1,1,1-triethoxyisobutane (27.5 g, 0.14 mol) and aluminium t-butoxide (30 g, 0.12 mol) was heated at 170° C. for 1 hour during which time t-butanol distilled off. The residue was distilled at 100°-130° C. (atomosphere pressure) to afford 12.1 g (58%) of 1,1-diethoxy-2,2-dimethylethylene (Formula III: R2 =R3 =CH3 ; R4 =R5 =OC2H5), as a clear oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1ccc2ccccc2c1
Product: CCCCOC(=O)c1nc(Oc2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and Naphthalen-2-ol in analogy to Example D-20 d); MS-(+)-ion: M+1=388.1.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(I)c2C)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (100.0 mg, 0.2761 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5522 mL, 1.104 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2262 mL, 1.380 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. The material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 140 °C

Procedure:
Method 1. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (3.5 g, 17.8 mmol), dimethylformamide dimethylacetal (DMF-DMA) (3.6 ml, 1.5 eq) in acetonitrile (35 mL) was heated in a microwave at 140° C. for 20 min. The solvent was removed. The residue (5.1 g) was carried onto the next step without further purification. Method 2. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (39.5 g, 0.19 mol) and DMF-DMA (30.6 g, 0.26 mol, 1.35 eq) in DMF (470 mL) was heated to 90° C. for 30 min. The solvent was removed in vacuo. The residue (78 g) was used without further purification in the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH2:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:31][C:32]1[CH:46]=[CH:45][C:35]2[NH:36][C:37]([CH2:39][C:40](OCC)=O)=[N:38][C:34]=2[CH:33]=1>C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[NH:19][C:40]([CH2:39][C:37]4[NH:38][C:34]5[CH:33]=[C:32]([CH2:31][N:22]6[C:23](=[O:30])[C:24]7[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=7)[C:21]6=[O:20])[CH:46]=[CH:45][C:35]=5[N:36]=4)=[N:18][C:16]=3[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(OCCCCc2ccccc2)cc1N
Reactant: CCOC(=O)Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2[nH]1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2nc(Cc3nc4cc(OCCCCc5ccccc5)ccc4[nH]3)[nH]c2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A mixture of 5-(4-phenylbutoxy)benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylacetate (0.1 g, 0.234 mmol) was heated 1 hour at 185° C. under nitrogen. The mixture was suspended in diethyl ether, stirred vigorously for 1 hour. The solids were collected by filtration, washed with diethyl ether and dried to provide 2-{2-[5-(4-phenylbutoxy)-1H-benzoimidazol-2-ylmethyl]-3H-benzoimidazol-5-ylmethyl}isoindole-1,3-dione (0.1 g, 0.18 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>ClCCl>[N:57]1([S:61]([NH:64][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([CH2:12][O:13][C:14]3[CH:15]=[N:16][C:17]([CH:21]4[CH2:23][CH2:22]4)=[C:18]([Cl:20])[CH:19]=3)=[CH:4][C:5]=2[F:11])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
To a stirred solution of 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoic acid (Preparation 27, 500 mg, 1.4 mmol) in dichloromethane (40 mL) was added HATU (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.78 mL, 4.49 mmol), the mixture was left to stir for 15 minutes. Azetidine-1-sulfonamide (Preparation 19, 573 mg, 4.21 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the crude product as an orange oil. This was purified by column chromatography on silica (eluent 1:1 heptane/EtOAc) to give the title compound as an off-white solid (450 mg, 67%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1>N1C=CC=CC=1>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(C)NCCCNc1ccc2ncc(Br)n2n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N(CCCNc1ccc2ncc(Br)n2n1)C(C)C
Reaction time: 17 h
Yield: 103.1 %

Procedure:
Acetyl chloride [75-36-5] (1.0 mL, 14.1 mmol) was added, in portions, to an ambient temperature solution of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N3-isopropylpropane-1,3-diamine (196.9 mg, 0.6 mmol) in pyridine (6.5 mL), and stirred under N2 blanket for 17 h. Pyridine was evaporated from the reaction mixture and the residue partitioned between aqueous 5% (w/v) sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford 219.2 mg of dark oil. LRMS (ESI) m/z 354.1/356.1 [(M+H)]+, calc'd for C14H20BrN5O: 354.25.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]([OH:7])=O)#[N:3].[CH2:8]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C@H:15]1[CH2:19][N:18]([C:5](=[O:7])[CH2:4][C:2]#[N:3])[C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: N#CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 23.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-cyanoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 129, (2S,4R)-4-benzyl-1-(2-cyanoacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (6.4 mg, 23.3%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.49 (m, 1H), 4.00 (m, 2H), 3.64 (m, 1H), 3.22 (m, 2H), 3.67 (m, 3H), 1.93 (m, 2H). MS (EI) for C27H24FN3O3. found 458.5 (MH+).
Reaction SMILES: [CH2:1]([Cl:3])Cl.[CH3:4][CH:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=C[CH:18]=[CH:17]2)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=C(Cl)C=C(C(OO)=O)C=1>CCOC(C)=O>[Cl:3][C:1]1[CH:18]=[CH:17][C:16]2[C:21](=[C:12]([O:11][CH:5]([CH3:4])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:13]=[CH:14][CH:15]=2)[N:20]=1
Reactant: CC(CC(C)(C)C)Oc1cccc2cccnc12
Reactant: ClCCl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(CC(C)(C)C)Oc1cccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round bottom flask charged with 2 mL of CH2Cl2, 0.500 g (2.07 mmol) of 8-(1,3,3-trimethylbutoxy)quinoline was slowly added with gentle heating in order to dissolve the material. To this was added 1.8 equiv m-CPBA (50–70% by weight) in three portions. After stirring for 30 min, the dense solution became a brown solid. The solid was dissolved in 25 mL EtOAc and the resulting solution was washed with 10% aqueous NaHSO3, saturated aqueous NaHCO3, and the organic layer evaporated in vacuo. After co-evaporation with toluene, the residue was dissolved in POCl3 (5 mL) and the flask fitted with a reflux condenser. The reaction flask was then placed in an oil bath that had been preheated to 95° C. for 15 min. After cooling to room temperature, the solution was concentrated down to a red oil, which was then dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 until the aqueous layers became basic. The organic layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (d, 1H), 7.55 (m, 3H), 7.34 (m, 1H), 4.70–4.93 (m, 1H), 1.90 (dd, 1H), 1.53 (dd, 1H), 1.30 (d, 3H), 0.94 (s, 9H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:26]1[C:20]([CH2:19][CH2:18][C:16]2[N:17]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:13]=[CH:14][CH:15]=2)=[N:21][N:28]=[N:27]1
Reactant: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(CCc3nnn[nH]3)n2)sc2ccccc12
Yield: 70 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionitrile (0.25 g, 0.85 mmol) and trimethylsilylazide (0.20 g, 1.7 mol) were dissolved in toluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs and kept at room temperature. The precipitated crystals were collected by filtration, washed with toluene and recrystallized from ethanol to give the titled compound (0.20 g, 68%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:27]([CH3:44])[NH:26][C:25]=1[CH:45]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:45]\[C:25]1[NH:26][C:27]([CH3:44])=[C:28]([CH2:29][CH2:30][C:31](=[O:43])[N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol), 3,5-dimethyl-4-[3-oxo-3-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-propyl]-1H-pyrrole-2-carbaldehyde (1.7 eq.) and piperidine (1.5 eq.) in ethanol (2 mL) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a pale orange solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:21]1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccsc3)cc2)c1

Procedure:
3-(4-Thiophen-3-yl-phenoxymethyl)-benzoic acid was prepared using the procedure described above for the preparation of Example 15 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and thiophene-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=311.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH:20]=[CH:19][N:18]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cccc(Cc2ccnc(Cl)n2)c1
Product: COc1cc(Nc2nccc(Cc3cccc(Cl)c3)n2)ccc1-n1cnc(C)c1
Yield: 55 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-(3-chloro-benzyl)-pyrimidine. It was obtained as a yellow solid in 55% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.Cl[C:19]1[C:20]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[CH2:9]([C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:19]3[C:20]4[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:3][C:4]=2[N:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc2[nH]c(Cc3ccccc3)nc2c1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Clc1cc2c(Nc3ccc4[nH]c(Cc5ccccc5)nc4c3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 5-amino-2-benzyl-1H-benzimidazole and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.13(1H,s), 8.93(1H,s), 8.84(1H,s), 8.60(1H,s), 8.05(1H,dd), 7.88(2H,d), 7.50(6H, m), 4.61(2H,s); m/z (M+1)+387.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]=[CH:4]B(O)O.[CH3:10][C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([NH:15][C:16]1[C:24](C2C=NC=CC=2)=[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1)=[O:14]>>[CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:24]1[C:16]([NH:15][C:13](=[O:14])[CH2:12][C:11]([CH3:31])([CH3:10])[CH3:32])=[N:17][N:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=12
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Reactant: CC(C)(C)C=CB(O)O
Product: CC(C)(C)/C=C/c1c(NC(=O)CC(C)(C)C)nn2cccnc12

Procedure:
3,3-Dimethyl-1-butenylboronic acid (Aalenchem) and the product from Example 110B were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.03-10.05 (bs, 1H), 9.00 (dd, J=6.9, 1.7 Hz, 1H), 8.57 (dd, J=4.1, 1.7 Hz, 1H), 7.03 (dd, J=6.9, 4.1 Hz, 1H), 6.75 (d, J=16.3 Hz, 1H), 6.23 (d, J=16.3 Hz, 1H), 2.26 (s, 2H), 1.09 (s, 9H), 1.07 (s, 9H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([C:7]4[CH:6]=[CH:5][O:4][C:3]=4[C:2]([F:1])([F:12])[F:11])=[O:10])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1ccoc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccoc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylfuran-3-carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.96, 7.56, 7.00, 6.54, 3.9-3.7, 3.6-3.5, 1.49, 0.79-0.66, 0.47-0.41, 0.09-0.04. 13C NMR (300 MHz, CDCl3) δ 161.78, 160.01, 145.60, 145.05, 138.14, 137.57, 127.15, 121.74, 120.54, 112.54, 110.88, 46.33, 44.59, 41.43, 39.67, 34.52, 8.64, 4.23. MS (ES+) m/z 438.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH3:2].[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH:26]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]([C:23]1[CH:24]=[C:25]([CH:26]=[CH:13][C:12](=[O:14])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)([CH3:11])[CH3:15])[CH:28]=[CH:29][C:30]=1[F:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOc1ccc(C(C)(C)C(C)=O)cc1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Product: CCOc1ccc(C(C)(C)C(=O)C=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Yield: 47.7 %

Procedure:
In the same manner as described in (a) of (1) of Synthesis Example 2, 12.0 g of the residue was obtained by using 6.2 g of 2-(4-ethoxyphenyl)-2-methyl-3-butanone and 6.5 g of 3-phenoxy-4-fluorobenzaldehyde. The residue was purified by column chromatography on 200 g of silica gel (eluent: benzene) to give 5.8 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 1,4-diiodobenzene (24.7 g), propargyl alcohol (1.68 g), BTPC (0.21 g) and CuI (28 mg) in diethylamine (180 ml) was stirred at room temperature under nitrogen for 18 h. The solvent was evaporated in vacuo at 35°, the residual solid taken up in MC (200 ml) and the solution washed with 2N hydrochloric acid (150 ml). The aqueous phase was extracted with further MC (75 ml), the organic layers combined, dried and purified by FCC eluting with EA-CX (1:6) and then EA-CX (1:3) to yield the title compound as a fawn crystalline solid (4.9 g) m.p. 101°-102°.