Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:52]1[CH2:55][CH:54]([OH:56])[CH2:53]1>CN(C=O)C>[CH:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([N:52]4[CH2:55][CH:54]([OH:56])[CH2:53]4)=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2nc(C3CCCCC3)oc2c1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-cyclohexyl-benzooxazole-6-carboxylic acid (0.47 g, 1.9 mmol) and HBTU (0.94 g, 2.5 mmol) in DMF (10 mL) was added DIPEA (1.4 mL, 7.6 mmol). The resulting mixture was stirred at room temperature for 10 min, and then the hydrochloride salt of azetidin-3-ol (0.452 g, 4.7 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, and then purified by reverse phase liquid chromatography. Fractions containing product were lyophilized to yield (2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone. MS m/z (M+H+) 301.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na].[CH:25](O)(C)C>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:25])[C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: CC(C)O
Agent: [Na]
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 60 MHz) 7.88 ppm (d, 1H), 7.38 ppm (d, 1H), 5.77 ppm (s, 1H), 5.30 ppm (m, 1H), 3.50 ppm (s, 3H), 2.36 ppm (s, 3H), 1.40 ppm (d, 6H),
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (180 mg, 0.618 mmol) [from Example 235(c)] in DCM (5 mL) at 25° C. was added PyBrOP in one portion, followed by addition of DIPEA (0.54 mL, 3.09 mmol). After stirring for 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (203 mg, 0.68 mmol) was added to above solution in one portion. After stirring for 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (285 mg, 77%) as a white solid: LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]=[C:25]([CH3:37])[C:22]=1[CH:23]=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[C:21]([CH3:20])=[CH:28][C:27]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:26][C:25]=4[CH3:37])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cc(OCCN2CCCC2)cc(C)c1C=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCCN5CCCC5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), 2,6-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 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 2-[2,6-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 483 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:19]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:29]=[O:30])[C:23]=2[CH:22]=[CH:21][N:20]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[C:3]=1[CH:29]([C:24]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:28]=2[CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: O=Cc1cccc2cnccc12
Reactant: Brc1ccc2c(c1)OCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1c(Br)ccc2c1OCO2)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a solution of 4-bromo-1,2-(methylendioxy)benzene (3.01 g, 15 mmol) in THF (20 mL) at −78° C. was added dropwise lithium diisopropylamide (10.6 mL of 1.5 M in cyclohexane, 16 mmol). The reaction mixture was stirred at −78° C. under argon for 20 minutes. A brown solution was formed. A solution of 5-isoquinolinecarboxaldehyde (1.90 g, 12 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes and warmed to room temperature. Stirring was continued for 30 minutes at room temperature, and then the mixture was quenched with saturated NH4Cl solution. The product was extracted with EtOAc and the solvent was removed under reduced pressure. Chromatography (SiO2 Type-H, 35% EtOAc in Hexanes) of the residue yielded the title compound as a yellow solid (2.8 g, 7.8 mmol, 65% yield): mp 173–175° C.;
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]([C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:23]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1.[OH-].[Na+].Cl>CO.O>[C:28]([C:24]1[CH:23]=[C:22]([C:21]#[C:20][CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:7]=2)[CH2:4][C:3]([OH:32])=[O:2])[CH:27]=[CH:26][CH:25]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC(C#Cc1cccc(C(=O)OC)c1)c1ccc(OC)c(OC2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C#CC(CC(=O)O)c2ccc(OC)c(OC3CCCC3)c2)c1
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a solution of (+/-)-methyl-3-(3-carbomethoxyphenyl)ethynyl-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate (0.14 g, 0.32 mmol) in 5:2 methanol/water was added NaOH (0.01 g, 0.32 mmol). After 24 h, 3N HCl was added, the methanol was evaporated and the aqueous residue was extracted twice with CH2Cl2 and was evaporated. Purification by flash chromatography (silica gel, 5% CH3OH/CHCl3) provided the title compound as a yellow oil (0.02 g, 13%). Anal (C25H26O6 ·0.25H20) calcd: C, 70.32; H, 6.26. found: C, 70A6; H, 6.45.
Reaction SMILES: [I-:1].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:13][CH2:14][CH2:15]Cl)[CH:11]=2)[C:6]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:5]1>CC(=O)CC>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:13][CH2:14][CH2:15][I:1])[CH:11]=2)[C:6]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:5]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Yield: 81.2 %

Procedure:
0.260 g of sodium iodide is added to a solution of 0.59 g of 2-[1-methyl-5-methoxy-6-(2-chloroethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 42 ml of 2-butanone, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is refluxed for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (silica, dichloromethane as eluent). The fractions containing the product are concentrated under reduced pressure. 0.565 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20](O)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:6][CH:5]=2.C([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1)C>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]([NH:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([OH:25])=[O:34])=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)O
Product: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)Nc1cccc(C(=O)O)c1

Procedure:
Same procedure as Example 82 except (2-Methyl-5-trifluoromethanesulfonylamino-indol-1-yl)-acetic acid and 3-aminobenzoic ethyl ester was used. 1H-NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H, COOH), 11.44 (s, 1H, SNH), 10.62 (s, 1H, NHCO), 8.23 (t, J=2 Hz, 1H, ArH), 7.82 (dq, J=1, 8 Hz, 1H, ArH), 7.65 (dt, J=1, 8 Hz, 1H, ArH), 7.45 (t, J=8 Hz, 1H, ArH), 7.39 (d, J=8.6 Hz, 1H, H-7), 7.33 (d, J=2.3 Hz, 1H, H-4), 6.94 (dd, J=2.3, 8.6 Hz, 1H, H-6), 6.30 (s, 1H, H-3), 5.02 (s, 2H, CH2), 2.39 (s, 3H, CH3), MS m/z 454 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[S:21])C=1>CN(C=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[C:20]=[S:21]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(N=C=S)cc2)=NN1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A solution of 10.0 g of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 200 ml of DMF is added dropwise over a period of three hours to a stirred solution of 10.5 g of 1,1-thiocarbonyldiimidazole while cooling in an ice-water bath. After completion of the addition, stirring is continued for 30 minutes at icebath temperature followed by an additional 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is diluted with 500 ml of water. The aqueous suspension is cooled in ice and the solid is filtered, washed with water, and dried to yield 10.8 g of the product, 4,5-dihydro-6-[4-(isothiocyano)phenyl]3(2H)pyridazinone as off-white powder, mp 181.5°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[F:30])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.Br[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:16][C:15]=2[F:30])[O:11][CH2:12][CH3:13])=[CH:32][CH:33]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccncc2)cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-ethoxy-acetamide (300 mg) in 1,2-dimethoxyethane (8 ml) was added 4-bromopyridine hydrochloride (387 mg). A solution of sodium carbonate (210 mg) in water (2.1 ml) and dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (II) (48 mg) were added. The mixture was stirred at 85° C. for 4 h and at rt overnight. After cooling to rt, ice water was added. The mixture was filtered and the filtrate was extracted with EtOAc. The org. phase was washed with brine, dried, filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 2:1=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-pyridin-4-yl-phenyl)-2-ethoxy-acetamide (189 mg). Off-white solid. MS 408.2 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH:4]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:24]([NH2:26])=[O:25])[CH:19]=[C:20]([OH:23])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:34](Br)[CH3:35]>CN(C=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH:4]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:24]([NH2:26])=[O:25])[CH:19]=[C:20]([O:23][CH2:34][CH3:35])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1
Reactant: CCBr
Reactant: CN(C)CC(Nc1ncnc2c(C(N)=O)cc(O)cc12)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(N)=O)c2ncnc(NC(CN(C)C)c3cccc(F)c3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A Wheaton vial equipped with a stir bar was charged with 4-[2-dimethylamino-1-(3-fluoro-phenyl)-ethylamino]-6-hydroxy-quinazoline-8-carboxylic acid amide, (37 mg, 0.1 mmol) Cs2CO3, (100 mg, 0.3 mmol) and dry DMF, (1 mL). The mixture was heated at 60° C. for 1 h. It was then cooled to RT and ethylbromide (11 mg, 0.1 mmol) was added a solution in DMF (0.5 mL). The mixture was left to stir overnight. After 18 h, LCMS indicated consumption of SM. The mixture was diluted with EtOAc, (30 mL) and added to water, (30 mL). The phases were separated and the aqueous was extracted with EtOAc, (30 mL) (×2). The EtOAc phase was washed with sat. LiCl, (30 mL) dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography using a 4 g silica cartridge eluting with DCM-[DCM-MeOH—NH4OH (9:1:0.1)], gradient 0 to 100% cocktail. Amount obtained: 6 mg, 0.015 mmol, 15% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[O:30]1[C:34]2([CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=[O:41])[CH2:35]2)[O:33][CH2:32][CH2:31]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:40]([OH:41])[CH2:39][CH:36]2[CH2:37][CH2:38][C:34]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:35]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCC2(C1)OCCO2
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCC3(C2)OCCO3)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (4.2 g, 16 mmol) in dry tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6 M, 15 mL, 24 mmol) dropwise. The mixture was stirred at −78° C. for 15 min and then treated with (1,4-dioxa-spiro[4.4]non-7-yl)-acetaldehyde (5 g, 29 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 30% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol as a colorless oil (5.5 g, 74%): LC/MS m/e calcd for C22H24N2O5S [M+H]+ 429.51, observed 429.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:37]([NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:40])([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([NH:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-tert-butyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 16g) in an analogous manner as described in example 25. LR-MS: 703.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[C:18]([CH3:35])[C:17]=1[CH3:36].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[C:18]([CH3:35])[C:17]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(C)cccc4C)c(C)c3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(C)cccc4C)c(C)c3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-2-(2,6-dimethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 473 (M++1)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:19].[H-].[Na+]>CN(C)C=O>[CH3:19][O:17][CH2:16][CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a 0° C. mixture of [1-(4-nitro-phenyl)-piperidin-4-yl]-methanol and iodomethane (0.25 mL, 4.0 mmol) in N,N-dimethylformamide (3 mL) is added sodium hydride (60% dispersion in mineral oil, 80 mg, 2.0 mmol). The cooling bath is removed and the mixture is stirred at room temperature for five hours before it is re-cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate solution. The precipitated solid is collected by Büchner filtration, washed with water, and dried under house vacuum to give 4-methoxymethyl-1-(4-nitro-phenyl)-piperidine as pale yellow crystals (0.15 g, 60%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH:33]=O>>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Product: CCCN(CCN1CCN(Cc2cc3ccccc3[nH]2)CC1)C1CCc2ccc(O)cc2C1
Yield: 87.5 %

Procedure:
Compound 40d was prepared according to Procedure A using 39a (100 mg, 0.32 mmol) and 1H-Indole-2-carbaldehyde (100 mg, 0.69 mmol) to give 40d (125 mg, 85%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J=7.2 Hz), 1.39-1.50 (m, 3H), 1.89 (brs, 1H), 2.41-2.73 (m, 18H), 2.82-2.88 (m, 1H), 3.65 (s, 2H), 6.35 (s, 1H), 6.44 (brs, 1H), 6.54-6.57 (m, 1H), 6.87 (d, 1H, J=8.8 Hz), 7.04-7.08 (m, 1H), 7.10-7.16 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 7.54 (d, 1H, J=8.0 Hz), 8.63 (s, 1H). The free base of 40d was converted into oxalate salt. m.p. 135-137° C. Anal. [C28H38N4O.3.0(COOH)2.0.3H2O] C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7]C1C=CC=C2C=1/C(=C/C1NC=CC=1OC)/C(=O)N2.[F:27][C:28]1[C:29](I)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:38]\[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7][C:29]1[C:28]([F:27])=[CH:36][CH:35]=[C:34]2[C:30]=1/[C:31](=[CH:38]/[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44])/[C:32](=[O:37])[NH:33]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) (Aldrich) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 15 mg, 21%).