Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)(C)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@@H:15]1[O:17][CH2:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@@H]1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CC(C)(C)O
Product: O=C1NC(=O)c2c(C[C@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
Into a reaction vessel were put potassium phthalimide (5.00 g, 27.0 mmol), benzyltrimethylammonium chloride (0.50 g, 2.70 mmol) and tert-buyl alcohol (50 ml) and then thereto was added (S)-epichlorohydrin (6.53 g, 54.0 mmol). The mixture was stirred at 20° C. for 24 hours and the solvent was removed. To the residue was added ethyl acetate (30 ml), the mixture was washed with water (20 ml), and then ethyl acetate was removed to give crude (S)-glycidylphthalimide (3.95 g, yield: 72%, optical purity: 97% e.e.) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 44.9 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)-amino]pyridin-2-yl}piperidin-3-yl)carbamate (98 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.30 mmol) to afford the product (56 mg) which was carried forward without any purification: ESI MS m/z 625 [M+H]+.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=O)[CH2:7]Br.[C:13]([NH2:16])(=[S:15])[CH3:14].CN(C)C=O.[OH-].[Na+]>O>[CH3:14][C:13]1[S:15][CH:7]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([NH2:2])[CH:4]=2)[N:16]=1
Reactant: Nc1cccc(C(=O)CBr)c1
Reactant: CC(N)=S
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cccc(N)c2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
A mixture of 3-amino-phenacyl bromide hydrobromide (11.78 g), thioacetamide (3 g) and dimethylformamide (20 ml) was stirred at room temperature for 24 hours and then poured into water (100 ml). The resulting solution was made alkaline with 10% sodium hydroxide, and the precipitate was filtered off and dried to give 6 g of 2-methyl-4-(3-amino-phenyl)-thiazole; M.p. 134°-137° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:48][CH2:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCCN1CCOCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 3-(4-morpholinyl)-1-propanamine (0.357 mL, 2.44 mmol) for 15 min. (150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68-1.76 (m, 2 H), 2.31-2.38 (m, 7 H), 2.78 (t, J=6.81 Hz, 2 H), 3.35-3.46 (m, 3 H), 3.55-3.62 (m, 5 H), 4.16 (s, 2 H), 4.22 (t, J=6.81 Hz, 2 H), 7.10-7.17 (m, 2 H), 7.38 (ddd, J=9.02, 5.79, 3.02 Hz, 2 H), 8.15 (s, 1 H), 8.50 (d, J=1.26 Hz, 1 H), 10.41 (d, J=3.93 Hz, 1 H); ES+ MS: 484 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([O:31][C:30]([F:29])([F:40])[F:41])[CH:33]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cccc(OC(F)(F)F)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (5.16 g, 20.05 mmol) in anhydrous tetrahydrofuran (60 mL), a solution of sodium bis(trimethylsilyl)amide (28 mL, 1M, 28 mmol) was added over a period of 30 min. The resultant mixture was stirred at −78° C. for 1 h, and 3-(trifluoromethoxy)benzyl bromide (5.90 g, 23.14 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Br)(Br)[Br:25].CO>C(Cl)Cl>[BrH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Br
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
1-Aminomethyl-3,4-dihydro-5,6-dimethoxy-3-phenyl-naphthalene hydrochloride (6.0 g, 20.2 mmol), from Step 2, was suspended in 200 mL of methylene chloride and boron tribromide (90.5 mL of 1M solution of BBr3 in methylene chloride) was added dropwise while the reaction mixture was being cooled (to -78° C.) in a dry ice/acetone bath. The reaction mixture was warmed to 0° C. and stirred for 0.5 h, then again cooled to -78° C. in a dry ice/acetone bath. Methanol (50 mL) was added dropwise to the reaction mixture, which was allowed to warm to ambient temperature then concentrated in vacuo. Methanol was added to the residue and the solution was reconcentrated. This residue was dissolved in a small amount of methanol and the methanol solution was aded to 700 mL of diethyl ether. The precipitate which formed was filtered, washed with diethyl ether and recrystallized from methanol/ether to give 2.5 g (45% yield) of 1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3 -phenyl-naphthalene hydrobromide, m.p. 223°-225° C. 1H NMR (d6DMSO) delta 2.68 (dd, 1H), 3.09 (dd, 1H), 3.6-3.7 (m, 1H), 3.9 (s, 2H), 5.97 (d, 1H), 6.69 (m, 2H), 7.2-7.35 (m, 5H), 8.1 (br s, 3H), 8.4 (s, 1H), 9.5 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH3:16])[CH3:15])=[O:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl-:1].[CH3:15][C:8]1([CH3:16])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3](=[O:4])[CH2:2][N+:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Reactant: c1ccncc1
Product: CC1(C)C(=O)Nc2ccc(C(=O)C[n+]3ccccc3)cc21
Product: [Cl-]
Temperature: 85 °C
Reaction time: 1.6 h

Procedure:
To 5-chloroacetyl-2,3-dihydro-3,3-dimethylindol-2-one (35 g) was added pyridine (140 ml) and the mixture was stirred to 1.6 hours at 85° C. After the mixture was cooled to ambient temperature, the crystal was collected by filtration and washed with pyridine and diethyl ether successively to give 1-[2-(2,3-dihydro-3,3-dimethyl-2-oxoindol-5-yl)-2-oxoethyl]pyridinium chloride (44.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN1CCN(C(=O)NCc2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CN1CCN(c2ncc3c(Cl)nccn23)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To N-((3-chloropyrazin-2-yl)methyl)-4-methylpiperazine-1-carboxamide (485 mg) in acetonitrile (3 mL) under a N2 flow was added phosphorus oxychloride (878 μl) and heated at 60° C. (bath temperature) for five hours and at 80° C. for one hour. Then the reaction mixture was concentrated in vacuo. Toluene was added and the mixture was concentrated in vacuo. Residue was taken up with acetonitrile, 7N ammonia in methanol was added with cooling and the suspension was stirred for 16 hours, then filtered and the filtrate concentrated in vacuo. Dichloromethane was added to the residue, again filtered and the filtrate concentrated in vacuo to give 8-chloro-3-(4-methylpiperazin-1-yl)imidazo[1,5-a]pyrazine (400 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH:20]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][C:18]=3[CH:31]=2)=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:3])[CH3:2].[C:33](OCC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[C:25]1([CH2:24][CH2:23][CH2:22][CH:20]2[CH2:19][C:18]3[CH:31]=[C:14]([C:12]([NH:11][C:6]4[C:5]5[O:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:2][C:1](=[O:3])[C:4]=5[CH:9]=[C:8]([F:10])[CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:21]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1cc(F)cc(NC(=O)c2ccc3c(c2)CC(CCCc2ccccc2)O3)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCO
Product: CCOC(=O)c1cc(=O)c2cc(F)cc(NC(=O)c3ccc4c(c3)CC(CCCc3ccccc3)O4)c2o1
Yield: 55 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-5-fluoro-2-hydroxyphenyl)-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by crystallization in ethanol (55% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:18](=[O:19])[C:13]=2[C:12]([CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)O)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCN1C2C=NNC(=O)C=2C(C(O)(C)C)=C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:28][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C(O)c3cccc(F)c3)cn2COCc2ccccc2)c1=O
Agent: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Product: O=c1[nH]ncc2c1c(Cc1cccc(F)c1)cn2COCc1ccccc1
Yield: 57.7 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 21-(e) except for using 2.60 g (5.10 mmol) of 1-benzyloxymethyl-3-[(3-fluorophenyl)hydroxymethyl]-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 37-(a) in place of 1-benzyloxymethyl-3-(1-hydroxy-1-methylethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 1.07 g of the title compound was obtained as a white solid. (Yield: 58%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1Cl

Procedure:
55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol. After addition of 25 g. of triethylamine (0.25 mol.), the mixture is heated at reflux temperature and then 20 g. of N-methylpiperazine are dropped in with stirring. When the addition is completed, the temperature is maintained for 30 minutes. The solvent is distilled off, the residue is dissolved in benzene and the precipitated triethylammonium chloride filtered off. After evaporation of the solvent, the residual 4-chloro-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is recrystallized from methanol, yield 40 g. (60%), m.p. 59°-61°.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(C(C)C)CC)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O.O>[CH3:5][O:4][N:3]([CH3:2])[C:28]([CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:27][CH2:26]1)=[O:30]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.6 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPEA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5%, aqueous sodium bicarbonate 4%, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99%) as yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[I:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.O.CCOC(C)=O>O1CCOCC1.CN(C1C=CN=CC=1)C>[C:14]([O:13][C:11](=[O:10])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(I)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(I)c(F)c1
Yield: 96 %

Procedure:
A solution of compound 143 (13.67 g, 57.7 mmol) in 1,4-dioxane (100 mL) was treated with BOC2O (13.83 g, 63.4 mmol, 1.1 equiv) and DMAP (700.0 mg, 5.8 mmol, 0.1 equiv) at room temperature. The resulting reaction mixture was then warmed up to refluxing for 4 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was treated with H2O (100 mL) and EtOAc (100 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, desired (3-fluoro-4-iodo-phenyl)-carbamic acid tert-butyl ester (compound 144, 18.67 g, 19.44 g theoretical, 96%) as pale-yellow oil, which solidified upon standing in vacuo at room temperature and was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For compound 144: C11H13FINO2, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=3)[CH2:35][CH2:34]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
143 mg (89%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(3,4-dichlorophenyl)piperazine (69 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:14].[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3]([CH2:2][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:4][C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[O:7][C:8]=2[CH:13]=1
Reactant: Clc1ccc2c(c1)Oc1ccccc1C=C2CBr
Reactant: C1CCNC1
Product: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1C=C2CN1CCCC1
Yield: 45 %

Procedure:
Preparation analogous to Example 2 from 10-bromomethyl-7-chloro-dibenz[b,f]oxepine and pyrrolidine. Yield: 45%; melting point: >225° C. decomposition. 1H-NMR (CD3OD, 200 MHz): 1.95-2.20 (m, 4H); 3.25 (m 2H); 3.55 (m, 2H); 4.52 (s, 2H); 7.20-7.45 (m, 7H); 7.60 (d, 1H).
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:5]
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Referring to Scheme 4, to a solution of 1.74 g (10 mmol) of tert-butyl hydrogen succinate (Buchi, G.; Roberts, C. J. Org Chem., 33:460, 1968) and 1.15 g (10 mmol) of N-hydroxy-succinimide in anhydrous tetrahydrofuran (20 ml) was added 2.06 g (10 mmol) of 1,3-dicyclohexylcarbodiimide. After stirring at room temperature overnight, the reaction was filtered to remove the dicyclohexylurea by-product. The filtrate was concentrated in vacuo to give a residue. Chromatography on silica gel using ethyl acetate-hexane (1:1), provided 2.3 g (84% yield) of tert-butyl succinimidyl succinate (4a) as a white solid. TLC: Rf 0.50 (ethyl acetate-hexane 1:1); NMR(d6 -DMSO) δ 1.39(s,9H), 2.56(m,2H), 2.80(bs,4H), 2.86 (m,2H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[S:25][C:26]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[N:43]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2nc(NCCNc3nc4ccc(Cl)cc4s3)ncc2-c2ncc[nH]2)c(Cl)c1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(6-chlorobenzothiazo 1-2-yl)amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2,6-dichlorobenzothiazole in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]([F:42])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:9][NH:10][C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:27]([CH3:29])=[CH:28][C:12]1=2.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:42][C:5]([F:4])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1)[CH2:9][N:10]([C:2]#[N:1])[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:31])[F:32])[C:27]([CH3:29])=[CH:28][C:12]1=2
Reactant: N#CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
Add cyanogen bromide (1.21 mL, 6.04 mmol, 5 M solution in acetonitrile) to a solution of (S)-tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.30 g, 4.03 mmol) and diisopropylethylamine (1.05 mL, 6.04 mmol) in tetrahydrofuran (50 mL) at room temperature under nitrogen and heat the mixture at 50° C. for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (2:3), to provide the title compound as a colorless oil (2.10 g, >99%), which is used in the next step without further purification: APCI MS m/z 496 (M+H−Boc)+.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[N:3][CH:4]=3)[S:10][C:11]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(N4CCCC4)nc3)nc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 6-chloro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-nicotinamide (297 mg, 0.75 mmol) in dioxane (10 ml) was added pyrrolidine (266 mg, 3.7 mmol, 5 eq.) and the mixture stirred at 100° C. for 2 h. After cooling the solvent was evaporated and the residue suspended in methanol (20 ml) at r.t., the solid was then filtered, washed with methanol and finally dried under vacuum (0.05 mmHg, 60° C.) to obtain the title compound as a white solid (230 mg, 71% yield), MS: m/e=431.4 (M+H+).