Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](F)[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1.[CH3:36][O-:37].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:37][CH3:36])[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCNCC4)c3)c2Oc2cccc(F)n2)N1C(=O)C1CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2c(-c3cnn(C4CCNCC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-cyclopropyl(5-(6-fluoropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.024 g, 0.05 mmol), and sodium methoxide (0.015 g, 0.28 mmol) in N,N-dimethylformamide (1 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (16% to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.0033 g, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.79-0.87 (m, 1H), 0.91-1.00 (m, 2H), 1.10-1.18 (m, 4H), 1.39-1.49 (m, 1H), 1.79-1.84 (m, 2H), 1.97-2.09 (m, 3H), 2.18-2.41 (m, 2H), 2.62-2.79 (m, 3H), 3.12-3.19 (m, 2H), 3.62 (s, 3H), 4.15-4.27 (m, 1H), 4.72-4.89 (m, 1H), 6.41 (t, J=8.00 Hz, 2H), 7.36 (d, J=8.40 Hz, 1H), 7.55-7.65 (m, 2H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 488 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.[CH2:27]([NH2:30])[C:28]#[CH:29]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:30][CH2:27][C:28]#[CH:29])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: C#CCN
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Solvent: CO
Product: C#CCNC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3C(CN21)N3C
Product: NC(=O)O
Yield: 95.6 %

Procedure:
A solution of 107 mg (0.27 mmol) of N-methylmitomycin A in 10 ml of anhydrous methanol was stirred with 85 mg (1.5 mmol) of propargylamine for 3 hours, whereupon TLC indicated no remaining starting material. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated under reduced pressure. Recrystallization from a mixture of methylene chloride and hexane gave 52.2 mg (50% yield) of the desired product as purple-colored crystals having a melting point of 86°-87° (decomposing) and providing the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.CCOCC>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:31]4[CH2:32][CH2:33][C:28]([F:34])([F:27])[CH2:29][CH2:30]4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCC(F)(F)CC4)nc4c3CCC4)cc2)CCC1
Yield: 76.8 %

Procedure:
A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.36 g, 1 mmol), 4,4-difluoropiperidine hydrochloride (0.23 g, 1.5 mmol), diisopropylethylamine (0.5 mL, 3 mmol) in anhydrous isopropanol (10 mL) was heated to reflux for 48 hours. Thereafter, the mixture was cooled to a temperature in the range of 40° C. to 60° C. and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed sequentially with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a semi solid residue. Ether was added to the residue and the precipitates were filtered to afford the title compound as a white solid (0.34 g, 77% yield).
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].NO[CH2:10][C:11](O)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH2:20][C:21](=O)[CH:22]=2)[CH:17]=[CH:16][N:15]=1>O.C(O)C.N1C=CC=CC=1>[C:5]([CH2:4][O:3][N:2]=[C:20]1[C:16]2[C:10]3[C:11]([CH:23]=[CH:14][N:15]=2)=[CH:21][CH:22]=[CH:23][C:14]=3[N:15]2[C:19]1=[CH:18][CH:17]=[CH:16]2)([OH:7])=[O:6]
Reactant: NOCC(=O)O
Reactant: O=C1C=c2cnccc2=CC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 111.5 %

Procedure:
A solution of aminooxyacetic acid hemihydrochloride (60.0 g.) in water (180 cc.) is added to a stirred boiling solution of 7H-indolizino 5,6,7-ij]isoquinolin-7-one (60.0 g.) in ethanol (1,800 cc.) and pyridine (27.3 cc.). Boiling is maintained for 2 hours 30 minutes. After cooling, the yellow crystals obtained are filtered off, washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-carboxymethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (67.6 g.), melting at 212° C. with decomposition, is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[C:24](Cl)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCCC(=O)NCc1ccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide as an off-white solid (349 mg, 58% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.12 min (96.3%); mp, 223-225° C.; 1HNMR (DMSO-d6) 0.84 (t, J=6 Hz, 3H, CH; of long chain), 1.24-2.20 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.36 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.56-7.88 (m, 3H, Ar), 8.41 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.86, 20.92, 21.95, 23.39, 25.23, 28.31, 30.61, 30.99, 35.33, 41.57, 56.51, 119.99, 123.79, 126.51, 133.96, 138.38, 145.74, 154.53, 160.40, 169.47, 172.25, 172.60. LCMS MH=413; Anal Calcd For C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 63.76; H, 6.68; N, 13.42.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:39])[N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nnn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(-c2nnn(C)n2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of N-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (100 mg, 0.20 mmol) in dimethylformamide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) and methyl iodide (100 μL, 1.6 mmol) and the mixture was allowed to stir at rt overnight. The mixture was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (51 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.84 (s, 1H), 8.20 (d, 2H), 8.16 (d, 1H), 8.02 (d, 2H), 7.91-7.78 (m, 5H), 7.66-7.64 (m, 3H), 7.47 (d, 1H), 7.42 (ddd, 1H), 4.43 (s, 3H), 2.35 (s, 3H). MS (EI) for C30H24N8O: 513.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[C:21]([O:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:34]Br)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:22]1([C:21]([O:29][CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=2[CH2:39][O:40][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])[CH2:34][O:1][C:2]2[C:3]([CH3:20])=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH3:19])[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C)c(-c2cccc(O)c2C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(C)c(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2C)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 980 mg (3.6 mmol) of methyl 3′-hydroxy-2,6,2′-trimethylbiphenyl-4-carboxylate with 1.75 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 570 mg (4.1 mmol) of potassium carbonate, the desired product is obtained in the form of white crystals (m.p.=131-132° C.; m=2.16 g; Y=95%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)[C:3]#[N:4].Cl.C(=O)([O-])[O-:13].[Na+].[Na+]>>[NH2:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)[C:3]([NH2:4])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N#CC(N)c1cncnc1
Agent: Cl
Agent: [Na+]
Product: NC(=O)C(N)c1cncnc1
Yield: 81 %

Procedure:
Amino(pyrimidin-5-yl)acetonitrile (1.1 g, 8.2 mmol) is hydrolyzed by refluxing in a small volume of dilute HCl for 1 hour. The pH is raised to 10 by addition of saturated sodium carbonate and the mixture then extracted with chloroform. Evaporation of the chloroform and chromatography (silica, chloroform/methanol) gives product as a yellow solid 950 mg (81%) ms m/z=142.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[N:20]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1nnc(Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH2Cl2, is added triethylamine (2 mmol). The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:34][CH2:35][C@H:36]([NH2:39])[CH2:37][OH:38]>>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:39][C@H:36]([CH2:37][OH:38])[CH2:35][CH3:34])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4.99 g (20 mmol) N-carbobenzoxy-L-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 1.78 g (20 mmol) d-(+)2-amino-1-butanol, substantially according to the mixed anhydride procedure described in Example 1. Crude product (5.16 g) was recrystallized from a mixture of 60 mL ethyl acetate and 15 mL n-hexane to give 4.18 g (13 mmol, 65%) of colorless, crystalline N-carbobenzoxy-L-prolyl-L-homoalaninol; m.p. 105.4°-106.3°, α25D-69.7 (C=1.04 g/100 mL in acetone). A stereochemical assignment for this product was based upon observed similarity of specific rotation to specific rotations measured for L-L isomers of carbobenzoxy-prolyl-leucinol (Example 1), carbobenzoxy-prolyl-valinol (Example 2) and carbobenzoxy-prolyl-alaninol (Example 5).
Reaction SMILES: Cl.Cl.C[O:4][C:5]1C=[CH:9][C:8](N2CCNCC2)=[CH:7][CH:6]=1.C(Cl)(=O)CC(C)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][C:33]=1[F:44])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)(=O)CCCC>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:5](=[O:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:40][CH2:39]2)=[CH:34][C:33]=1[F:44])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Agent: CC(C)CC(=O)Cl
Agent: CCCCC(=O)Cl
Agent: Cl
Product: CCCCC(=O)N1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)-piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (286 mg) and valeryl chloride (131 μL), respectively, to provide crude 4-(4-benzyloxy-3-fluorophenyl)-1-valerylpiperazine (367 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[CH2:26]([N:28]([CH2:31]C)[CH2:29]C)[CH3:27].ClCC(Cl)=[O:36].Cl.CNC>C(Cl)(Cl)Cl>[Cl:25][C:3]1[C:2]([NH:1][C:27](=[O:36])[CH2:26][N:28]([CH3:31])[CH3:29])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Agent: CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg) and triethylamine (54 mg) in chloroform (3 ml) was added chloroacetyl chloride (36 mg) under ice cooling. The mixture was stirred at ambient temperature for 2 hours, and then dimethyl amine hydrochloride (65 mg) was added to the mixture and additionally the mixture was stirred for 12 hours. The mixture was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (ethyl acetate: n-hexane=1:1) and the obtained oil was crystallized from ethanol to give 6-[2,6-dichloro-3-(2-dimethylaminoacetylamino)benzoylamino]-1,2,3,4-tetrahydrodibenzofuran (62 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:9]([CH2:10]O)=[C:8]([CH3:17])[C:7]=1[N+:18]([O-:20])=[O:19].O>C1C=CC=CC=1>[Br:2][CH2:17][C:8]1[C:9]([CH3:10])=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:6]([Cl:5])[C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: BrP(Br)Br
Reactant: Cc1c(CO)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Phosphorus tribromide (18.0 g; 0.067 mol) is added dropwise at 10° C. to a stirred slurry of 4-chloro-2-methyl-3,5-dinitrobenzyl alcohol (50.0 g; 0.20 mol) in benzene (100 ml). The reaction mixture is allowed to warm to room temperature and then heated to reflux for 5 hours. After standing at room temperature overnight, the mixture is poured into water and extracted with ether. Insoluble material present is collected and dried to yield 18.9 g solid, melting point 115°-120° C. Removal of the ether from the extracts yields additional 38.6 g solid, melting point 106° C.-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:12]2[CH:13]=[C:14]([CH3:20])[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[C:12]2[CH:13]=[C:14]([CH3:20])[N:15]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:36][CH:35]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(=O)n2c(C)cc3c(C(=O)OCc4ccccc4)cccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyindole-4-carboxylic acid benzyl ester (690 mg; prepared in Reference Example 11) in N,N-dimethylformamide (8 ml) was added sodium hydride (114 mg; 60%) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 4-butoxybenzoyl chloride (0.54 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and ethyl acetate, and then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (1.02 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:53]([NH:59][CH2:60][C:61]1[CH:73]=[CH:72][C:64]2[O:65][C:66]([CH3:71])([CH3:70])[O:67][C:68](=[O:69])[C:63]=2[CH:62]=1)[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:59]([CH2:60][C:61]3[CH:73]=[CH:72][C:64]4[O:65][C:66]([CH3:71])([CH3:70])[O:67][C:68](=[O:69])[C:63]=4[CH:62]=3)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:19])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccc2c(c1)C(=O)OC(C)(C)O2)C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A solution of 4-(4-butylphenylethynyl)benzoic acid (330 mg, 1.19 mmol), EDC.HCl (231 mg, 1.21 mmol), HOBT (163 mg, 1.21 mmol) and DIEA (256 μl, 1.51 mmol) in DCM (15 mL) was stirred 10 min at rt. Then a solution of 6-[(hexylamino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (293 mg, 1.01 mmol) in DCM (5 mL) was added and the resulting mixture was stirred 3 hrs at rt. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, an aqueous solution of HCl (1N) and brine. Organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/c-Hex (20/80)) gave 420 mg (73%) of the title compound. HPLC, Rt: 6.18 min (purity: 92.3%). A second purification by preparative HPLC with a X-Terra column allowed the isolation of the title compound (300 mg, 54% yield) as a white powder. HPLC, Rt: 6.15 min (purity: 99.1%). LC/MS, M+(ESI): 552.7. 1H NMR (CDCl3) δ: 0.82 (m, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.09-1.41 (m, 8H), 1.53 (m, 4H), 1.72 (s, 6H), 2.60 (t, J=7.6 Hz, 2H), 3.16-3.45 (m, 2H), 4.50-4.70 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.52-7.84 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.N[C@H]1C2C(=CC=CC=2)C[C@H]1O>CC(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CC#CC(CC(=O)O)c1ccc(O)cc1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CC(C)O
Product: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5 L RB flask was charged with compound 1.3 (66.4 g, 325 mmol) and 2-propanol (1 L) and then heated to 70° C. (1S,2R)-1-amino-2-indanol (46.1 g, 309 mmol) was dissolved in 2-propanol (1 L) with gentle warming. The solution of amine was added to the dissolved carboxlic acid and the resulting solution was allowed to cool to room temperature. After 16 h, the crystals were collected and dried. The salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. This material was found to have 96% ee by chiral HPLC. This material was suspended in ethyl acetate (300 mL) and water (100 mL). Saturated aqueous KHSO4 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated and the aqueous layer extracted with ethyl acetate (100 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil which crystallized on drying in vacuo. Compound 1.4 was obtained as an off-white solid (23.5 g, 35%).