Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11]([C@@H:13]1[C@@H:15]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14]1)=[O:12].[N-:20]=[N+:21]=[N-:22].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O>[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11](=[O:12])[C@@H:13]([OH:14])[C@@H:15]([N:20]=[N+:21]=[N-:22])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)N[C@H]1CCCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 2 h
Yield: 72.8 %

Procedure:
30 ml of a methanol suspension containing 1.64 g (7 mmol) of (2S)-trans-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-butyloxiranecarboxamide, 910 mg (14 mmol) of sodium azide and 868 mg (7.2 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was poured into 300 ml of water and the resulting mixture was stirred for 2 hours. The resulting crystals were collected by filtration and washed with water, and dried to obtain 1.45 g (Yield: 73%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)coc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)coc2C1
Yield: 68.2 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.087 g), concentrated hydrochloric acid (0.037 ml), water (0.037 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 37) (0.17 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:31][C:32]([NH2:34])=[O:33])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CC(N)=O)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 123.2 %

Procedure:
A solution of 50 mg of amine prepared in Example 11, 33 mg of iodoacetamide and 0.05 mL of DIPEA in 0.5 mL of acetonitrile was heated in a sealed vial at 50° C. for 2 h (or room temperature for 16 h). The volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with 5% MeOH in methylene chloride to afford 70 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:43]([CH:49]=O)[O:42][C:41]1([CH3:52])[CH3:51])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[C@H:43]([CH:49]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:42][C:41]1([CH3:51])[CH3:52])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Yield: 88.1 %

Procedure:
71.6 mg of lithium chloride was suspended in 5 ml of dry THF under an argon atmosphere, and 426 mg of ethyl 2-diethylphosphonobutanoate dissolved in 0.6 ml of dry THF was added thereto under stirring. The mixture was stirred at room temperature for 5 minutes, and then 323 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to simply as DBU) was added thereto in the form of a 50% dry THF solution, and the mixture was stirred at room temperature for 10 minutes. Then, 450 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine dissolved in 1.0 ml of dry THF was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the solution was extracted three times with ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 518 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:4]2[C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:5]2=[N:6][CH:7]=1.CN(C)C1C=CC=CC=1.[F:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=2[F:30])=[CH:7][N:6]=[C:5]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:4]=12
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (150 mg) and N,N-dimethylaniline (0.065 ml) in dichloromethane (3 ml) was added dropwise 2,4-difluorobenzoyl chloride (0.07 ml) with ice-cooling. The mixture was stirred for 10 minutes with ice-cooling and then stirred at room temperature for 2 hours. Then, the mixture was washed in turn with water, aqueous saturated NaHCO3 solution and water, and dried over MgSO4. The solvent was distilled off to obtain 4-(2-chlorophenyl)-3-(2,4 -difluorobenzoylamino)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (206 mg, 93.6%) as crystals. The crystals were recrystallized from acetone to obtain colorless prisms, mp: 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[N:30]1([C:36]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 99.2 %

Procedure:
To 19.0 g (68.8 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 51.3 g of acetone and 10.5 g (75.7 mmol) of potassium carbonate, and the resultant mixture was stirred at 30° C. To the mixture was added dropwise 11.3 g (75.7 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 30° C. for 5 hours. After completion of the reaction, pure water was added to the reaction mixture to deposit solids, and then the solids were taken out by filtration. The resultant solids were dried under a reduced pressure, and the solids were quantitatively determined by an HPLC internal standard analysis method, which showed that 26.6 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:36])[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN>C(O)C>[NH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:37])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:36]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 99.3 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-(phthalimido-acetyl)-N-methylamino]benzyloxy)-2-methylquinoline (3.98 g), hydrazine monohydrate (0.72 ml) and ethanol (40 ml) was heated under reflux for 1 hour. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was dissolved with dichloromethane and the precipitate was removed by vacuum filtration. The filtrate was evaporated in vacuo to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy)-2-methylquinoline (2.99 g) as a yellow amorphous powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:32])[CH3:31])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: NCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propylamine (25 mg, 0.06 mmol) in pyridine (1 mL) at room temperature is added acetic anhydride (500 μL, 5.3 mmol). The mixture is stirred for 2 h, concentrated in vacuo, and the residue chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 12 mg (47%), as a light brown solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.C1COCC1.Cl.[CH2:51]([NH2:53])[CH3:52]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][NH:53][CH2:51][CH3:52])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.415 g, 0.641 mmol) in 2.0 M ethylamine in THF (8.0 mL, 16.0 mmol) was stirred at 70° C. for 3 hours and then at 80° C. for 19 hours. The reaction mixture was allowed to cool to ambient temperature and solvent evaporated. It was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with magnesium sulfate, filtered and concentrated. Drying in vacuo at 80° C. for 20 minutes resulted in {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-amine as an orange semi-solid (0.270 g, 81.1%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 83° C. for 16 hours. The hydrochloride as a pale orange foam resulted (0.276 g); Mass Spectrum (+EI, [M+H]+) m/z 520. 1HNMR (500 MHz, DMSO-d6): δ8.71-8.77 (m, 3H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H) 7.05 (d, 1H, J=7.56 Hz), 5.73 (s, 2H), 4.24-4.27 (m, 2H), 3.30-3.32 (m, 2H), 2.97-3.03 (m, 2H), 1.16-1.20 ppm (m, 3H). Elemental Analysis for C28H26ClN3O3S.1.00 HCl.0.60 mole H2O: Calcd: C, 59.28; H, 5.01; N, 7.41; Found: C, 58.95; H, 5.06; N, 7.14.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.CCOCC>C(O)C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:27][CH2:28][CH2:29][CH2:30]4)[S+:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(-c2cc[s+]c(-c3ccccc3)c2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccc4c(c3)CCCN4)c2)cc1

Procedure:
2,4-diphenylthiopyrylium trifluoromethane sulfonate (2.0 g) and 1,2,3,4-tetrahydroquinoline (1.4 g) in ethanol (20 ml) were heated at 90° for 30 minutes. After cooling the solution was poured into ether (50 ml) and the precipitated dye was filtered, washed with ether and recrystallized from ethanol as black needles having a melting point of 233° C., λ max (CHCl3) 656 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[I-].[CH3:18][N+:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(OCC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:24]1[CH:23]=[C:22]([CH3:25])[CH:21]=[CH:20][N:19]1[CH3:18]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Cc1cc[n+](C)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2C=C(C)C=CN2C)c(OC)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5 g, 2.3 mmol) in diethyl ether (10 ml) cooled at −78° C. under nitrogen was added a solution of n-butyl lithium (1.0 ml, 2.5 mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at −78° C. for 2 hours and then 1,4-dimethylpyridinium iodide (2) (0.54 g, 2.5 mmol) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and extracted with diethyl ether (2×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.5 g, 93%) as a brown oil, 1H NMR CDCl3 ??1.7 (s, 3H), 2.7 (s, 3H), 3.8 (s, 6H), 4.45 (dd, 1H, J=2,7) 4.85 (m, 1H), 5.4 (d, 1H, J=4), 6.05 (d, 1H, J=7), 6.45 (d, 1H, J=3), 6.55 (m, 1H), 7.5 (d, 1H, J=9).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][O:16][CH3:17]>CCN(CC)CC.CS(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:15][O:16][CH3:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(I)cc2)on1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOc1cc(-c2ccc(I)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of 5-(4-iodophenyl)isoxazol-3-ol (128 mg, 0.43 mmol) in Et3N/DMSO (10:1 v/v, 5.5 mL) at 0° C., chloro(methoxy)methane (45 mg, 0.64 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as white solid (55 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 7.79 (d, 2H), 7.46 (d, 2H), 6.23 (s, 1H), 5.36 (s, 2H), 3.57 (s, 3H). LCMS: 332 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:32](O)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
L-Serine methyl ester hydrochloride, 5 g., is dissolved in 75 ml. of dimethylformamide and the solution cooled in an ice bath. Triethylamine, 4.9 ml., is added then 11.9 g. of Nα -benzyloxycarbonyl-L-tryptophan, 5.25 g. of 1-hydroxybenztriazole and finally 8.0 g of dicyclohexylcarbodiimide. The reaction is stirred with ice bath cooling overnight, allowing the temperature to rise to room temperature, then an additional twenty-four hours at room temperature. The mixture is filtered and the solid washed with dimethylformamide. The filtrate is evaporated under reduced pressure and the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid, saturated salt solution, three times with 5% sodium bicarbonate solution, saturated salt solution, and finally with water. The ethyl acetate solution is then dried over magnesium sulfate and evaporated. The residue is crystallized from 250 ml. of benzene and then from ethyl acetate and petroleum ether; 12.5 g.; m.p. 133°-135° C.; [α]D23 -12.4° (c 2, methanol); ultraviolet in methanol λmax 290 E11 115; λmax 281 E11 131; λmax 274 E11 122.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:36]1[N:35]=[CH:34][C:33]2=[CH:32][CH:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[N:38]2[N:37]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc([C@H]2CC[C@H](N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, 2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]aniline (0.125 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (98 mg, 0.26 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-{2-methoxy-4-[trans-4-(morpholin-4-yl)cyclohexyl]phenyl}-7-(2-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine as a yellow solid (65 mg, 48%). LCMS (E/I+) 514.23 (M+H). NMR 1H (DMSO-d6)-9.71 (bs, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=8.03 Hz), 7.81 (d, 1H, J=7.74 Hz), 7.60 (s, 1H), 7.46 (t, 1H, J=7.74 Hz), 7.22 (d, 1H, J=8.32 Hz), 7.10 (t, 1H, J=7.74 Hz), 6.98 (d, 1H, J=4.64 Hz), 6.94 (d, 1H, J=4.64 Hz), 6.89 9 s, 1H), 6.69 (d, 1H, J=8.33 Hz), 4.02 (d, 2H, J=12.02 Hz), 3.87 (s, 3H), 3.79 (s, 3H), 3.70 (t, 2H, J=11.78 Hz), 3.46 (d, 2H, J=12.02v), 3.28 (bs, 1H), 3.15 (q, 2H, J=11.54 Hz), 1.97-2.10 (m, 4H), 1.47-1.64 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][C@H:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.O>CN(C=O)C>[CH3:12][N:9]1[CH2:8][C@H:7]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[CH:19]=[C:2]([O:1][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[N:26][N:25]=3)[C:3]([CH3:20])=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: Cc1cc2c(cc1O)[C@@H](c1ccccc1)CN(C)CC2
Reactant: Clc1nnnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1Oc1nnnn1-c1ccccc1)[C@@H](c1ccccc1)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-8-Hydroxy-3,7-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (13.35g, 0.0499 mol) was dissolved in DMF (70 ml) and 50% sodium hydride in mineral oil (2.4 g, 0.0499 mol) was added with stirring under nitrogen. The solution was stirred at room temperature for one hour longer. A solution of 5-chloro-1-phenyl-1H-tetrazole (9.90 g) in DMF (40 ml) was added dropwise to the solution with stirring. The solution was stirred for two hours longer and then at 45° C. for another 0.5 hour. The solution was chilled and poured into 900 ml of ice and H2O. The solution was extracted with 2× 250 ml of ether. The combined ethyl layers were washed with 300 ml of water. The ether solution was dried and reduced to about 125 ml. The solid was filtered off, m.p. 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH2:26])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)=[O:12])=[O:7])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(N)c1
Reactant: O=Cc1ccc(C(=O)N2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(NCc2ccc(C(=O)N3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
120 mg (0.30 mmol) of methyl 4-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-3-aminobenzoate and 66 mg (0.33 mmol) of 4-(1-pyrrolidinecarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.034 ml (0.6 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 158 mg (0.75 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound