Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]3)([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]([N:14]5[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Product: CC(C)(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 401. (400 MHz CDCl3): 1.48 (6H, s, CH3), 2.66-2.68 (4H, m, CH2), 2.75 (3H, s, CH3), 3.21 (4H, m, CH2), 3.86-3.88 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 7.29 (1H, s, ar), 7.42-7.46 (1H, m, ar), 7.53 (1 h, d (J=8.33), ar), 8.21 (1 h, d (J=7.09), ar), 8.95 (1H, s, ar), 10.04 (1H, b, NH). MH+=542.46
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([CH2:30][O:31][CH3:32])([CH3:29])[CH2:26][O:27][CH3:28])[CH3:19])([OH:15])[CH2:6][CH2:5]2.CCN(C(C)C)C(C)C.[F:42][CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[F:42][CH2:43][C:44]([N:23]([CH2:22][CH2:21][CH2:20][N:18]([CH2:17][CH2:16][C@@:7]1([OH:15])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:14])[CH3:13])[CH3:19])[CH2:24][C:25]([CH2:26][O:27][CH3:28])([CH3:29])[CH2:30][O:31][CH3:32])=[O:45]
Reactant: COCC(C)(CNCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)COC
Reactant: O=C(Cl)CF
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(C)(COC)CN(CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)C(=O)CF
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.73 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-{[3-(3-methoxy-2-methoxymethyl-2-methyl-propylamino)-propyl]-methyl-amino}-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol in DCM (29 mL) was added at 0° C., 1.5 mL of DIPEA and 1.1 mL of fluoroacetyl chloride. The mixture was stirred for 20 min at 0° C. then allowed to warm up to rt for 1 h and quenched with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude ester was dissolved in EtOH (29 mL) and treated with 15 mL of a 1M NaOH solution. The mixture was stirred for 15 min at rt and concentrated in vacuo. The resulting residue was taken up in DCM and washed with sat.-NaHCO3 and brine. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude was purified by CC using EtOAc/MeOH/NEt3 from 100/0/1 to 90/10/1 to yield 2.07 g of 2-fluoro-N-(3-{[2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-N-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-acetamide as orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([O:30][CH3:31])[CH:16]=1)(=[O:14])=[O:13])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])=[CH:16][C:17]=2[O:30][CH3:31])[CH:3]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)c(OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-1-fluoro-2-iodobenzene (420 mg, 1.39 mmol), 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 500 mg, 1.53 mmol), 2M aqueous sodium carbonate solution (2.5 mL) and dioxane (10 mL) was degassed with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol) was added and the reaction warmed to 110° C. and stirred for 1 hour. The reaction was cooled to room temperature, diluted with water (10 mL), extracted with EtOAc (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with heptanes/EtOAc 7/3 to afford the title compound as a pale yellow solid in 73% yield, 418 mg.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:27][CH:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:29].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)=[N:27][CH:28]([CH3:29])[C:30]([CH3:33])([CH3:32])[CH3:31])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(N)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Yield: 46 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 2-amino-3,3-dimethylbutane (0.88 mmol, 0.09 g) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 8 h at 75° C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 2:1) to give the title compound (140 mg, 46%) as white crystals. Mp 165.5-166.5° C.; EI SP/MS: 380 (M+); 1H-NMR (CDCl3): δ 0.92 (s, 9H),1.13 (d, 3H), 3.8 (m, 1H), 4.8 (br d, 1H), 7.74 (br s, 3H), 8.5 ppm (br, 1H); MA calc for C16H18F6N4 : C, 50.53%; H, 4.77%; N, 14.73%. Found: C, 50.48%; H, 4.74%; N, 14.45%.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](C2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Reactant: COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cn(Cc3ccccc3)c(=O)c3ccccc23)cc1OC
Temperature: 90 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.377 g, 1.20 mmol), 2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3-dioxolane (0.380 g, 1.44 mmol) and Na2CO3 (0.382 g, 3.60 mmol) was degassed under nitrogen. Toluene (20 mL), ethanol (20 mL) and water (2 mL) were then added. The reaction mixture was degassed again and Pd(PPh3)4 (0.139 g, 0.12 mmol) was added. The reaction was stirred at 90° C. for 16 h under nitrogen. After that time, the mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give 2-benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one (0.385 g, 86%) as a pale yellow solid: mp 174-176° C.; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=7.81 Hz, 1H), 7.47-7.66 (m, 3H), 7.24-7.42 (m, 5H), 7.06 (s, 1H), 6.85-6.98 (m, 3H), 5.27 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). ESI MS m/z 372 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:3]([C:4]([O:6][CH3:7])=[O:5])([C:2](=[O:1])[CH2:8][CH3:9])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCCCC1
Product: CCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
39.9 g (0.31 mol) of methyl 3-oxo-pentanoate and 1.9 g (0.012 mol) of DBU were mixed at room temperature in a three necked round bottom flask, equipped with a dropping funnel and a reflux condenser. 66.4 g (0.77 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior has leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. Cyclohexane was added and the mixture was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 21.4 g (0.20 mol) of 4-(methoxycarbonyl)-4-(1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 64%; boiling temperature: 130° C. at 0.02 mbar; colorless).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH2:33][CH:32]=[CH2:31]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCCBr
Product: C=CCCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and 4-bromo-1-butene, white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])O[C:11](C)(C)[O:12][C:13]=1[CH3:14].C=[N:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])[N:19]([C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][O:12][C:13]=1[CH3:14]
Reactant: CC1=C(c2ccccc2F)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2F)C1=O
Yield: 62.5 %

Procedure:
A mixture of 5-(2-fluorophenyl)-2,2-dimethyl-6-methyl-4H-1,3-dioxin-4-one (2.0 g) and ethyl 2-(N-methyleneamino)-2-methylpropionate (1.45 g) was heated under reflux in xylene for 10 hours. After evaporation to dryness the residue was purified by dry column chromatography on silica gel eluting with cyclohexane/ethyl acetate to give ethyl [5-(2-fluorophenyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate as a pale yellow oil (1.7 g), NMR 1.24(t,3H), 1.42(s,6H), 1.57(s,3H), 4.15(q,2H), 5.3(s,2H), 7. 74(m,4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
Amine preparation: a mixture of benzylpiperazine, methoxyacetyl chloride and triethylamine was stirred in DCM for 2 h to yield 1-(4-benzyl-piperazin-1-yl)-2-methoxy-ethanone following standard work up.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:23][CH:20]3[CH2:22][CH2:21]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC1CC1
Product: O=C(NC1CC1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 92.5 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and cyclopropylamine (100 μL, 1.0 mmol) to give 310 mg of the title compound (93%): mp 222°~225° C.; 1H NMR (270 MHz, DMSO-d6) δ12.13 (s, 1H), 8.22 (d, 1H, J=4.0 Hz), 7.18 (bs, 1H), 7.16 (bs, 1H), 5.02~5.06 (m, 1H), 2.79 (dm, 1H, J=16.8 Hz), 2.45~2.62 (m, 2H), 2.36 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 0.62 (dm, 2H, J=7.2 Hz), 1.33~1.41 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[C:24]([C:7]1[C:8]2[C:13](=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:25]
Reactant: COC(=O)c1nc(C#N)c2cccc(Oc3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccc(F)cc3)cccc12

Procedure:
The title compound was synthesized from 1-cyano-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=380.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:18])[NH:14][CH2:15][C:16]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40](I)[CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[N:7]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:18])[N:14]([C:42]3[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=3[F:44])[CH2:15][C:16]=2[N:17]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccccc2)c(OC)c1
Reactant: Fc1ccc(Cl)cc1I
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(c2cc(Cl)ccc2F)C(=O)N3c2ccccc2)c(OC)c1

Procedure:
(2,4-Dimethoxy-benzyl)-(2-oxo-1-phenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (380 mg, 0.77 mmol) was treated according to the procedure of Example 21, Step 1, using 4-chloro-1-fluoro-2-iodo-benzene instead of 1-chloro-4-iodo-benzene to afford [3-(5-chloro-2-fluoro-phenyl)-2-oxo-1-phenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (233 mg). MS: [M+H]+=619.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([Cl:31])[N:16]=1.C(NC(C)C)(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([N:21]3[CH2:30][CH2:29][C:24]4([O:25][CH2:26][CH2:27][O:28]4)[CH2:23][CH2:22]3)[CH:18]=[C:17]([Cl:31])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCN(Cc3ccccc3)CC2)n1
Yield: 83.6 %

Procedure:
1-Benzylpiperazine (7.59 g, 43.1 mmol) was added to a solution of 8-(2,6-dichloro-4-pyrimidinyl)-1,4-dioxa-8-azaspiro[4.5]decane (10.0 g, 34.5 mmol) in tetrahydrofuran (100 mL), followed by diisopropylamine (9.26 g, 71.7 mmol). The reaction mixture was then heated at reflux overnight. The crude product was concentrated under reduced pressure and the residue was re-dissolved in CH2C12 and then washed with aqueous citric acid (2×100 mL) and brine (2×200 mL). The organic layer was dried over -anhydrous Na2SO4 and filtered. Upon standing, crystallization occurred, giving the desired product (12.4 g, 84%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:4](=[O:16])[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[CH3:3].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>C1(C)C=CC=CC=1>[N:18]1([CH:5]([CH2:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:8])[C:4](=[O:16])[C:2]([CH3:17])([CH3:1])[CH3:3])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)C=CC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(CC(=O)c1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Yield: 75 %

Procedure:
2,2-Dimethyl-6-p-chlorophenyl-hex-4-en-3,6-dione (0.05 mol) and 1,2,4-triazole (0.05 mol) were suspended in toluene (200 ml) and refluxed for 24 hours. After cooling to room temperature, the excess triazole was filtered off and the organic layer washed with water (2×150 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a brown solid which on recrystallisation from petrol/chloroform gave 4-(1,2,4-triazol-1-yl)-2,2-dimethyl-6-p-chlorophenyl-hexan-3,6-dione (75% yield) as colourless needles m.p. 116°-119°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[C:5]3[C:11]4[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=4[C:13](=[O:15])[NH:14][C:3]=1[C:4]=23.[Br:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:9]1[C:8]2[NH:7][N:6]=[C:5]3[C:11]4[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=4[C:13](=[O:15])[NH:14][C:3]([C:4]=23)=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc2[nH]nc3c2c1NC(=O)c1ccccc1-3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c2[nH]nc3c2c1NC(=O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 50 mg of 5-methyl-6,7-dihydro-2H-benzo[5,6]azepino[4,3,2-cd]indazol-7-one prepared in Example 25-c in 1 ml dimethylformamide was added 40 mg of N-bromosuccinimide [CAS No. 128-08-5], followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 2 ml of ethyl acetate and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and dried in vacuo, to give 45 mg of the title compound as ocher yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)([C:19]2[CH:23]=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[N:21]([CH2:28][CH2:29][CH3:30])[CH:20]=2)[N:13]=1>>[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:36]=2)([C:19]2[CH:23]=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[N:21]([CH2:28][CH2:29][CH3:30])[CH:20]=2)[N:13]=1
Reactant: CCCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C(=O)CC
Reactant: OB(O)c1cccnc1F
Product: CCCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C(=O)CC

Procedure:
Using essentially the same procedure described in Example 43, step e, and employing 2-fluoro-pyridin-3-yl boronic acid and 2-amino-5-(3-bromophenyl)-3-methyl-5-(5-propionyl-1-propyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one as reactants, the title product was obtained as a white solid, mp 118° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.73 (t, 3H), 0.96 (t, 3H), 1.54 (m, 2H), 2.67 (m, 2H), 2.92 (s, 3H), 4.13 (m, 2H), 6.60 (bs, 2H), 6.92 (s, 1H), 7.01 (s, 1H), 7.41 (m, 3H), 7.53 (m, 1H), 7.67 (m, 1H), 7.97 (m, 1H), 8.19, (m, 1H), m/e (M−H)− 446.2.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:41]=2[CH:59](O)[CH3:60])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P([N:76]=[N+:77]=[N-:78])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[N:76]([CH:59]([C:41]1[N:42]([S:49]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)(=[O:50])=[O:51])[C:43]2[C:48]([C:40]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:60])=[N+:77]=[N-:78]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C(C)N=[N+]=[N-])c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
A solution of DIAD (1.80 g, 8.89 mmol) in dioxane (5 mL) was added to a solution of triphenylphosphine (2.33 g, 8.89 mmol) in dioxane (20 mL) at 0° C. under a nitrogen atmosphere. After 10 min stirring, 1-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethanol (1.74 g, 4.44 mmol) in dioxane (15 mL) was added followed by diphenylphosphoryl azide (1.47 g, 5.53 mmol) in dioxane (5 mL). The reaction mixture was stirred at 20° C. for 16 h then the reaction mixture was diluted with DCM and purified by column chromatography (Si—PCC, gradient 10-100% DCM in pentane) affording the title compound as a gum (1.39 g, 75%). LCMS (Method C): RT 4.77 min [M-N3]+ 374.1.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:28])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.15 h

Procedure:
To a mixture of acid 1 (10.0 g, 79 mmoles) in 100 ml of oxalyl chloride was added one drop of dimethylformamide. The mixture was stirred for 1.15 h at 23° and then the excess oxalyl chloride was distilled off at 23° and 10-20 torr to give acid chloride 2 as a brown oil, 11.4 g (100%). ##STR178##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Br)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NCc2ccccc2)C1
Temperature: 0 °C
Yield: 60.7 %

Procedure:
Stir a mixture of crude rac-trans-3-bromo-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0 g) and aqueous 1 N sodium hydroxide (400 mL) at room temperature for 2 h. Add benzylamine (0.86 mol, 80.0 g,), stir at 65° C. for 4.5 h and then cool to 0° C. Collect the resultant precipitates by filtration, wash with water and isopropyl ether and dry to obtain the title compound as a white solid (50.0 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.21-7.38 (m, 5H), 4.06-4.15 (m, 1H), 3.84 (d, J=5.0 Hz, 2H), 3.57-3.75 (m, 2H), 3.10-3.35 (m, 3H), 1.65 (br s, 2H), 1.46 (s, 9H).