Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(C)c(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
62.1 mg of the target compound (0.17 mmol, 21.2%) was obtained using 1-(2,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:21][C:20]2=[CH:22][CH:23]=[C:17]([CH:18]=[CH:19]2)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:24]([CH3:26])[CH3:25])[NH:4][C:3]1=[O:27].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].C(N(CC)CC)C.Cl.[NH2:48][C@@H:49]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61]C(OC(C)(C)C)=O)[C:50]([O:52]C(C)(C)C)=[O:51]>CN(C=O)C>[NH2:61][CH2:60][CH2:59][CH2:58][CH2:57][C@H:49]([NH:48][C:28]([NH:1][C@@H:2]1[CH2:21][C:20]2=[CH:19][CH:18]=[C:17]([CH:23]=[CH:22]2)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:24]([CH3:25])[CH3:26])[NH:4][C:3]1=[O:27])=[O:29])[C:50]([OH:52])=[O:51]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@H]1COCCCCCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COCCCCCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
A solution of 0.18 g (0.37 mmol) of (13S,16R)-16-amino-13-isopropyl-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22),19-trien-15-one in 3.8 ml of DMF was added to 60 mg (0.37 mmol) of 1,1′-carbonyldiimidazole and, after addition of 0.2 ml (0.15 g, 1.47 mmol) of triethylamine, stirred under argon. After 10 min, 124 mg (0.37 mmol) of tert-butyl(S)-2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride were added, and the mixture was stirred for 3 h. It was concentrated and partitioned between water and ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The required fractions were combined and concentrated. The residue was taken up in 20 ml of dichloromethane/TFA (1:1, v/v) and left to stand for 2 h. The mixture was concentrated, dissolved in 1N hydrochloric acid with a little acetonitrile and freeze dried. An amorphous solid (0.12 g) was obtained as hydrochloride.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]2[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=2)=[CH:17][N:18]=1.[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)[CH2:32][CH2:31]1.CN(C)C=O>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH:30]1([N:33]2[CH2:34][CH2:35][CH:36]([C:39]([NH:13][C:14]3[S:15][C:16]([S:19][CH2:20][C:21]4[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=4)=[CH:17][N:18]=3)=[O:40])[CH2:37][CH2:38]2)[CH2:32][CH2:31]1
Reactant: O=C(O)C1CCN(C2CC2)CC1
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(C4CC4)CC3)s2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture was stirred at rt for 1 h, diluted with water (30 mL), and extracted with ethyl acetate (2×70 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 0-10% triethylamine in ethyl acetate. The material was crystallized from ethyl acetate and hexanes to provide 0.7 g (65%) of 1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as white crystals. MS: 421 [M+H]+; HPLC: 100% at 3.13 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[S:11]([CH3:14])(=[O:13])=[O:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:18]([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: COC(=O)c1cc(F)ccc1S(C)(=O)=O
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
To a stirred solution of 5.23 g (22.5 mmol) 5-Fluoro-2-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 17a was obtained in 56% yield (3.24 g, 12.6 mmol).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(C2CCCCC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
5.81 g (33.0 mmol) of 4-cyclohexylphenol, 5.57 g (30.0 mmol) of 4-chloro-2,5-dimethylnitrobenzene and 6.22 g (45.0 mmol) of potassium carbonate are suspended in 30 ml of N,N-dimethylformamide and the suspension is stirred at 150° C. for 12 h. It is then poured into ice-water and the precipitate is isolated by filtration, washed repeatedly with hexane and dried under reduced pressure (12.1 g, purity 71.9%, yield 88.9%, log P (pH 2.3)=6.69).
Reaction SMILES: [CH:1]([OH:14])([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.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19]O>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:19][CH2:18][CH2:17][CH2:16][Cl:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCl
Reactant: OC(c1ccccc1)c1ccccc1
Product: ClCCCCOC(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
Starting with benzhydrol and 4-chloro-1-butanol, the procedure of Reference Example 15 was otherwise repeated to provide the title compoun. Yield 90%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[C:4](=[O:15])[N:3]1[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18](O)=[O:19].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=[O:45]>O1CCCC1>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]([CH:16]([N:3]2[C:2](=[O:1])[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[CH:7]=[CH:6][C:5]=3[C:4]2=[O:15])[CH2:17][C:18]2[O:19][CH:44]=[N:46][N:47]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH3:31].[O:1]=[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[C:4](=[O:15])[N:3]1[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18]([NH:47][N:46]=[C:44]=[O:45])=[O:19]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC
Yield: 122.9 %

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]benzo[e]isoindoline-1,3-dione was prepared by the procedure used in Example 1. Thus, reaction of 3-(1,3-dioxobenzo[e]isoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.50 g, 3.58 mmol), carbonyidiimidazole (0.70 g, 4.3 mmol) and formic hydrazide (310 mg, 5.16 mmol) in tetrahydrofuran (20 mL) gave crude 3-(1,3-dioxobenzo[e]isoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy4-methoxyphenyl)propanamide (1.0 g, 2.2 mmol), which was then treated with phosphorus oxychloride (POCl3, 0.4 mL, 4.3 mmol) in acetonitrile (10 mL). The product was obtained as a yellow solid (135 mg, 8% overall yield): mp, 139.0-141.5° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.2 Hz, 3H, CH3), 3.85 (s, 3H, CH3), 3.87 (dd, J=6.0, 15.6 Hz, 1H, CHH), 4.13 (q, J=6.9 Hz, 2H, CH2), 4.42 (dd, J=10.2, 15.6 Hz, 1H, CHH), 5.87 (t, J=5.9, 10.4 Hz, 1H, NCH), 6.84 (d, J=8.7 Hz, 1H, Ar), 7.18-7.27 (m, 2H, Ar), 7.64-7.75 (m, 2H, Ar), 7.81 (d, J=8.3 Hz, 1H, Ar), 7.94 (d, J=7.6 Hz, 1H, Ar), 8.14 (d, J=8.2 Hz, 1H, Ar), 8.29 (s, 1H, CH), 8.90 (d, J=7.5 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.63, 27.79, 51.69, 55.84, 64.39, 111.34, 112.53, 118.41, 121.22, 124.83, 126.88, 127.93, 128.62, 128.74, 129.44, 130.31, 130.87, 135.06, 136.59, 148.37, 149.36, 152.95, 164.04,168.51, 169.07; Anal Calcd for C25H21N3O5: C, 67.71; H, 4.77; N, 9.48. Found: C, 67.80; H, 4.95; N, 9.20.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33][C:34](=[O:82])/[C:35](/[C:57]4[N:58]=[C:59]([NH:62]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:60][CH:61]=4)=[N:36]\[O:37]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:31](=[O:83])[N:13]3[C:14]=2[C:15]([O:17]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:16])[CH2:4][O:3]1.Cl.O>C(O)=O>[NH2:62][C:59]1[S:60][CH:61]=[C:57](/[C:35](=[N:36]/[OH:37])/[C:34]([NH:33][C@@H:32]2[C:31](=[O:83])[N:13]3[C:14]([C:15]([OH:17])=[O:16])=[C:9]([CH2:8][S:7][C:5]4[CH2:4][O:3][C:2](=[O:1])[CH:6]=4)[CH2:10][S:11][C@H:12]23)=[O:82])[N:58]=1
Reactant: O=C1C=C(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CO1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSC4=CC(=O)OC4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)-7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (744 mg) was dissolved in 98-100% formic acid (13 ml) and 1N hydrochloric acid (0.65 ml) and water (0.65 ml) were added. The mixture was stirred at room temperature for 30 mins and then concentrated hydrochloric acid (0.52 ml) was added. After stirring for a further hour the solvents were removed on a rotary evaporator. A mixture of toluene and tetrahydrofuran was evaporated from the residue twice, and the residue triturated with ether. The solid was filtered off, and washed with ether. The solid was suspended in water and the pH adjusted to 2.6 with 0.1N sodium hydroxide, the mixture was stirred for a further 30 mins, occasionally adjusting the pH to 2.6. The solid was then filtered off, washed with cold water and dried under vacuum to give the title compound (128 mg) as an off-white solid. υmax (KBr) 1773, 1735, 1670, and 1629cm-1. δH [(CD3)2SO] 3.49 (1H, d, J 18.0Hz), 3.72 (1H, d, J 18.1Hz), 4.10 (1H, d, J 13.2Hz), 4.18 (1H, d, J 13.2Hz), 4.97 (2H, s), 5.18 (1H, d, J 4.8Hz), 5.79 (1H, dd, J 4.8 and 8.0Hz), 6.11 (1H, s), 6.67 (1H, s), 9.51 (1H, d, J 8.1Hz), 11.40 (1H, s). [mass spectrum: +ve ion (thioglycerol) MH+ 498].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 1-benzyl-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (500 mg, 1.68 mmol), pivaloyl chloride (0.250 mL, 2.02 mmol), 4-dimethylaminopyridine (21 mg, 0.168 mmol) and triethyl amine (0.468 mL, 3.36 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h; then the reaction mixture was diluted with EtOAc, washed with saturated NaCl solution and subsequently the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified with column to give the desired product as a clear oil (599 mg, 93%). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.62 (s, 1H), 7.31-7.20 (m, 6H), 6.53-6.51 (m, 1H), 5.40 (s, 2H), 4.41 (q, 2H, J=7.3 Hz), 1.47 (s, 9H), 1.41 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2c(C)noc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)c2c(C)noc2c1
Yield: 139.7 %

Procedure:
3,6-dimethyl-4-[(4-nitrophenyl)oxy]-1,2-benzisoxazole (Intermediate 20, 208 mg) was dissolved in ethanol (10.0 ml) and tin chloride dihydrate (991 mg, 4.39 mmol) was added. The reaction mixture was stirred and heated at reflux for 4 hours. After the removal of the volatiles, water was added and the reaction mixture was extracted two times with ethyl acetate. The collected organic were dried over sodium sulphate, filtered and evaporated to afford 260 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH:21](C(OCC)=O)[C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC1(CC=C(C)Cl)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 58.2 %

Procedure:
Crude diethyl 2-[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]malonate (36.9 g, 0.075 mole) was refluxed with stirring in a mixture of ethanol (100 ml), water (100 ml) and sodium hydroxide (15 g) for 2 hours. The reaction mixture was cooled, diluted with water and extracted with hexane. The aqueous layer was acidified with hydrochloric acid and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum to obtain 17 g of product which after recrystallization from a mixture of methyl cyclohexane and butyl chloride melted at 111°-114° C. and was shown by HPLC to be a 95% trans, 5% cis mixture.
Reaction SMILES: [C:1]([C@@:3]1([F:25])[C@H:7]([OH:8])[CH2:6][O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19]C(=O)C(C)C)=[N:11][C:10]1=2)#[CH:2]>N.C(OCC)(=O)C>[C:1]([C@@:3]1([F:25])[C@H:7]([OH:8])[CH2:6][O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)#[CH:2]
Reactant: C#C[C@@]1(F)[C@H](O)CO[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Agent: N
Solvent: CCOC(C)=O
Product: C#C[C@@]1(F)[C@H](O)CO[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound B4 (0.78 g, 1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C18) eluting with a gradient 2-15% of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give D961 (Compound B5) (134 mg, 33%) as a yellow solid. NMR 1H (400 MHz, DMSO-d6): δ 10.70 (1s, 1H, NH), 7.98 (s, 1H, H-8), 6.60 (1s, 2H, NH2), 6.21 (d, 1H, OH-3′, JOH-3′=7.6 Hz), 5.83 (d, 1H, H-1′, J1′-F=16.9 Hz), 5.29 (t, 1H, OH-5′, JOH-5′=5.2 Hz), 4.50 (td, 1H, H-3′, J3′-F=22.8 Hz, J3′-4′=9.2 Hz), 3.93-3.81 (m, 3H, H-4′, H-5′ and ethynyl), 3.70 (m, 1H, H-5″).
Reaction SMILES: FC(F)(F)S(OC1C=CC2[C:31]3[C:19](=[CH:20][C:21]4[N:22]([CH2:32][CH3:33])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:29]=4[CH:30]=3)C3C(=CC=CC=3)C=2C=1)(=O)=O.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([N:22]1[C:21]2[CH:20]=[C:19]3[C:37]4[C:36]([C:20]5[CH:21]=[C:29]([C:28]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[CH:30]=[CH:31][C:19]=5[C:31]3=[CH:30][C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:33]
Reactant: OB(O)c1ccccc1
Reactant: CCn1c2ccccc2c2cc3c4ccc(OS(=O)(=O)C(F)(F)F)cc4c4ccccc4c3cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc3c4ccc(-c5ccccc5)cc4c4ccccc4c3cc21
Reaction time: 5 h
Yield: 135.9 %

Procedure:
10.0 g (20.28 mmol) of 10-ethyl-10H-phenanthro[9,10-b]carbazol-3-yl trifluoromethanesulfonate synthesized in Synthetic Example 9, 3.71 g (30.42 mmol) of phenylboronic acid, and 0.23 g (0.20 mmol) of Pd(PPh3)4 were dissolved in 150 ml of toluene, and 4.30 g (40.56 mmol) of Na2CO3 was put into 50 ml of distilled water, and then refluxed and agitated for 5 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of Hexane:MC=7:3 (v/v) to obtain 5.81 g of 10-ethyl-3-phenyl-10H-phenanthro[9,10-b]carbazole (yield 68%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12OCC[O:22]1)(=[O:11])=[O:10].Cl[CH2:27][C:28]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:27][C:28]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:35][N:36]=[C:16]3[C:15](=[O:22])[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: N#CC1(CCl)CCCCCC1
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCCCC3)CN12

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cycloheptanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/EtOAc (9:1). NMR (400 Mz, DMSO-d6): consistent. Analytical HPLC (Chromolith Monolith 0.46×10 cm column, gradient of acetonitrile in water/trifluoroacetic acid): 93.2% (254 nm). MS: (API-ES+) m/z 446.2 [M+H]; (API-ES−) m/z 444.2 [M−H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([C:29]#N)=[CH:25][CH:24]=1.[CH:31](N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:31]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (10.0 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][CH2:34][OH:35])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:41][C:42]([O:44]CC)=[O:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[C:8]2[CH2:33][CH2:34][O:35][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:37]=1
Reactant: CC(C)(C)Sc1c(CCO)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)Sc1c(CCOCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 91 mg of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethanol from Step B in 2 mL THF at 0° C. under an argon atmosphere was added 40 mg of 80% sodium hydride over 30 min. Ethyl bromoacetate (0.3 ml) was added to the solution and the reaction stirred at RT overnight. The reaction was poured onto 10 mL of NH4OAc (25% solution), extracted with 3×10 mL of EtOAc, washed with 20 mL of H2O and dried over MgSO4. Removal of the solvent followed by column chromatography on silica gel afforded the ethyl ester of title compound. Hydrolysis of this ester under the conditions described in Step B of Example 1 provided the title compound, m.p. 185° C. (dec.).