Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[Br:20]Br>ClC1C=CC=CC=1>[Br:20][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: BrBr
Solvent: Clc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Temperature: 240 °C

Procedure:
In an apparatus as described in Example 1, 1265 parts pf 1-nitroanthraquinone are melted by heating to 240° C. and then elemental bromine is pumped in, with efficient stirring, at 245°-250° C. The rate of addition is so chosen that gentle bromine reflux is constantly mantained in the reflux condenser. After about 624 parts of bromine have been added over about 10 hours, no more bromine is taken up by the reaction mixture and the presence of 1-nitroanthraquinone can no longer be detected in a thin-layer chromatogram. The mixture is cooled to 200° C. and the melt is discharged into 1200 parts of efficiently stirred chlorobenzene. The resultant suspension is cooled to 20° C. and filtered. The filter cake is washed with chlorobenzene and the crystals are dried in vacuo at 120° C., affording 1350 parts of 1-bromoanthraquinone in 99-99.5% purity. The yield, based on 1-nitroanthraquinone, is 96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][N:27]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:28]=4)[C:12]=3[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc(Br)cc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(Br)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
A mixture of methyl 6-(4-bromophenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxylate (353 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 6 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 317 mg (63%) of methyl 6-(4-bromophenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15]Br.[C-:17]#[N:18].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][C:17]#[N:18]
Reactant: [C-]#N
Reactant: Clc1cccc(Oc2ccccc2)c1CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Cl)cccc1Oc1ccccc1
Yield: 63 %

Procedure:
A solution of 21.0 g (70.57 mmol) of (2-chloro-6-phenoxy-phenyl)-bromomethane in 16.5 ml of ethanol is added dropwise at 80° C. to a solution of 4.5 g (91.74 mmol) of sodium cyanide in 9.2 ml of water and 2.3 ml of ethanol and the reaction mixture is boiled under reflux for 4 hours. After cooling, the mixture is concentrated using a rotary evaporator, the residue is taken up in ethyl acetate and the organic phase is washed 2× with water and 1× with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel with ethyl acetate to yield 10.82 g (44.40 mmol)=63% of (2-chloro-6-phenoxyphenyl)-acetonitrile in the form of a brown oil; TLC (silica gel; ethyl acetate; UV): Rf =0.42; 1H-NMR (CDCl3, 200 MHz): 3.96 (s, 2H); 6.74-7.46 (m, 8H)
Reaction SMILES: [CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH:6]=[O:7])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH2:6][OH:7])[CH3:2]
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=CC(CO)=NO)C(C)[N+](=O)[O-]
Yield: 79.2 %

Procedure:
To a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in dry ethanol (10 ml) was added sodium borohydride (15 mg) at 0° C. with stirring. The resulting mixture was stirred at the same temperature for 10 minutes and 1N hydrochloric acid was added thereto. The reaction mixture was extracted with ethyl acetate and the extract was washed with successively with water, an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo to give an oil. The oil was purified by a preparative thin layer chromatography [solvent: methanol-chloroform (10:90)] to give 4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-ol (80 mg).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)=[O:14]
Reactant: CC(=O)C1=CCCCC1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C1C=CCCC1)C(F)F
Yield: 93 %

Procedure:
Ethyl difluoroacetate (4.71 g, 38 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (20 mL). To the stirred solution was added 25 weight % sodium methoxide (9.68 g, 45 mmol) followed by 1-acetyl-1-cyclohexene (4.27 g, 34 mmol The reaction was stirred at room temperature overnight 17.5 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil (6.48 g, 93%). 1H NMR (CDCl3) 300 MHz 15.00 (br s, 1H), 6.09 (s, 1H), 5.92 (t, J=54.4 Hz, 1H), 2.31 (m, 4H), 1.64 (m, 4H); 19F NMR (CDCl3) 300 MHz: -126.94; M+202.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:28][CH:29]1[CH2:31][CH2:30]1>O>[CH:29]1([CH2:28][N:12]2[CH2:13][CH2:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[CH2:11]2)[CH2:31][CH2:30]1
Reactant: ClCC1CC1
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C2=CCCN(CC3CC3)C2)c1
Temperature: 75 °C

Procedure:
A mixture of 10 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of dimethylformamide, 14 g of sodium carbonate and 4.4 ml of chloromethyl cyclopropane was heated at 75° C. for 24 hours and was then cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture to obtain 9.25 g of 1-cyclopropylmethyl-3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]([OH:15])[CH3:17])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To the stirred solution of (trans)-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (4.55 g, 20 mmol) in THF (250 ml) was added methylmagnesium bromide (3M in diethyl ether) (6.67 ml, 20 mmol) during 2 min at −70° C. Stirring was continued for 20 min at −70° C. and then quenched with 1M NH4Cl (200 ml). The mixture was extracted with TBME (2×). The organic phases were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography, eluting with EtOAc-heptane 1:1, gave the title compound after crystallization (diisopropyl ether-heptane) as a white solid (1.72 g, 7.0 mmol, 35%). TLC (EtOAc-heptane 1:1) Rf=0.37; 1H NMR (600 MHz, DMSO-d6): 0.86-1.81 (m, 9H), 0.99 (d, 3H), 1.36 (s, 9H), 3.09 (m, 1H), 3.32 (m, 1H), 4.27 (d, 1H), 6.67 (d, 1H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[N:4][CH:3]=1.[C:40](=[O:47])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:43]([O:42][C:40]([NH:41][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[N:4][CH:3]=1)=[O:47])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 90 °C
Reaction time: 38 h
Yield: 75.4 %

Procedure:
To a solution of 0.85 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 5 mL of 1,4-dioxane, 0.20 g of tert-butyl carbamate, 0.69 g of cesium carbonate and 13 mg of tris(benzylideneacetone)dipalladium and 24 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added, and the mixture was stirred at 90° C. for 38 hours under a nitrogen atmosphere. After cooling to room temperature, the insoluble substance was separated by filtration, and the filtrated solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of hexane:ethyl acetate=33:67 to 5:95 to obtain 0.68 g of tert-butyl (1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2)=C.C[OH:14]>C(Cl)Cl>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[O:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: C=Cc1ccc2cnccc2c1
Reactant: CO
Solvent: ClCCl
Product: O=Cc1ccc2cnccc2c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a 150 mL round-bottomed flask was added 6-vinylisoquinoline (2.47 g, 16 mmol) and MeOH (35 mL)/DCM (35 mL). The resulting solution was cooled to −78° C. The reaction was ozonized until a blue color persisted, then nitrogen gas was bubbled through the solution for 15 minutes to purge the ozone. The reaction was then treated with solid sodium bicarbarbonate. (1.5 g) and dimethyl sulfide (3.2 mL, 0.2 mL/mmol of SM) and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined organic layers were dried over Na2SO4, filtered, and the residue product isoquinoline-6-carbaldehyde (2.35 g, 94% yield) was used without further manipulation. LCMS (API-ES) m/z (%): 158.1 (100%, M++H).
Reaction SMILES: [NH2:1][C@@H:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40](O)=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][C:40]([NH:1][C@@H:2]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([NH:5][C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][C@@H:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:4])=[O:41])[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in dichloromethane (2 mL) under nitrogen was added 3,5-difluorophenylacetic acid (40 mg, 0.232 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, 1N aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane: ethyl acetate (TLC Rf=0.42) to afford the title compound (85 mg, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) δ3.54 (s, 2H), 5.08 (t, 1H, J=7.0 Hz), 5.19 (d, 1H, J=6.5 Hz), 5.79 (d, 1H, J=7.0 Hz), 6.16 (br d, 1H, J=6.5 Hz), 6.62 (br d, 1H, J=7.0 Hz), 6.66-6.86 (m, 3H), 6.87-7.04 (m, 3H), 7.08-7.39 (m, 10H), 7.50 (br s, 1H). MS APCI, m/z=560 (M+1). LC/MS: 2.61 min.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:9]3[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
8-Chloro-7-(2-chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (142 mg) and piperazine-1-carboxylic acid tert-butyl ester (500 mg) were mixed, and the reaction mixture was stirred at 150° C. for 4 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 143 mg of the title compound from a fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]C(Cl)=O.Cl>N1C=CC=CC=1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCCOCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2,2-Dimethyl-1,3-dioxane-4,6-dione (1.72 g) was suspended in anhydrous pyridine (20 ml) and cooled to 0° C. (2-methoxyethoxy)acetyl chloride (2 g) was added slowly. The mixture was stirred at room temperature for 3 h. The mixture was poured into 2 N HCl (30 ml) and extracted with DCM (×3). The combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The orange oil was dissolved in EtOH (20 ml) and was refluxed for 7 h. The solvent was removed in vacuo and the brown oil was Kugelrohr distilled affording the title compound as a colourless oil (1.55 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].Br[CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([O:8][CH3:9])=[O:7]>C(#N)C>[N:1]([CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:16]([O:18][CH3:19])=[O:17])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Reactant: [N-]=[N+]=[N-]
Solvent: CC#N
Product: COC(=O)CCCCCCC(N=[N+]=[N-])C(=O)OC
Yield: 99.1 %

Procedure:
Soldium azide (4.87 g, 75 mmol) was added to a solution of dimethyl 2-bromoazelate (5.9 g, 20 mmol) prepared according to Auguston, M, et al; Acta Chim. Acad. Sci. Hung; 46: 85 (1965) in acetonitrile, and the mixture was heated at reflux temperature for 4 h. The solvent was removed in vacuo, dichloromethane (80 ml) was added to the residue, and the mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as an oil (5.1 g, 98% yield).
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 64 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give (R,Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 2 (42 mg, yield 64%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C)C=O>[Cl:37][CH2:36][CH2:35][CH2:34][CH2:33][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: ClCCCCBr
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 120.9 %

Procedure:
A mixture of 0.185 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 1.5 mL of dimethylformamide, 0.813 g (2.5 mmole) of cesium carbonate and 0.173 mL (1.5 mmole) of 1-bromo-4-chloro-butane was heated at 100 degrees for 1 hour. The mixture was concentrated under reduced pressure, diluted with water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.279 g of 2-[6-(4-chloro-butoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.37a) as a light brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].N1CCCC1>C1(C)C=CC=CC=1>[C:14]1([C:11](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC(=C1C(=O)Nc2ccccc21)c1ccccc1
Yield: 85 %

Procedure:
Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2 mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture refluxed for 3 hand monitored by TLC. When the reaction was finished the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 10-25% ethyl acetate in petroleum ether) to give 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder (200 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 5.96 (d, J=7.83 Hz, 1H) 6.51-6.57 (m, 1H) 6.77 (d, J=7.58 Hz, 1H) 7.00-7.10 (m, 1H) 7.30-7.37 (m, 2H) 7.44-7.58 (m, 3H) 10.54 (br. s., 1H). MS calcd. for C16H13NO 235, obsd. (ESI+) [(M+H)+] 236.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[N:7][N:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:37]=[CH:36][C:35](O)=[CH:34][C:33]=3[CH3:39])=[CH:29][CH:30]=2)[N:25]([CH:40]([CH3:42])[CH3:41])[N:24]=1)=[O:22].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:37]=[CH:36][C:35]([O:18][CH2:17][C:5]4[N:6]([C:9]5[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=5[Cl:16])[N:7]=[N:8][C:4]=4[CH:1]4[CH2:3][CH2:2]4)=[CH:34][C:33]=3[CH3:39])=[CH:29][CH:30]=2)[N:25]([CH:40]([CH3:42])[CH3:41])[N:24]=1)=[O:22]
Reactant: OCc1c(C2CC2)nnn1-c1c(Cl)cccc1Cl
Reactant: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(O)cc3C)ccc12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(OCc4c(C5CC5)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Nitrogen is bubbled through a solution of [5-cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (0.23 g, 0.80 mmol) and 6-(4-hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (0.2 g, 0.62 mmol) in toluene (10 mL) for 10 minutes. Tri-n-butyl phosphine (0.21 mL, 1.05 mmol) is added. Nitrogen is bubbled for an additional 10 min followed by addition of 1,1′-(azocarbonyl)-dipiperidine (0.27 g, 1.05 mmol). The reaction is stirred at room temperature for 18 h. The crude reaction is concentrated onto silica and chromatographed (40 g SiO2, 0% to 40% EtOAc/Hexanes) to yield the title compound (0.11 g, 30%). LC-ES/MS m/e 590.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)ccc21
Yield: 27.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (37.1 mg,) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (59 mg) were converted to the title compound as a white solid (25 mgs). δ 9.47 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.28-7.24 (m, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.07 (s, 1H), 3.31 (s, 3H), 2.77 (s, 6H), 2.32 (broad s, 2H), 2.07 (broad s, 2H), 1.27 (s, 6H). LC/MS: (M+H)+ found=529.16; MP 198-200° C.