Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[C:8]12([CH2:21][CH2:20][CH2:19][CH2:18]1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10](=[O:17])[CH2:9]2.C1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1([OH:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:9]1
Reactant: O=C1CC2(CCCC2)c2ccccc21
Reactant: COCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COCCCC1(O)CC2(CCCC2)c2ccccc21

Procedure:
The Grignard reagent is prepared from γ-methoxypropyl bromide (30.6 g; 0.2 moles) and magnesium flakes (4.8 g; 0.2 gram-atoms) in tetrahydrofuran and reacted with spiro(cyclopentane-1,1'-indane)-3'-one (18.6 g, 0.1 moles) in a manner analogous to example 1. The reaction product is shaken out with benzene, the combined benzene solutions are dried with anhydrous magnesium sulphate and the solvent is distilled off in vacuum. 3'-γ-methoxypropyl-spiro(cyclopentane-1,1'-indan)-3'-ol is obtained as a yellowish oil (yield 27.1 g). The crude methoxy compound is refluxed for 62 hours with 48% hydrobromic acid (50 ml) and acetic acid (100 ml). The solution is concentrated in vacuum, ether is added to the oil obtained, and then the solution is washed with water and 2 N sodium hydroxide solution. After drying with magnesium sulphate the solvent is distilled off and a brown oil is obtained, which essentially consists of 3'-γ-bromopropyl-spiro(cyclopentane-1,1'-indene). The compound can be purified by distillation in vacuum and is then obtained as a colourless oil of mp, 148° C./1 mm Hg. nD25 =1.5769.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)/[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.542 mmol) was dissolved in dry DCM (10 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.1 mL, 1.6 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.36 (d, 2H), 7.30 (s, 1H), 6.98 (m, 2H), 6.82 (d, 2H), 6.70 (s, 1H), 3.60 (s, 2H), 2.70 (m, 4H), 2.50 (m, 5H), 1.20 (t, 3H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[S:45]1[C:49]2[CH:50]=[CH:51][C:52]([NH2:54])=[CH:53][C:48]=2[N:47]=[CH:46]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:54][C:52]4[CH:51]=[CH:50][C:49]5[S:45][CH:46]=[N:47][C:48]=5[CH:53]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 128; 60.0 mg, 0.097 mmol) and benzo[d]thiazol-5-amine (29.0 mg, 0.193 mmol) (Maybridge, Trevillet, UK) in THF (1.0 mL) at 0° C. was treated with LiHMDS (1.0 M in THF, Aldrich, St. Louis, Mo.) (483 μL, 0.483 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 15 min, then was quenched with sat. aq. NH4Cl (3 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amine (51.0 mg, 0.068 mmol, 70.3% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 9.16 (1H, br. s.); 8.99 (1H, s); 8.40-8.54 (2H, m); 7.84 (1H, d, J=8.8 Hz); 7.58 (1H, d, J=8.6 Hz); 7.12-7.25 (4H, m); 6.77-6.92 (4H, m); 4.93 (2H, s); 4.89 (2H, s); 4.15 (2H, s); 3.79 (12H, d, J=18.0 Hz); 3.35-3.51 (2H, m); 2.87-2.97 (2H, m); 2.85 (3H, s); 2.69 (3H, s). m/z (ESI, positive ion) 752 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2cccc(F)c2)cc1

Procedure:
In a manner similar to Example 4, Step (c), 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (0.9258 g, 0.00340 mol) was allowed to react with hydroxylamine hydrochloride (0.284 g, 0.00409 mol) in the presence of sodium carbonate (0.434 g, 0.00409 mol) in absolute ethanol (19 mL) to give 4-(3′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale gray solid; mp 155-157° C.
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(P(N(C)C)N(C)C)C.[CH:44]([C:46]1[C:55]([CH3:56])=[C:54]([O:57][C:58](=[O:60])[CH3:59])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([F:61])[CH:52]=2)[N:47]=1)=O>O1CCCC1.O.CCCCCC>[CH:44](/[C:46]1[C:55]([CH3:56])=[C:54]([O:57][C:58](=[O:60])[CH3:59])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([F:61])[CH:52]=2)[N:47]=1)=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccc(F)cc12
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC/C=C/c1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.2 %

Procedure:
0.29 ml of a hexane solution of 0.48 mmols of n-butyl lithium was added to a solution of 218 mg (0.48 mmols) of octyltriphenylphosphonium bromide in 3 ml of tetrahydrofuran and stirred at room temperature for 5 minutes. This solution was cooled to -78° C., after which 1.43 g (8 mmols) of hexamethylphosphorus triamide was added and stirred for 5 minutes, followed by further addition of 2 ml of a tetrahydrofuran solution of 98.8 mg (0.40 mmols) of 2-formyl-3-methyl-4-acetoxy-6-fluoroquinoline and stirring at -78° C. for 15 minutes and -42° C. for 30 minutes. The reaction solution was added to 20 ml of water and extracted with ethyl acetate, followed by washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate. After removal of the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (solvent n-hexane ethyl acetate=30:1 ) to obtain 14 mg (yield 10 %) of 2-(trans-1-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31]
Reactant: C=CCN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
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: CN(C)C=O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Temperature: 90 °C
Yield: 49.8 %

Procedure:
A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.160 g, 0.287 mmol) and 4-allyl-5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.096 g, 0.287 mmol) in DMF (3 mL) was treated with 2.0 M aq. Na2CO3 (0.358 mL, 0.717 mmol), sparged with N2 for 10 min, treated with Pd(Ph3P)4 (0.033 g, 0.029 mmol), sparged for 5 min, then sealed and heated (90° C.) for 16 h. The reaction was cooled, diluted with EtOAc (20 mL) and washed with 1:1 water/brine (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (4 g Isco SiO2, 0% (5 CV), 0%-80% (15 CV), EtOAc/hexanes) to afford semi-purified product (0.122 g, 0.143 mmol, 49.9% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.98 (t, J=1.7 Hz, 1H), 7.76 (dt, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.99-7.03 (m, 1H), 6.93-6.97 (m, 1H), 6.85 (s, 1H), 5.99-6.10 (m, 1H), 5.36 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.5 Hz, 1H), 5.05 (s, 1H), 4.23-4.32 (m, 2H), 3.69 (dd, J=12.1, 6.0 Hz, 2H), 3.65 (s, 3H), 3.17-3.29 (m, 2H), 2.84 (s, 3H), 1.17 (s, 9H). LCMS (M+H)=641.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH2:23][NH2:24])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1CN1CCOCC1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3CN3CCOCC3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-morpholin-4-ylmethyl-benzylamine (132 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-morpholin-4-ylmethyl-benzylamino)-2H-phthalazin-1-one: 52 mg (23.3%): m/z (M+H)=385. 1H-NMR (DMSO-d6) δ: 12.27 (s, 1H), 7.85 (d, 1H), 7.51 (m, 1H), 7.22 (m, 2H), 7.16 (m, 2H), 7.11 (dd, 1H), 6.73 (s, 1H), 4.55 (d, 2H), 3.50 (m, 6H), 2.23 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1N=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=[O:13])[C:3]1=[O:4].C(C(N=C(C1C=CC=CC=1)C1C=CC=CC=1)C(N[C:21]([CH3:24])([CH3:23])[CH3:22])=O)#N.Cl.NC(C#N)C(NC(C)(C)C)=O>>[NH2:10][C:9]1[N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:6]=[N:7][C:8]=1[C:12]([NH:14][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:13]
Reactant: CC(C)(C)NC(=O)C(C#N)N=C(c1ccccc1)c1ccccc1
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Agent: CC(C)(C)NC(=O)C(N)C#N
Agent: Cl
Product: CNC(=O)n1cnc(C(=O)NC(C)(C)C)c1N

Procedure:
Another process for preparing Temozolomide is described in U.S. patent application having the Publication No. 2002/0095036 (see Scheme 4 below). In this process, the imine (V) is converted to 2-cyano-N-(1,1-dimethylethyl)-2-[(diphenyl-methylene)amino]-acetamide, which is converted to 2-amino-2-cyano-N-(1,1-dimethyl-ethyl)-acetamide hydrochloride. The latter is reacted with compound (VI) to obtain 5-amino-N4-(1,1-dimethylethyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide, which is converted to 3,4-dihydro-N-(1,1-dimethylethyl)-3-methyl-imidazo-[5,1-d]-1,2,3,5-tetrazine-8-carboxamide (tert-butyl-Temozolomide), which yields Temozolomide under acidic treatment with concentrated sulfuric acid.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN([CH:20]=[O:21])C>C1COCC1.C(OC1C=C(F)C=CC=1)C1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH:20]=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1cccc(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A (1 g). A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux. After completion of addition the reaction was allowed to proceed until it cooled to 25° C. and was then heated at reflux for 1 h. The reaction was allowed to cool to 25° C. and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25° C. and was then filtered through a plug of Celite. The THF was removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of 2-benzyloxy-4-fluorobenzaldehyde. 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 2 H), 6.70-6.76 (m, 2 H), 7.34-7.44 (m, 5 H), 7.87-7.92 (m, 1 H), 10.43 (s, 1 H). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][O-:11].[Na+].Cl>CO.[Cu](I)I>[Cl:9][C:4]1[CH:3]=[C:2]([O:11][CH3:10])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: C[O-]
Reactant: Nc1ccc(Br)cc1Cl
Agent: I[Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)c(Cl)c1
Yield: 41 %

Procedure:
A mixture of 4-bromo-2-chloro-aniline (25.0 g, 121 mmol), copper iodide (23.1 g, 121 mmol), and a solution of sodium methoxide in methanol (28%, 125 mL) was stirred for 1 h at 100° C. The reaction mixture was poured into a mixture of hydrochloric acid (6 M, 100 mL) and ice, and washed with ethyl acetate. The aqueous phase was basified with aqueous sodium hydroxide (8 M) and extracted with ethyl acetate. The extracts was washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale yellow oil (7.90 g, 50.1 mmol, 41%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][NH:5][CH:6]=1.Cl.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:7]([NH:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[O:9])=[CH:4][NH:5][CH:6]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c[nH]cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1c[nH]cc1C
Yield: 43.1 %

Procedure:
Using 7.63 g (60 mmol) of 4-methyl-3-pyrrolecarboxylic acid, 15.4 g (100 mmol) of β-alanine ethyl ester hydrochloride, 14 ml (100 mmol) of triethylamine, 17.3 g (90 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 100 ml of methylene chloride, 5.80 g of the title compound were obtained in a similar manner as in Example 2 (yield: 26%).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:24][C:23]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:29]([N:28]1[C:22]2[CH:21]=[CH:20][C:19]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=3)=[CH:49][C:23]=2[CH:24]=[C:25]([C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[CH:38][CH:39]=2)=[O:32])[CH2:26][CH2:27]1)[CH3:30]
Reactant: CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-propoxyethoxy)phenyl borate (272 mg) and 7-bromo-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (404 mg). To the solution was added potassium carbonate (269 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (37 mg), and the mixture was heated to reflux under argon atmosphere for 14 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10:0.5) and recrystallized from ethyl acetate/IPE to give 1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 17) (221 mg, 46%) as yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:27]
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC(c1ccccc1)C(O)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 2-hydroxy-1,2-diphenylethylamine (95.5 g, 0.39 m) (obtained by catalytic reduction of benzoin oxime) and triethylamine (43.3 g, 0.429 m) in chloroform (1 liter) maintained under nitrogen was added dropwise chloroacetylchloride (46.2 g, 0.41 m) and the mixture heated to reflux for 1 hour. After cooling, the mixture was washed with 10% HCl (1 liter) and water and the organic phase dried over MgSO4. The solvent was evaporated to a solid residue which was recrystallized from methanol to give 91.0 g of N-chloroacetyl-2-hydroxy-1,2-diphenylethylamine, m.p. 166°-169°.
Reaction SMILES: C(N=C=NCCCN(C)C)C.Cl.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[C:24](O)(=[O:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[C:24]([NH:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1)(=[O:26])[CH3:25]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NNc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethyl-3-(3'-dimethylamino-propyl)carbodiimide (5.87 ml) was added to a mixture of 4-isopropylphenylhydrazine hydrochloride (5.0 g), acetic acid (1.84 ml), triethylamine (3.73 ml) and 1-hydroxybenzotriazole hydrate (40.4 mg) in dichloromethane (50 ml) under ice-cooling and then the mixture was stirred overnight at room temperature. After removal of solvent by evaporation, the resulting residue was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-acetyl-2-(4-iso-propylphenyl)-hydrazine (3.00 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](Cl)=[O:14].[OH-].[NH4+:17]>>[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:14])[NH2:17]
Reactant: [NH4+]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Cl
Agent: [OH-]
Product: Cc1oc(-c2ccccc2)nc1C(N)=O
Reaction time: 8 h

Procedure:
9.4 Grams (0.0425 mole) of 5-methyl-2-phenyl-4-oxazolecarboxylic acid chloride is added in small portions to 200 ml. (3.33 mole) of concentrated ammonium hydroxide. The mixture is vigorously stirred and the temperature is maintained at about 0° during the addition step. After the addition, the temperature is allowed to rise to room temperature and the mixture is left standing overnight. The solid which forms is collected by filtration, washed with water, dried and recrystallized from methanol. 6.35 Grams of the title product is obtained; m.p. 154°-157° (from methanol).
Reaction SMILES: [CH3:1][C:2]([OH:17])([CH3:16])[CH2:3][O:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1.Cl.CC(C)=O>O>[OH:17][C:2]([CH3:16])([CH3:1])[CH2:3][O:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: CC(C)(O)COC1(C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(O)COC1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A mixture of 2-methyl-1-[(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)oxy]propan-2-ol (1.81 g), 3N hydrochloric acid (20 mL) and acetone (20 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless oil (1.05 g, 71%).