Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:30])[CH:28]=[CH:29][N:23]4[C:22]4[CH:21]=[CH:20][C:19]([Br:31])=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:31][C:19]1[CH:20]=[CH:21][C:22]2[N:23]3[CH:29]=[CH:28][C:27](=[O:30])[C:25]4[CH:26]=[C:14]([O:13][CH2:12][C:8]5[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=5)[CH:15]=[C:16]([C:17]=2[CH:18]=1)[C:24]3=4
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)ccn4c5ccc(Br)cc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-10-bromo-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 69 was suspended in methanol (12 ml), and a solution of sodium hydroxide (100 mg) in water (0.8 ml) was added to the suspension. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (170 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](Br)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.C([O:21][B:22](OCC)[O:23]CC)C>>[CH3:1][O:2][C:3]1[C:12]([B:22]([OH:23])[OH:21])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1cc2c(cc1Br)CCCC2
Agent: [Li]CCCC
Product: COc1cc2c(cc1B(O)O)CCCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 106.7 %

Procedure:
A 10 mL round bottom flask was charged with 3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl methyl ether (560 mg, 2.32 mmol) and dried under high vacuum for 18 hours. The aryl bromide was diluted with THF (3.5 mL) and cooled to −78° C. with a dry ice/acetone bath. After 20 minutes, n-butyl lithium (2.5 M in hexane, 1.02 mL, 2.55 mmol) was added semi-drop wise. The reaction was kept at −78° C. for another hour before triethylborate (0.435 mL, 2.55 mmol) was added semi-drop wise and stirred at −78° C. for two hours. The reaction was quenched at −78° C. with 3M aq. HCl and allowed to warm to room temperature. The resulting biphasic mixture was partitioned between H2O and ethyl acetate (2×). The organics were combined and dried over Na2SO4, filtered and concentrated to give 510 mg (theoretical 478 mg) of 3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid as an ivory solid. 1H NMR shows contamination with ˜11% of the des-bromo by product. 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1 H), 6.61 (s, 1 H), 5.73 (s, 2 H), 3.87 (s, 3 H), 2.78 (m, 2 H), 2.71 (m, 2 H), 1.79 (m, 4 H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:28][N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26]
Reactant: CNCc1ccco1
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)Cc2ccco2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylfurfurylamine (367 mg, 3.3 mmol) is added to the filtrate and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provided the title compound. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=11 Hz, 2H), 3.79 (d, J=6 Hz, 2H), 6.32 (d, J=2 Hz, 1H), 6.21 (d, J=3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.53 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: O[C:2]1([C:17]2[C:26]([OH:27])=[CH:25][C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16]>I>[OH:27][C:26]1[C:17]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]2=[O:16])=[CH:18][C:19]2[S:23][C:22]([CH3:24])=[N:21][C:20]=2[CH:25]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3sc(C)nc3cc2O)c2ccccc21
Agent: I
Product: CCCCCN1C(=O)C(c2cc3sc(C)nc3cc2O)c2ccccc21

Procedure:
A suspension of 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (0.50 g, 1.31 mmol) in hydroiodic acid (10.0 mL) was refluxed for 1.5 days. The reaction mixture was concentrated in vacuo to dryness. The residue was used directly in next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2C.C(N(CC)CC)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:28]([O:27][C:26]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:2])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(F)cc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cccnc2)cc2cc(F)ccc21
Reaction time: 15 h

Procedure:
To a solution of 5-fluoro-2-pyridin-3-yl-indole (Example 3, 0.100 g, 0.452 mmol) in DMF (1 mL) is added triethylamine (0.083 g, 0.814 mmol), DMAP (0.006 g, 0.045 mmol) and di-tert-butyl carbonate (0.120 g, 0.543 mmol). After 15 h, the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried over MgSO4, filtered and the filtrate is concentrated in vacuo to give a residue which is purified by silica gel chromatography (heptane-ethyl acetate, 9:1 to 4:1) to give 5-fluoro-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a yellow oil. Trituration with ether and heptane, followed by standing for several days affords a solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 9H), 6.58 (s, 1H), 7.07-7.12 (m, 1H), 7.23 (dd, J=8.6, 2.5 Hz, 1H), 7.36 (dd, J=7.8, 5.1 Hz, 1H), 7.72-7.75 (m, 1H), 8.21 (dd, J=9.1, 4.9 Hz, 1H), 8.62 (dd, J=4.9, 1.5 Hz, 1H), 8.69 (d, J=1.5 Hz, 1H). MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].P(Cl)(Cl)(Cl)(Cl)[Cl:16].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]

Procedure:
Reaction of 30 g of 3-methoxy-2-nitrobenzoic acid and 31.6 g of phosphorus pentachloride in 400 ml of methylene chloride at reflux for 2 hours followed by treatment of the crude product obtained with toluene 3 times gave 3-methoxy-2-nitrobenzoyl chloride as a solid. A solution of 30 g of this acid chloride in 50 ml of tetrahydrofuran was added to a solution of 28.7 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water. A white precipitate appeared immediately but the mixture was allowed to stand for 3 hours. It was then diluted with water and the white solid was separated by filtration and air dried to give 3-methoxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 271° C. after recrystallization from dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[O:33]1[CH2:37][CH2:36][C:35](=O)[CH2:34]1.[BH3-]C#N.[Na+]>CO.CC(O)=O.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCOC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(NC3CCOC3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
General Procedure T. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 15 mg, 0.035 mmol) in MeOH (1 ml) was added dihydrofuran-3(2H)-one (Compound 129, 6.0 mg, 0.069 mmol), NaBH3CN (2.2 mg, 0.035 mmol), and HOAc (1 drop). The reaction was stirred at room temperature for 3 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.CCOCC>CN(C=O)C.CCOC(C)=O>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[CH3:7]
Reactant: CCOC(=O)CO
Reactant: BrCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
A solution of ethyl glycolate (4.6 g, 44 mmol) in DMF (50 mL) was cooled to 0° C. and sodium bis(trimethylsilyl)amide (1.0 M in THF, 53 mL, 53 mmol) was slowly added. The reaction was stirred for 15 minutes and 1,4-dibromobutane (5.6 mL, 48.4 mmol) was added. The reaction was warmed to room temperature and was stirred for 24 h. Et2O was added, and the organic solution was washed consecutively with HCl (1N, 3×), water (3×), and brine (1×). The organic solution was dried (Na2SO4), filtered, and concentrated. Attempted vacuum distillation removed a majority of the impurities and provided a mixture of product and 1,4-dibromobutane (3.539 g). Flash chromatography (9:1 hexanes:EtOAc) of this material provided (4-bromo-butoxy)-acetic acid ethyl ester (1.862 g). 1H NMR (400 MHz, CDCl3) δ 4.19 (q, 2H), 4.04 (s, 2H), 3.54 (t, 2H), 3.45 (t, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 1.26 (t, 3H); MS 239.1 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCc1nc(-c2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2nc(-c3ccccc3)no2)cc1
Yield: 92 %

Procedure:
4-Nitrophenol (0.36 g, 2.56 mmole), 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.5 g, 2.56 mmole) and anhydrous K2CO3 (0.39 g, 2.82 mmole) were dissolved in anhydrous acetone (20 mL) and heated to reflux for 12 h. Reaction mixture was cooled and the solvent removed under vacuum. The crude solid formed was collected by filtration, washed with water and dried under vacuum to provide 5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.70 g, 92%). 1H NMR (CDCl3): δ 8.25 (d, 2H, J=8.8 Hz), 8.08 (dd, 2H, J=8.2 Hz), 7.52-7.49 (m, 3H), 7.13 (d, 2H, J=8.8 Hz), 5.45 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:24])=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:24])=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:29])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (S)-7-chloro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (33.3 g, 85.2 mmol) and 1,2-dichloroethane (DCE, 500 mL). Add formaldehyde (37% wt. in water, 6.91 g solution, 2.56 g, 85.2 mmol) in one portion and stir at ambient temperature for 5 minutes. Add sodium triacetoxyborohydride (3.41 g, 16.1 mmol) in portions over 5-10 minutes, keeping the pot temperature below 25° C. Stir at ambient temperature overnight. Add saturated aqueous sodium bicarbonate (333 mL). Stir for 15 minutes, and then separate layers. Extract the aqueous layer with methylene chloride (250 mL). Wash the combined organic layers with water (3×333 mL), dry over sodium sulfate, and then concentrate ins vacuo to a residue (>100% recovery). Purify the residue by flash column chromatography, eluting with (100% CH2Cl2 to 93/7 CH2Cl2/MeOH) 91.2% recovery of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.49 (m, 1H), 1.82 (m, 1H), 2.13 (m, 2H), 2.20 (s, 3H), 2.27 (s, 3H), 2.74 (m, 2H), 2.98 (bt, 1H), 3.19 (s, 3H), 3.32 (m, 2H), 3.77 (bm, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32]1[S:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>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.O1CCOCC1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:35]4[S:36][C:32]([CH2:31][N:27]5[CH2:28][CH2:29][CH2:30][CH:26]5[CH3:25])=[CH:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CC1CCCN1Cc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCCC5C)s4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 29.3 %

Procedure:
A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave for 20 min at 150° C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150° C. Additional tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave for an additional 20 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL H2O), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing crude product solution was concentrated under a stream of nitrogen, and the residue was taken up in DMSO (3 mL). This DMSO solution of crude product was purified as three separate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The two fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 40° C. to give 13 mg of the title compound (29.3%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[NH:11][C:10](=[O:12])[C:5]3=[CH:6][CH:7]=[CH:8][C:9]=1[N:4]23.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]2[C:3]3=[CH:2][N:1]=[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([N:4]34)[C:10]2=[O:12])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: O=c1[nH]c2cnc3cccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1c(=O)c2cccc3ncc1n32
Yield: 20.9 %

Procedure:
To a suspension of 81 mg (0.51 mmol) of 3,4-dihydro-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of DMF was added, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 151 mg (0.51 mmol) of N-(5-bromopentyl)phthalimide in 1 ml of DMF. The mixture was stirred for two hours at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to afford 40 mg of the desired compound (20.9%, a colorless solid).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][O:11][C:12]([N:14]([C:30]1[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]2[C:33]([CH:34]3[CH2:44][CH:35]3[CH2:36][O:37]2)=[CH:32][CH:31]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27][CH2:28]O)(=[O:17])=[O:16])=[O:13].[CH:45]([N:48](C(C)C)[CH2:49][CH3:50])(C)[CH3:46].C(NCC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12]([N:14]([C:30]1[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]2[C:33]([CH:34]3[CH2:44][CH:35]3[CH2:36][O:37]2)=[CH:32][CH:31]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27][CH2:28][N:48]([CH2:49][CH3:50])[CH2:45][CH3:46])(=[O:17])=[O:16])=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CCO)ccc2c1OCC1CC21
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CC/C=C\c1cc(F)ccc1S(=O)(=O)N(C(=O)OC)c1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
Methyl sulfonic anhydride (0.062 g) was added to a stirred, cooled mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-4-hydroxybut-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 73, 0.12 g) and N,N-di-isopropyl-N-ethylamine (0.046 g) in DCM (15 mL) at 0° C. The resultant mixture was stirred at 0° C. for 20 minutes. Diethylamine (0.026 g) was added and the mixture was then stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with DCM, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 2-10% to give methyl (1aRS,7bSR)-5-{N-(methoxycarbonyl)-N-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.08 g) as alight yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1.I[CH3:25]>C(#N)C.[Ag-]=O>[CH3:25][O:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Product: CO[C@@H]1CCN2C(=O)N(c3ccc(C#N)c4ccccc34)C(=O)[C@H]12
Temperature: 85 °C
Yield: 68.7 %

Procedure:
To a solution of compound 6C (100 mg, 0.326 mmol) in acetonitrile (2 mL), at RT, was added iodomethane (86 μL, 1.38 mmol), followed by silver(I) oxide (42 mg, 0.18 mmol). The mixture was refluxed at 85° C. for 16 hours. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by using a preparative HPLC (gradient, 20 to 90% of MeOH/H2O containing 0.1% of CF3CO2H over 10 minutes) to yield the title compound (racemate) (72 mg, 69% yield) as an off-white solid. mp. 185-186° C. HPLC: 99% at 2.45 min (retention time) (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), MS (ES): m/z 322 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C[C@H]1C[C@H](C)OC2(CN(C(=O)[C@H](C(C)C)NC(OC)=O)[C@H](C(OC)=O)C2)O1>>[CH2:6]1[C:2]2([O:24][CH2:23][CH2:22][CH2:21][O:1]2)[CH2:3][C@@H:4]([C:17]([O:19][CH3:20])=[O:18])[N:5]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Reactant: OCCCO
Agent: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OC)O[C@@H](C)C[C@H](C)O2)C(C)C
Product: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCCO2
Yield: 84.3 %

Procedure:
3-Methyl 2-(phenylmethyl) (3S)-6,10-dioxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (Intermediate 24) (1.02 g, yield 84%) was prepared from 2-methyl 1-(phenylmethyl) (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 3.61 mmol) and 1,3-propanediol (0.55 g, 7.21 mmol) following the similar procedure outlined in the preparation of Intermediate 14 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05-7.61 (m, 5H) 4.91-5.25 (m, 2H) 4.29-4.68 (m, 1H) 3.75-4.07 (m, 5H) 3.38-3.75 (m, 4H) 2.25-2.67 (m, 2H) 1.51-2.00 (m, 1H). ES LC-MS m/z=336.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([SH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.BrC1SC2C=CC=CC=2N=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([S:11][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(S)c1ccccc1
Reactant: Clc1nc2ccccc2s1
Agent: Brc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Sc1nc2ccccc2s1)c1ccccc1

Procedure:
18.2 g of 2-mercapto-2-phenylacetic acid methyl ester is added to a suspension of 2.4 g of NaH in 200 ml of DMF and the mixture is stirred until the evolution of gas has ceased. 17 g of 2-chlorobenzothiazole (or 21.5 g of 2-bromobenzothiazole) is then introduced. The mixture is stirred for 5 hours at 80° and is worked up in the customary manner to give 2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester, in the form of an oil.