Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: COc1nc(N=C=S)nc(OC)n1
Reactant: NS(=O)(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(NC(=S)NS(=O)(=O)c2cccnc2)nc(OC)n1
Yield: 75.8 %

Procedure:
A mixture of 1.58 g of 3-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3-5-triazine and 1.5 g of anhydrous potassium carbonate was stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture was then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product was removed by filtration to yield 2.7 g of the desired compound, m.p. 158°-160°.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:27][C@H:26]([O:28][CH2:29][C@H:30]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@H:25]([OH:62])[C@@H:24]([OH:63])[C@H:23]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:1]([O:62][C@@H:25]1[C@@H:24]([O:63][C:26](=[O:27])[CH3:25])[C@@H:23]([O:64][C:29](=[O:28])[CH3:30])[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:27][C@@H:26]1[O:28][CH2:29][C@H:30]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:20])[CH3:2]
Reactant: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 192.9 %

Procedure:
3-O-(6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetra-decyl-Sn-glycerol (4) (672 mg) was dissolved in acetic anhydride (3 ml) and pyridine (3 ml). The solution was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was subjected to column chromatography (Wakogel C-300, 70 g) and eluted with 0.5% methanol-containing chloroform to obtain 3-O-(2,3,4-tri-O-acetyl-6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (5) (740 mg, 96.4%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2N3C(CN(CC4CC4)C)=NN=C3CN=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.C=[O:30]>C(O)=O>[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:28]=1
Reactant: C=O
Reactant: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2)CC1CC1
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2-[3-[[(cyclopropylmethyl)methylamino]methyl]-5-](dimethylamino)methyl]-4-H-1,2,4-triazol-4-yl]benzophenone. This product is identical to that given in Example 21.
Reaction SMILES: Cl.[C:2](=N)(OCC)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[CH2:3]([C:2]1[NH:22][C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)OCC
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1nc2cc(C(=O)OC)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 128.8 %

Procedure:
5.47 g of ethyl pentanimidoate hydrochloride (J.A.C.S., Vol. 64, p. 1827 (1942)) were added to a solution of 5 g of methyl 3,4-diaminobenzoate in 60 ml of tetrahydrofuran, and the mixture was stirred for 3 hours and 30 minutes at 90° C. The tetrahydrofuran was evaporated off and 50 ml of a saturated solution of sodium bicarbonate were added. The mixture was extracted with methylene chloride and the extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 9 g of product which was crystallized from isopropyl ether to obtain 6.65 g of the desired product melting at 114° C.
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A cooled (0° C.) solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 1; 164 mg, 0.57 mmol) in dichloromethane (10 mL) and N,N-dimethyl-formamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.43 mL, 0.86 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.42 mL, 2.0 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulf uiric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-acetamide (116 mg, 71% yield) as a white solid, mp 88.3-91.4° C.; FAB-HRMS m/e calcd for C13H15NCl2O2 (M+) 288.0558, found 288.0572.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:31])[C:10]2[O:16][C:15]3[C:17]([Cl:27])=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:20][C:14]=3[CH2:13][S:12](=[O:29])(=[O:28])[C:11]=2[CH:30]=1)=[O:6]>O.O1CCCC1>[Cl:27][C:17]1[C:15]2[O:16][C:10]3[C:9]([CH3:31])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:30][C:11]=3[S:12](=[O:28])(=[O:29])[CH2:13][C:14]=2[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (0.22 g, 5.49 mmol) in water (15 mL) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.88 g, 1.83 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 40° C. for 4 h, the solvent was removed under vacuum. The reaction mixture was acidified to pH 4-5 using 10% aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried to obtain the title compound. Yield: 0.84 g, (98%); 1H NMR (DMSO-d6, 300 MHz): δ 2.65 (s, 3H, CH3), 3.26 (s, 4H, 2CH2), 3.43 (s, 4H, 2CH2), 5.16 (s, 2H, CH2), 7.20 (s, 2H, Ar), 8.08 (s, 1H, Ar), 8.18 (s, 1H, Ar); MS: m/e (ES−) 421 (M−1); analysis: C19H19ClN2O5S.2H2O requires C, 49.73; H, 5.05; N, 6.10; Cl, 7.73; S, 6.99. found: C, 50.27; H, 5.12; N, 6.12; Cl, 7.47; S, 6.92%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:35]1[N:40]=[CH:39][C:38]2=[CH:41][CH:42]=[C:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[O:50][CH3:51])[N:37]2[N:36]=1)=O.C([O-])(=O)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:35]4[N:40]=[CH:39][C:38]5=[CH:41][CH:42]=[C:43]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=6[O:50][CH3:51])[N:37]5[N:36]=4)=[C:25]([O:30][CH3:31])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 110 °C
Yield: 87.5 %

Procedure:
A mixture of 4-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester (0.62 g, 0.0015 mol), 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.3 g, 0.0009 mol) and Potassium acetate (0.59 g, 0.0060 mol) in N,N-Dimethylformamide (10 mL) was heated at 110° C. for 40 hr. The solvent was evaporated and the residue chromatographed on silica gel prep plates 2× with ethyl acetate-IPA (20-1) giving 4-(1-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-piperazine-1-carboxylic acid benzyl ester as a tan solid (0.51 g, 9%). MP: 75-76° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 8.80 (s, 1H), 7.84-7.81 (d, 1H, J=8.40 Hz), 7.48 (s, 1H), 7.45-7.35 (m, 7H), 7.20 (s, 1H), 7.18 (s, 1H), 7.12-7.02 (t, 1H), 6.95-6.89 (q, 2H, J=4.68 Hz), 6.62 (d, 1H), 6.38-6.35 (q, 1H) 5.08 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.70-3.65 (d, 2H), 3.39 (br, 8H), 2.70-2.51 (m, 3H), 1.87-1.78 (m, 2H), 1.60-1.52 (m. 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[C:9]=1[F:16].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([F:16])[C:10]=2[CH3:15])[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1c(O)ccc(N)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Temperature: 100 °C
Yield: 42.2 %

Procedure:
Potassium tert-butoxide (3.5 g, 0.031 mol) was added to a solution of 4-amino-3-fluoro-2-methylphenol (4.2 g, 0.03 mol) in DMAc and the resultant mixture was stirred for 30 min at RT. To this mixture was added a solution of 2,4-dichloropyridine (4.38 g, 0.03 mol) in DMAc and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel, washing forward with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (3.2 g, 42% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=6.0 Hz, 1H), 6.84 (s, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67 (m, 2H), 5.12 (s, 2H), 1.91 (s, 3H); MS (ESI) m/z 253.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[Cl-].[NH4+].[CH2:44]1COC[CH2:45]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])[CH2:44][CH3:45])[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (22.7 g) in THF (20 ml) was added 1Methylmagnesium bromide-THF solution (119 ml) at room temperature, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (14.96 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[OH:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[O:30][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 7-(4-fluorophenyl)-7-(2-hydroxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.5 g) in dimethylformamide (1 ml) was added to a mixture of 60% sodium hydride (51 mg) and dimethylformamide (2 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Methyl iodide (82 ml) was added dropwise and the mixture was stirred at the same temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-(2-methoxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.4 g) (Compound 58). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([OH:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 60 %

Procedure:
2-(4-Fluorophenyl)benzoxazole-4-carboxylic acid was prepared via the lithium hydroxide mediated hydrolysis of methyl 2-(4-fluorophenyl)benzoxazole-4-carboxylate as described in Step B of Example 14. This material was obtained in 60% yield as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J=14.9, 11.8 Hz, 2H), 8.17 (d, J=13.1 Hz, 1H), 7.83 (d, J=13.6 Hz, 1H), 7.53 (t, J=13.4 Hz, 1H), 7.29 (m, 2H). MS (ESI) m/z 258 [M+H]+
Reaction SMILES: [H-].[Na+].[CH2:3]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](I)[CH3:24]>CN(C=O)C.O>[CH2:3]([C:11]1[N:12]([CH2:23][CH3:24])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2[nH]c(CCc3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(CCc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h

Procedure:
A 60% dispersion of NaH (0.5 g, 2.02 mmol) was added to a solution of 2-phenethyl-5-nitro-1H-indole (0.16 g, 0.6 mmol) in DMF (30 ml). The reaction mixture was kept under stirring for 30 minutes. Then, ethyl iodide (0.15 ml, 1.9 mmol) was added, and the mixture was left under stirring overnight at room temperature. The next morning, the mixture was poured in H2O left under stirring overnight, obtaining a precipitate which was filtered to give 2-phenethyl-1-ethyl-5-nitro-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 80.7 %

Procedure:
(2,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10 ml). The mixture was heated at 70° C. for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate). The desired fractions were concentrated to yield N-(2,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7% yield) as a colorless viscous oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 7.27-7.70 (m, 3H), 4.77 (s, 1H), 4.14-4.35 (m, 2H), 3.45-3.68 (m, 4H), 1.09-1.29 (m, 6H). LC/MS RT=2.03; [M+H]+=304.9.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: BrBr
Reactant: c1ccc(-c2nccc3ccccc23)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cnc(-c2ccccc2)c2ccccc12
Yield: 41.2 %

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]2[C:29]([O:31][C:32](=O)[C:20]=12)=[O:30]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[C:32](=[O:31])[C:20]3[CH:19]=[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[CH:22][C:21]=3[C:29]2=[O:30])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccccc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A pressure tube was charged with N-(4-methoxyphenyl)-2-aminobenzamide (500 mg, 2.07 mmol), 2,3-napthalenedicarboxylic anhydride (409 mg, 2.07 mmol), and tetrahydrofuran (10 mL). The resultant slurry was then placed in a bath heated to 110 C for 16 h. After cooling to ambient temperature and concentration to ½ of the solution volume, the product was triturated with 50% hexanes/50% ethyl acetate and the resulting solid collected by filtration. Recrystallization from hexanes/ethyl acetate yielded 476 mg (55%) of the title compound.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:18]1([C:24]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]2[N:25]([C:24]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=[N:27][N:28]=2)=[CH:41][CH:40]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 25 %

Procedure:
L-phenylalanine t-butyl ester hydrochloride (Bachem Bioscience, Inc.) (1.0 g, 3.9 mmol) was suspended in ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and the solvent removed in vacuo. This residue was dissolved in 20 mL of THF and 1.95 g (3.5 mmol) of 2'-(N-triphenylmethyl tetrazol-5-yl)-4-bromomethylbiphenyl (prepared as described in EP 0 324 377) and 0.54 mL (3.9 mmol) triethylamine were added. The reaction was stirred at room temperature for 5 days. The THF was removed in vacuo and the residue dissolved in ethyl acetate. This was extracted 3× with K2CO3 and 1× with brine, dried over (MgSO4), filtered, and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate-hexanes to yield 0.61 g (25%) of a white glass.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][CH:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)O)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH:15]=[CH:16][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C=C[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.8 %

Procedure:
A solution of 2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(2R)-tetrahydrofuran-2-yl]ethanol (420 mg, 1.21 mmol) and Et3N (370 mg, 3.63 mmol) in anhydrous DCM (5 ml) was cooled at 0° C., then methanesulfonyl chloride (0.14 ml, 1.82 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 5 min., then at RT for 15 hours. The reaction mixture was poured into a 1N aqueous solution of HCl and extracted with EtOAc (2×). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as an orange solid (400 mg, quantitative). HPLC, Rt: 3.7 min (purity: 94.2%). LC/MS, M+(ESI): 328.2.