Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([C:7]2[CH:17]=[CH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][NH:15][C:9]=3[CH:8]=2)CCOCC1.[OH-].[Na+]>CO>[N:15]1[CH2:14][CH:13]=[CH:12][CH:11]=[C:10]2[CH:16]=[CH:17][CH:7]=[CH:8][C:9]=12
Reactant: C1=CNc2cc(N3CCOCC3)ccc2C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C1=CCN=c2ccccc2=C1
Temperature: 25 °C
Yield: 192.1 %

Procedure:
To a solution of the N-acetyl benzazepine (0.14 g, 0.40 mmol) from step I above in methanol (10 mL) was added an aqueous 2N solution of sodium hydroxide (10 mL). The reaction solution was heated under reflux for 72 hours and then cooled to room temperature. The resultant reaction mixture was extracted with dichloromethane, washed with water and aqueous saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (dichloromethane to 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to give the desired 2H-benzazepine (0.11 g, 89%) as a white foam: 1H NMR (DMSO-d6, 500 MHz) δ 7.35 (t, J=7.5 Hz, 2H), 7.24 (t, J=7.5 Hz, 1H), 7.14 (d, J=7.5 Hz, 2H), 6.84 (d, J=2.5 Hz, 1H), 6.65-6.60 (m, 1H), 6.49-6.38 (br, 1H), 4.33 (d, J=8.5 Hz, 1H), 3.95 (d, J=14.5 Hz, 1H), 3.77 (d, J=14.5 Hz, 1H), 3.71 (t, J=5.0 Hz, 4H), 3.10-2.87 (m, 6H), 2.21-2.12 (m, 1H), 2.03-1.85 (m, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19](O)[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (10 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-hydroxypyrrolidine (19.95 g) and triethylamine (27 ml) in tetrahydrofuran (200 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into water (200 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with ethyl acetate (150 ml×2). The organic layer was washed with brine (200 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonylpyrrolidine (24.85 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([NH2:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:16]([NH:22][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCNc1nc(N)nc(N)n1

Procedure:
A mixture of 72.8 g. (0.500 mole) of 2,4-diamino-6-chloro-s-triazine, 63.6 g. (0.600 mole) of anhydrous sodium carbonate, and 200 ml. of N,N-dimethylformamide (DMF) was heated over 43 minutes of 124° C. To this was added, over a period of 2.35 hours, a solution of 60.7 g. (0.600 mole) of n-hexylamine in 100 ml. of DMF; temperature was controlled at 122°-127° C. during the addition. The reaction mixture was heated for an additional 19 hours at 124°-125° C., then was filtered hot. The filter cake was washed with 100 ml of hot DMF, and the combined filtrate was cooled and added with stirring to about 5 liters of ice-water. The precipitate was recovered by filtration, reslurried with 3 liters of water, filtered again, washed thoroughly with deionized water, and dried to constant weight in a vacuum oven at 60° C. The yield of n-hexylmelamine, m.p. 115°-117.5° C., was 91.4 g. (87.0%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CO.O>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:1]([O:6][CH2:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: OCCCCCCCCCCCBr
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: C=C(C)C(=O)OCCCCCCCCCCCBr
Reaction time: 3 h
Yield: 91 %

Procedure:
Methyl methacrylate (1.15 L, stabilised with 50 ppm of BHT), 11-bromoundecanol (200 g, 0.8 mole) and titanium tetraisopropoxide (11.4 g, 0.04 mole) are mixed together. A constant slow stream of dry air is bubbled through the reaction mixture during the reaction. The reaction mixture is heated under gentle reflux for 1 hour (internal temperature 90°). After this reflux period the methyl methacrylate/methanol azeotrope is removed under atmospheric distillation. During this time the internal temperature rises to 104° and the temperature at the still head rises from 65° to 101° (a total of 550 ml of distillate is collected). The reaction mixture is then cooled to 40° and quenched with water (1.5 ml, 2 equiv. based on titanium tetraisopropoxide). The resulting mixture is stirred for 3 hours then treated with celite (20 g). After stirring for a further 10 minutes the reaction mixture is filtered through a pad of celite. The filter pad is washed with methyl methacrylate (50 ml). The filtrate and wash are combined and distilled under vacuum (4-10 mmHg) at room temperature, then at 50°-60° to remove last traces of methyl methacrylate. During distillation a slow stream of dry air is bubbled through the residue in the distillation vessel. The product, 11-bromoundecyl methacrylate (233 g, 91% yield) is obtained as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([OH:18])=[O:17])[N:13]=[N:12][N:11]=3)=[CH:9][C:2]1=2.S(=O)(=O)(O)O.[CH2:24](O)[CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][O:17][C:16](=[O:18])[CH2:15][N:14]1[C:10]([C:8]2[CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][C:2]=3[CH:9]=2)=[N:11][N:12]=[N:13]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccc2ccsc2c1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc2ccsc2c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.5 %

Procedure:
To a solution of 400 mg (1.54 mM) of [5-(6-benzo[b]thienyl)tetrazol-1-yl] acetic acid in 3 ml of ethylene glycol was added 0.3 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 400 mg (yield 85.5%) of [5-(6-benzo[b]thienyl)tetrazol-1-yl]acetic acid 2-hydroxyethyl ester.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].O=[C:8]1[CH2:32][C@@H:31]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3([CH2:30]2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[NH:9]1.[CH3:33]I>C1COCC1>[CH3:33][N:9]1[C@H:10]2[C@H:31]([CH2:30][C:17]3([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=42)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH2:32][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CC(=O)N[C@@H]1c1ccccc12
Reactant: CI
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CN1CC[C@H]2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersed in oil, 58 mg) was washed with anhydrous 2,2,4-trimethylpentane and suspended in anhydrous THF. Lithium perchlorate (78 mg, 0.73 mmol) was added to the suspension at 0° C., followed by (3aR,9bS)-tert-butyl 2-oxo-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate (142 mg, 0.4 mmol) in THF (10 ml) at 0° C. After 15 min, methyl iodide (0.04 ml, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then heated under reflux for 1 h. Concentration gave the title compound. LC-MS: m/e=371.6 (M+), 315.5 (M−tBu+1, 100%). Rt=3.12 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](=[O:14])[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)N(Cc2ccccc2)Cc2ccccc2)c2ccccc21

Procedure:
N,N-Dibenzyl-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and dibenzylamine. Yield (70%). HPLC ret. time 3.70 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.43-7.25 (m, 12H), 4.55 (s, 2H), 4.40 (s, 2H), 3.93 (s, 3H); ESI-MS 383.3 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.C(=O)([O-])O.[Na+]>CC(C)=O.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]1[CH2:7][O:8][C:15]([CH3:20])([CH3:16])[O:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)Cc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCC(Cc2cccc(Br)c2)CO1
Reaction time: 1 h
Yield: 1400.7 %

Procedure:
2-(3-Bromobenzyl)-1,3-propanediol (1.85 g) was dissolved in a mixture of 8 ml of acetone/18 ml of benzene, and 70 mg of p-toluenesulfonic acid monohydrate was added. The solution was subjected to azeotropic dehydration with Dean-Stark apparatus for 1 hour. After addition of saturated sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 1.47 g of the objective compound as colorless oil.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:38])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:38])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:26]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc3c(I)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate (410 mg, 1 mmol) and NIS (247 mg, 1.1 mmol, 2.0 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (35 mg, 0.3 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to r.t. and stirred for another 1.5 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give product the title compound as a slight red solid (300 mg, 56%). ESI-MS (M+H+): 536.2. 1H NMR (400 MHz, CDCl3) δ: 8.19 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.22 (d, 1H), 4.34-4.28 (m, 4H), 3.91-3.67 (m, 1H), 3.80-3.78 (m, 3H), 3.75 (s, 3H), 2.24-2.21 (m, 2H), 1.90-1.88 (m, 2H), 1.62-1.58 (m, 2H), 1.15-1.12 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][N:13]([N:17]=O)[C:12]=2[CH:19]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][N:13]([NH2:17])[C:12]=2[CH:19]=1
Reactant: O=NN1CCOc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
LiAlH4 in THF (1 M, 6.58 mL) is added to a solution of 6-fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (0.8 g) in THF (10 mL) at 00 C. and then stirred at rt overnight. The reaction mixture is quenched with a few drops of water followed by addition of EtOAc (10 mL). The solid is filtered off and washed with EtOAc (15 mL). The filtrate is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 15% EtOAc in heptane to afford 6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (0.44 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4]N1CC(C)(C)N(CC2C=C(C3C=CC(O)=CC=3F)N=C3NN=C(C)C=23)CC1(C)C.[CH3:35][O:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:50]=[C:49]3[N:51]([CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)[N:52]=[C:53]([CH3:54])[C:48]3=[C:47]([CH2:61][N:62]3[CH2:67][C:66]([CH3:69])([CH3:68])[NH:65][CH2:64][C:63]3([CH3:71])[CH3:70])[CH:46]=2)=[CH:41][CH:40]=1.BrCC(OC)=O>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:65]1[CH2:64][C:63]([CH3:71])([CH3:70])[N:62]([CH2:61][C:47]2[CH:46]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:37][O:36][CH3:35])=[CH:44][CH:43]=3)[N:50]=[C:49]3[N:51]([CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)[N:52]=[C:53]([CH3:54])[C:48]=23)[CH2:67][C:66]1([CH3:69])[CH3:68]
Reactant: COC(=O)CN1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: COC(=O)CBr
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CC(=O)OC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1

Procedure:
The title compound was prepared in analogy to Example 74 ({4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-acetic acid methyl ester employing 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and methyl bromoacetate and was used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1
Yield: 79.1 %

Procedure:
Tertiary butyl 4-(azidomethyl)piperidine-1-carboxylate (30 g, 124.8 mmol) was dissolved in tetrahydrofuran (300 mL), and triphenylphosphine (39.3 g, 149.8 mmol) was added thereto, followed by stirring under reflux for 2 hours. Water (120 mL) was added thereto, followed by stirring under reflux for another 3 hours and concentration under reduced pressure. The resulting residue was extracted with ethyl acetate and a 1N hydrochloride solution, and the aqueous layer was neutralized with a 2N sodium hydroxide solution, followed by re-extraction with dichloromethane. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (21.16 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[N:34]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:35]=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:37]([NH:34][C:35]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][N:11]([C@@H:19]([C:20](=[O:21])[NH2:22])[CH2:23][CH:24]([CH3:26])[CH3:25])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:18][CH2:17]1)=[O:36])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCCc1ccccc1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)NCCc2ccccc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.10 g, 0.22 mmol) and Et3N (32 μL, 0.25 mmol) in CH2Cl2 (3.0 mL) was added (2-isocyanato-ethyl)-benzene (0.040 mL, 0.30 mmol). The reaction was stirred at rt for 18 h and then was poured into sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to an oily residue. The residue was further purified on a BIOTAGE® system (eluted with 75% EtOAc/hexanes) to afford the desired product as a white solid (67 mg, 52%). MS (ESI), (M+H)+549.00; 1H NMR (CDCl3, 500 MHz) δ 7.71 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.9), 7.15-7.35 (m, 5H), 6.64 (s, 1H), 5.86 (s, 1H), 4.15 (dd, 1H, J=5.2, 9.5), 3.88 (d, 1H, J=13), 3.76 (d, 1H, J=13), 3.46 (t, 2H, J=6.7), 3.21-3.29 (m, 1H), 2.97 (dd, 1H, J=4.6, 14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H), 1.00-1.30 (m, 5H), 0.75-0.80 (m, 1H), 0.72 (d, 3H, J=6.7), 0.67 (d, 3H, J=6.7).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[ClH:26].CN(C)CCCOC1C(C)=C2N(C=1)N=CN=C2OC1C=CC(N[C:50]([NH:52][C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[O:51])=CC=1F>>[ClH:26].[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:50]([NH:52][C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[O:51])=[CH:18][C:17]=1[F:23]
Reactant: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Yield: 19 %

Procedure:
4-(6-(2-(Dimethylamino)ethoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (20 mg, 0.06 mmol) was converted to the title compound (6.5 mg, 19%) in a manner similar to the preparation of Compound C of Example 32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:13]1[O:21][CH:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:13][CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: COc1ccc(CNCC(O)c2ccccc2)cc1OC
Yield: 46.7 %

Procedure:
Heat a solution of 3,4-dimethoxybenzylamine (16.7 g) and styrene oxide (12.0 g) in acetonitrile (250 mL) at reflux for 16 h. Concentrate to a residue and distill the residue, collecting the fraction distilling above 120° C. (0.5 mm). Recrystallize the solidified distillate from benzene/hexane to give N-(3,4-dimethoxybenzyl)-2-hydroxy-2-phenylethylamine (13.4 g), mp=93°-94° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1F

Procedure:
In a similar manner to Example 2, starting material step (b), t-butyl bromoacetate (5.6 ml), 2-fluoro-4-nitrophenol (5 g), anhydrous potassium carbonate (5.3 g) and acetone (200 ml) were reacted to give t-butyl 2-fluoro-4-nitrophenoxyacetate (8.3 g) as an off-white solid: m.p. 62°-64° C.; NMR Spectrum (DMSO-d6) 1.49 (9H, s), 4.70 (2H, s), 6.94 (1H, m), 8.01 (2H, m); Mass Spectrum m/Z 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].CO>C1COCC1.C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:26]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(Cl)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-chlorobenzoyl chloride (0.51 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.82 g (100%) of product as an off-white solid: mp 257-259° C.; 1H NMR (DMSO-d6) d 11.06 (s, 1H), 10.43 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.99-7.88 (m, 3H), 7.75-7.61 (m, 3H), 5.17 (dd, J=5.5 and 12.7 Hz, 1H), 2.99-2.84 (m, 1H), 2.67-2.49 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) d 172.36, 169.78, 169.36, 167.59, 166.39, 163.57, 135.99, 135.31, 133.59, 132.11, 131.33, 130.73, 127.07, 126.76, 125.78, 118.93, 118.55, 48.91, 30.77, 21.85; Anal. Calcd. For C20H14ClN3O5: C, 58.33; H, 3.43; N, 10.20. Found: C, 58.38; H, 3.23; N, 9.95.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To an ice-cold mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (4.00 g, 3.43 mmol), and triethylamine (4.43 g, 43.8 mmol) in tetrahydrofuran (70 mL) was added 2,2,2-trichloroethyl chloroformate (3.06 g, 14.4 mmol) and the mixture was stirred at room temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was filtered through a pad of silica gel eluted with ethyl acetate to afford a white solid. The solid was triturated with hexane to give the title compound (2.54 g, 47%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.ClC1C=CC([C:27]2C3C=CC=C(CC#N)C=3C=C[N:28]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:27]#[N:28])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: N#CCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Reactant: COc1ccc(-c2nccc3c(C)cccc23)cc1
Product: COc1ccc(-c2nccc3c(CC#N)cccc23)cc1

Procedure:
1-(4-Methoxyphenyl)-5-methylisoquinoline was reacted successively in the same way as in steps (d) and (e) of Example 1 to afford 1-(4-methoxyphenyl)isoquinoline-5-acetonitrile as slightly yellow scales having a melting point of 130.5° to 132.0° C.