Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25]Cl)[C:3]=1[F:28].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:3]=1[F:28]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CN4CCCCC4)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
515 mg (1.25 mmol) of Compound 159 obtained in EXAMPLE 159 was dissolved in 10 mL of dimethylformamide, 0.62 mL (6.2 mmol) of piperidine and 0.22 mL (1.25 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C. for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=4:1) and recrystallized from ethyl acetate, to give 441 mg of Compound 164 (yield: 77%).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cc(C(=O)O)n[nH]1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5-tert-Butyl-1H-pyrazol-3-carboxylic acid (5 g, 29.7 mmol) was added portionwise to concentrated sulfuric acid (25 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 5.15 ml) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 2.5 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (6.0 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=13.50-13.88 (2H, brs), 1.13 (9H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 236, [M−H]+ 212.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:23]C.[CH3:25]COCC>CO>[I-:23].[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[CH2:21][CH2:20][N+:19]([CH3:25])([CH3:22])[CH2:18][CH:17]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CC=C(C2c3ccccc3CCc3ccccc32)CC1
Reactant: CI
Reactant: CCOCC
Solvent: CO
Product: C[N+]1(C)CC=C(C2c3ccccc3CCc3ccccc32)CC1
Product: [I-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine (0.80 g, 2.8 mmol) in 25 mL of methanol, and added 1 mL of iodomethane. Refluxed for 1 hour. Cooled to room temperature, and evaporated. Triturated solid with 1:2 acetonitrile:ether to give 1.1 g (92% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1,1-dimethyl-1,2,5,6-tetrahydropyridinium iodide as a cream solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1.O1CCOC1.C(OC1C=CC(NC2C3C=C(C4OC(C=O)=CC=4)N=CC=3N=CN=2)=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:35]4[O:36][C:32]([CH:28]5[O:29][CH2:30][CH2:31][O:27]5)=[CH:33][CH:34]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Agent: Cl[Pd]Cl
Agent: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCO1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1

Procedure:
Reaction of (4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)amine (5.44 g, 15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (10.4 g, 24.2 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic amount) in dioxane (150 ml) according to Procedure B, followed by purification by silica gel chromatography (eluted with 50-100% EtOAc/i-hexane), allowed the isolation of the dioxolane product (3.45 g, 7.40 mmol, 49%); δH [2H6]DMSO 10.28 (1 H, s), 9.13 (1H, s), 8.69 (1H, s), 8.61 (1H, s), 7.71 (2H, d), 7.31-7.52 (5H, m), 7.14 (1H, d), 7.09 (2H, d), 6.77 (1H, d), 6.03 (1H, s), 5.15 (2H, s), 3.95-4.19 (4H, m). This could then be converted to 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (identical to that described above) using Procedure C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([CH3:13])([CH3:12])[CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:4][CH:5]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]2[CH:9]([CH2:26][N:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:28]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OC1CC(C)(C)C=CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CC(C)(C)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 23.2 g of 6-acetoxy-4,4-dimethylcyclohex-2-enone and 0.8 cm3 of trifluoroacetic acid in 770 cm3 of dichloromethane are added, at room temperature, 43 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is stirred at room temperature for 15 hours then 5 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8 cm, height 53 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 250 cm3 fractions. Fractions 18 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.6 g of (3aRS,5RS,7aRS)-5 -acetoxy-2-benzyl-7,7-dimethyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:42](=[O:44])[CH3:43])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(C(C)=O)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.218 mmol, 1. eq.) was dissolved in 2 ml of dry dichloromethane. First 94 μl of dry N,N-diethylethanamine (0.676 mmol, 3.1 eq.) and then 23 μl of acetyl chloride (0.327 mmol, 1.5 eq,) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. Then the mixture was partitioned between water and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 29.8 mg (0.06 mmol, 26.8%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][C:7]([N:9]1[CH2:12][C@H:11]([NH:13]C(OCC2C=CC=CC=2)=O)[C:10]1=[O:24])=[O:8])(=[O:5])=[O:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H].N1CCC1=O>C(#N)C.[Pd]>[NH2:13][C@H:11]1[CH2:12][N:9]([C:7]([NH:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[O:8])[C:10]1=[O:24]
Reactant: CNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C1CCN1
Solvent: CC#N
Product: CNS(=O)(=O)NC(=O)N1C[C@H](N)C1=O
Reaction time: 0.5 h

Procedure:
(S)-N-[(Methylamino)sulfonyl]-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinecarboxamide (2.1 g; see Example 37) was suspended in 25 ml of acetonitrile and bis(trimethylsilyl)acetamide (3.3 g) was added. The solution was added to a suspension of 1 g of 10% palladium on charcoal in 25 ml of acetonitrile, through which hydrogen was passed for 30 minutes prior to the addition of the solution of the starting azetidinone. After 15 minutes the catalyst was removed by filtration and 2 ml of methanol was added to the filtrate to precipitate 1.3 g of the title compound.
Reaction SMILES: C12(C)C(C)(C)C(CC1)CC2C(Cl)=O.N[CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].CC[N:25](CC)CC>C(Cl)(Cl)Cl>[NH2:25][N:18]1[C:19](=[O:22])[CH2:20][CH2:21][CH2:15][C:16]1=[O:17]
Reactant: NC1CCC(=O)NC1=O
Reactant: CCN(CC)CC
Agent: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: ClC(Cl)Cl
Product: NN1C(=O)CCCC1=O
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of (+)-camphanic chloride (19 mg, 00868 mmol), aminoglutarimide (21 mg, 0.0868 mmol) and Et3N (24 μl) in CHCl3 (1 ml) was stirred at room for 16 hours. The solution was diluted with CHCl3, washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, concentrated and purified by chromatography (silica gel, CH2Cl2; EtOAc=10:1) to give product (16 mg, 60.0% yield) as a colorless gel: 13CNMR (CDCl3) δ 172.6, 169.4, 168.6; 165.5, 90.3, 58.3, 53.3, 48.2, 47.6, 29.2, 28.2, 26.9, 22.7, 14.6, 7.6; MS (CI/CH4) m/z 308 (M+). This compound exhibited angiogenic activity in the assay of Example 13.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[CH3:11][N:12]1[C:19](=[O:20])[CH2:18][C:16](=O)[N:15]([CH3:21])[C:13]1=[O:14]>C(OCC)(=O)C.CCCCCC>[Cl:3][C:16]1[N:15]([CH3:21])[C:13](=[O:14])[N:12]([CH3:11])[C:19](=[O:20])[C:18]=1[CH:8]=[O:9]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
Phosphorous oxychloride (690 ml) was added slowly to dry N,N-dimethyl formamide (180 ml) at 0° C. The mixture was then allowed to warm to room temperature. 1,3-Dimethylbarbituric acid (60 g, 384.27 mmol) was added portion wise and refluxed for 45 min. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure and the viscous residue was poured into ice-cold water (2000 ml). The reaction mixture was allowed to room temperature and extracted with chloroform (3×500 ml). The combined organic extracts were dried over Na2SO4 and concentrated. The crude material obtained was then stirred in 10% ethyl acetate in hexane (150 ml) to obtain 58 g of the product as the pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 3.41 (s, 3H), 3.69 (s, 3H), 10.18 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[NH2:20].N1C=CC=CC=1.[C:27](Cl)(Cl)=[O:28]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]([N:20]=[C:27]=[O:28])=[CH:4][C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(N)c(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(N=C=O)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine (0.15 g, 0.393 mmol) in toluene (3 ml) was added pyridine (0.038 ml, 0.472 mmol), DMAP (0.048 g, 0.393 mmol) and 20% phosgene in toluene (0.224 ml, 0.433 mmol). The mixture was stirred at room temperature for two hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give [2-(4-bromo-2-chloro-5-isocyanato-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (0.155 g) as a white solid, which was used directly in the next step.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH3:15])[C:5]1=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:15][O:14][C:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[C:5]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)NCCN
Reactant: COc1cccc2c1CCC(CC=O)C2=O
Solvent: CC(=O)O
Product: COc1cccc2c1CCc1ccn(CCNC(C)=O)c1-2
Yield: 39.9 %

Procedure:
175 mg of 2-(2-oxoethyl)-5-methoxy-1-tetralone and 144 mg of N-acetylethylenediamine were heated to reflux under argon in 4 ml of acetic acid for 1.5 hours. The solvent was removed in a vacuum. The residue was taken up in 25 ml of water and extracted several times with dichloromethane. Chromatography on 20 g of silica gel with ethyl acetate gave a greenish coloured oil. This was crystallized from toluene for purification. 91 mg (46%) of N-[2-(4,5-dihydro-6-methoxy-1H-benz[g]indol-1-yl)ethyl]-acetamide with m.p. 133° were obtained.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([Cl:9])[CH:11]=2)=[CH:3][N:4]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: Nc1ncc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cnc(N)nn2)cc1Cl
Temperature: 82 °C
Yield: 55.7 %

Procedure:
To a mixture of 6-bromo-1,2,4-triazin-3-amine (Step 1, 1.0 g, 5.7 mmol) and [3-chloro-4-(methoxycarbonyl)phenyl]boronic acid (1.5 g, 6.8 mmol) (VMR, Cat. #100013-404) in 1,4-dioxane (22 mL) was added a solution of potassium phosphate (2.4 g, 11 mmol) in water (5.1 mL). The mixture was degassed by purging nitrogen for 10 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and again was degassed with nitrogen. The mixture was stirred and heated at 82° C. (an oil bath) for 1 h. The mixture was cooled to r.t., diluted with water, stirred for 30 min, and a grey solid formed. The solid was isolated by filtration, rinsed several times with water, and dried in air. The solid was then triturated sequentially with hexanes, dichloromethane-hexanes (1:1), and hexanes to afford the desired product (840 mg, 55.54%). LCMS (M+H)+: m/z=264.9/267.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1)=O.[H][H]>C(O)(=O)C.Cl(O)(=O)(=O)=O.[Pd].[C]>[CH3:1][C:3]1[CH:4]=[CH:5][C:6]2[CH:21]3[CH2:22][C:8]4([CH2:12][N:11]([CH2:13][CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)[CH2:10][CH:9]4[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=43)[C:7]=2[CH:27]=1
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3

Procedure:
A solution of 5.0 g of 5-formyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (Example 69) in 120 ml of acetic acid and 10 ml of perchloric acid was hydrogenated in the presence of 1.5 g of 10% Pd/carbon catalyst at 25°, 50 psi hydrogen pressure, overnight. The mixture was filtered and the solvent was evaporated to leave the product, 5-methyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, as an oil.
Reaction SMILES: F[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[NH:3]1.C(O)(=O)CCC(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:4]1[N:3]=[N:2][C:7]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:21][CH2:22]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Reactant: FC1=CC=CN(F)N1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCC2CCN(c3ccc(F)nn3)CC2)cc1
Yield: 64.3 %

Procedure:
A mixture 1.2 parts of 2,6-difluoropyridazine, 4 parts of ethyl 4-[2-(4-piperidinyl)-ethoxy]benzoate butanedioate(1:1), 5.3 parts of sodium carbonate and 141 parts of N,N-dimethylformamide was stirred for 48 hours at 60° C. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.4 parts (64.3%) of ethyl 4-[2-[1-(6-fluoro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 131.9° C. (comp. 73).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 61.4 %

Procedure:
Into a 1 L round-bottomed flask containing 500 ml of acetonitrile was added 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g, 344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq). The mixture was stirred for 3.5 hours at 60° C. (oil bath). The solids were filtered off and the filtrate was concentrated under vacuum leaving 25.0 grams of the crude product as a yellow oil; 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)[C:34]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as yellow solid. MS; m/e=489.1 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C([O:43][CH:44]([CH2:47]O)[CH2:45]O)N=1.[H-].[Na+]>CC(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([O:43][CH:44]([CH3:47])[CH3:45])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step 3 g) in propan-2-ol (20 ml) was added NaH (0.43 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.8 g
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([Cl:43])=[CH:23][N:22]=1>>[Cl:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.005 g, 10%). MP: 82-100° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.20 (d, 1H, J=8.8 Hz), 8.12 (s, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.39-7.31 (m, 1H), 6.63 (s, 1H), 6.56 (d, 1H), J=2.0 Hz), 6.50 (dd, 1H, J=8.7 and 2.4 Hz), 3.91 (s, 3H), 3.86 (s, 3H), 3.23-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.83 (m, 2H), 2.83-2.78 (m, 2H), 2.72-2.65 (m, 4H), 2.65-2.58 (m, 4H), 2.38 (s, 3H). MS: 595 (MH)+.
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[CH2:7]([O:9][C:10]([C:12]1[NH:30][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])[CH3:8]>[Fe].O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1[NH:30][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ncnc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(Oc3ccc(N)cc3)ncnc2[nH]1
Temperature: 82.5 °C
Reaction time: 2.5 h

Procedure:
After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 ml of ethanol and 2 ml of water to 4-(4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, the mixture was stirred at 80-85° C. for 2.5 hours. After returning the mixture to room temperature, 20 ml of tetrahydrofuran was added, the mixture was stirred for 5 minutes and filtered with celite, and 100 ml of ethyl acetate and 50 ml of water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 90 mg of the title compound.