Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
In a mixture of 17 mL of methylene chloride and 13 mL of methanol was dissolved 5.79 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate and the solution was cooled to 5° C. To this solution was added 3.7 mL of methanol containing 0.344 g of hydrogen chloride dropwise and the mixture was stirred at 5°-6° C. for 2 hours. Then, 11 mL of ethyl acetate and 11 mL of water were added and the mixture was adjusted to pH 6.2 with a saturated aqueous solution of sodium hydrogen carbonate. Then, 6 mL of ethyl acetate and 20% NaCl--H2O were added. The aqueous layer was taken and extracted with 12 mL of ethyl acetate. The organic layers were combined and redistributed into 22 mL of ethyl acetate and 20% NaCl solution. The organic layer was separated and concentrated and the residue was stirred in 15 mL of toluene at room temperature for 30 minutes. Then, 100 mL of hexane was added and the mixture was stirred under ice-cooling for 1 hour. The resulting crystals were collected by filtration, washed with 20 mL of toluene-hexane (1:9), and dried to provide 3.65 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 91%).
Reaction SMILES: C=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[O:11]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:11]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: C=C1CCC(C(=O)OC)C1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C1CCC(=O)C1
Reaction time: 8 h
Yield: 54 %

Procedure:
A solution of methyl 3-methylenecyclopentane carboxylate (Trost, B. M., Chan, M. T., J. Am. Chem. Soc., 1983, 105, 2315) (2.84 g, 20.26 mmol) in dichloromethane (60 mL) was cooled to −78° C. and a slow stream of ozone was passed through until the permanent blue color indicated complete ozonide formation. The excess ozone was purged with stream of nitrogen. Triphenylphosphine (10.62 g, 40.52 mmol) was added, and stirring was continued overnight, allowing the temperature to warm up to ambient. Solvent was removed in vacuo, the residue dissolved in 10 mL of ethyl acetate/hexane (1:4) mixture. The crystalline triphenylphosphine oxide was removed by filtration, and the residue was purified by mplc (ethyl acetate/hexanes (1:4) to yield 1.5651 g (54%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11](OCC)=[O:12])=O)=[CH:5][N:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:7]2[C:9]3[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:12])[NH:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccc(OC)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-(6-methoxynicotinoyl)benzoate (0.496 g, 1.74 mmol) and hydrazine hydrate (0.39 mL, 6.9 mmol) in ethanol (6 mL) was stirred at 80° C. for 2 hours, concentrated, and azeotroped with PhMe to give crude 4-(6-methoxypyridin-3-yl)phthalazin-1(2H)-one, which was used without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([N:1]5[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]5)=[O:30])[CH:27]=4)[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: C1CNCCN1
Product: O=C(c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCNCC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from piperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O2: 471, observed (M+H)+: 472.2 1H NMR (400 MHz, MeOD-d4) δppm 2.17-2.30 (m, 2 H) 3.51 (br. s., 8 H) 3.21-3.35 (m, 1 H) 5.04-5.23 (m, 2 H) 6.10 (d, J=7.58 Hz, 1 H) 6.74 (t, J=7.45 Hz, 1 H) 6.95 (d, J=7.83 Hz, 1 H) 7.05-7.16 (m, 1 H) 7.23 (d, J=8.34 Hz, 2 H) 7.29-7.38 (m, 2 H) 7.40-7.49 (m, 2 H) 7.49-7.58 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/Cc1ccccc1OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a mixture of methyl 4-(2-benzyloxyphenyl)crotonate (14.4 g) and nickel chloride hexahydrate (1.19 g) in methanol (200 ml) was added portionwise sodium borohydride (3.78 g). During addition, the reaction temperature was kept at 20° C. by ice cooling. After the addition was completed, the mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated under reduced pressure. To the residue, water (100 ml) was added and the solution was extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated in vacuo and the residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to give methyl 4-(2-benzyloxyphenyl)butyrate (11.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([OH:35])[CH:34]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:31]1[CH:32]=[C:33]([OH:35])[CH:34]=[C:29]([F:28])[CH:30]=1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nn2cccc2c(=O)n1-c1ccccc1
Product: C[C@H](Nc1ncnc(N)c1-c1cc(O)cc(F)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 3 %

Procedure:
(S)-2-(1-(6-Amino-5-iodopyrimidin-4-ylamino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 3-fluoro-5-hydroxyphenylboronic acid (34 mg, 0.22 mmol) were stirred at 80° C. following the experimental procedure described in Example 3. 5 mg (3% yield) of the title compound were obtained as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.CO.[S:22]([O-:25])([O-:24])=[O:23].[Na+:26].[Na+]>O.C(O)C>[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH2:2][S:22]([O-:25])(=[O:24])=[O:23])[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2.[Na+:26]
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: COCN1c2cc(CS(=O)(=O)[O-])ccc2Sc2nccnc21
Temperature: 90 °C
Yield: 58.7 %

Procedure:
To a solution of 900 mg of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in a mixture of water (8 ml)/methanol (4 ml) was added 0.8 g of sodium sulfite and the resulting mixture was heated to 90° C. for 2 hours. Then the reaction mixture was brought back to room temperature and diluted with ethanol. After filtering off the inorganic salt, silica gel was added to the filtrate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/acetic acid) to thereby give 650 mg of the title compound as yellow crystals.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C>Cl>[C:16]1([C:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)N1CCc2ccc(C(=O)c3ccccc3)cc2C1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc2c(c1)CNCC2
Yield: 64.5 %

Procedure:
(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-(phenyl)methanone (11.10 mmol, 3.10 g) was heated in hydrochloric acid (7 M, 250 ml) to reflux for 6 h. The resulting mixture was concentrated, made alkaline with sodium hydroxide solution and extracted with ethyl acetate. Drying of the organic phase and concentration resulted in 1.7 g of the title compound as a brown oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43]>C1COCC1.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:41](=[O:44])[CH2:42][CH3:43])[CH2:18][CH2:17]1)#[N:24]
Reactant: CCC(=O)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Reaction time: 18 h

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (50 mg, 0.11 mmol) in THF (1 mL) was added DIPEA (0.060 mL, 0.34 mmol), followed by propanoyl chloride (0.020 mL, 0.18 mmol). The resulting mixture was allowed to stir for 18 hours before the reaction mixture was concentrated in vacuo to afford an orange oil. The residue was dissolved in DMSO (2 mL) and purified by mass-triggered reverse phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound, Example #33-1, as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1.[C:20](=O)(OC1C=CC=CC=1)N>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([NH2:19])=[CH:14][C:13]=1[C:12]#[C:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=12
Reactant: NC(=O)Oc1ccccc1
Reactant: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Product: Cc1ccc(N)cc1C#Cc1cncc2c1cnn2C

Procedure:
The following example compound 3.2 was synthesized in analogy to GP 7 and example compound 3.1 by reaction of Intermediate 3.1 with the respective phenyl carbamate.
Reaction SMILES: [Na+].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([O-:19])=[O:18].Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>CN(C)C=O>[O:34]=[C:30]1[N:29]([CH2:28][CH2:27][O:18][C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:3]([F:24])([F:2])[F:25])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32][O:31]1
Reactant: O=C1OCCN1CCCl
Reactant: O=C([O-])c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture comprising 10.62 g of N-(8-trifluoromethyl-4-quinolyl)-anthranilic acid sodium salt, 4.98 g of 90% 3-(β-chloroethyl)-oxazolidin-2-one and 60 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, filtered, and poured into 300 ml of water. The crude product was extracted with ethyl acetate, the solvent evaporated off and the residue crystallized from ethanol to give 6 g of N-(8-trifluoromethyl-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 158°-160° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4]1.[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])c1cccc2ccc3c(c12)C(CCl)CN3
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c(c3c([N+](=O)[O-])cccc13)C(CCl)CN2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A stirred solution of amine 136 (900 mg, 3.43 mmol) in conc. H2SO4 (9 mL) was cooled to −5° C. and treated with powdered KNO3 (520 mg, 5.14 mmol). The mixture was stirred at 0° C. for a further 15 min, then poured into ice-water and the solid was collected Chromatography on silica gel, eluting with petroleum ether/EtOAc (3:1), followed by two recrystallizations from CH2Cl2/iPr2O gave 1-(chloromethyl)-5,9-dinitro-1,2-dihydro-3H-benzo[e]indole (137) (394 mg, 37%) as a red solid: mp 130-131° C.; 1H [(CD3)2SO] δ 8.21 (dd, J=8.6, 1.1 Hz, 1H), 8.10 (dd, J=7.6, 1.1 Hz, 1 H), 7.75 (s, 1H), 7.44 (dd, J=−8.6, 7.6 Hz, 1H), 7.02 (s, 1H), 3.89-3.81 (m, 1H), 3.72-3.62 (m, 2H), 3.41-3.35 (m, 2H). Anal. (C13H10ClN3O4) C, H, N, Cl.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](=[O:25])[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[O:19][CH:20]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]>C(O)C.[H][H].[Pd]>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][O:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH:16]2[OH:25])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCc1c(OCCCCCOc2coc(C(=O)OC)cc2=O)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(OCCCCCOC2COC(C(=O)OC)CC2O)ccc(C(C)=O)c1O
Yield: 16.9 %

Procedure:
The title product of Example 2 (840 mg, 1.96 mmole) was dissolved in 110 ml ethanol, and then hydrogenated at room temperature using 2 psi of hydrogen and 5% palladium on carbon as catalyst. Insolubles were removed by filtration and the filtrate was concentrated in vacuo, and the incompletely reduced residue (as determined by nmr in (CD3)2SO) was again hydrogenated. Purification by high performance chromatography on silica gel (using 30% by volume acetone-hexane) afforded 145 mg of the title compound as an oil. Spectral data indicate complete reduction of the pyranone moiety to the hydroxy-substituted cyclic ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([C:11]2([OH:14])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1>Cl.CO>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]2[C:8]([C:11]1([OH:14])[CH2:12][CH2:13]1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10]
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(NC(=O)OC(C)(C)C)cccc21)C1(O)CC1
Agent: Cl
Solvent: CO
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cccc21)C1(O)CC1

Procedure:
Compound from step A (96 mg, 0.22 mmol) was treated with 10 mL 4N HCl/MeOH solution over night. The solvents were removed by reduced pressure to give white product. LC/MS m/z=341.0[M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH:17]([OH:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(CC(=O)C(C)(C)C)c2ccncc2)CCN(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(CC(O)C(C)(C)C)c2ccncc2)CCN(C)C1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
6-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one (400 mg, 0.99 mmol) was dissolved in MeOH (30 mL). Sodium borohydride (263 mg, 6.9 mmol) was added under nitrogen. The reaction mixture was heated at 60° C. for 8 h. After consumption of starting material, the reaction mixture was concentrated and 2N HCl was added (pH-acidic) and extracted with DCM (2×200 mL) for removing impurities. The aqueous layer was basified with saturated bicarbonate and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 350 mg of 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.44 (d, 2H), 7.15 (s, 1H), 7.0 (d, 1H), 6.94 (d, 1H), 6.92 (d, 2H), 4.25 (dd, 1H), 4.0 (dd, 1H), 3.64 (d, 1H), 3.51 (m, 2H), 2.88 (dd, 1H), 2.73 (t, 1H), 2.58 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.2 (m, 1H), 2.02 (t, 1H), 1.71 (t, 2H), 0.837 s (9H). Separation by chiral HPLC provided diastereomers II-227a-b.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([O:18][C:19](=[O:26])[CH:20]=[C:21](OCC)[CH3:22])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1.C(O)C.O>[CH2:16]([O:18][C:19]([C:20]1[C:11]([OH:13])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:26])[CH3:17]
Reactant: CCOC(=O)C=C(C)OCC
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1O)CCCC3
Temperature: 165 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (33.8 g; 150 mmol) and ethyl-3-ethoxybut-2-enoate (25 g; 157.5 mmol) in xylene (600 mL) was added a catalytic amount of p-toluenesulfonic acid mono hydrate. The resulting reaction mixture was heated to reflux (temp. of bath 165° C.) equipped with a Dean-Stark trap and condenser to collect ethanol. After 18 h, the solution was cooled to room temperature, transferred to a dropping funnel and then added dropwise to a stirred solution of sodium ethoxide (21% in ethanol, 59 mL; 157.5 mmol) in ethanol (350 mL). The resulting solution is heated to reflux for 18 h and, after cooling, the volatiles were removed under reduced pressure to yield a black oil. This material was suspended in water (150 mL) and washed with diethylether (2×150 mL). The aqueous phase was separated, cooled at 0° C. and slowly acidified to pH 4 with a 1N HCl with rapid stirring. The resulting precipitate was filtered, washed with diluted hydrochloric acid solution and dried to furnish 25.5 g (58%) of the title compound as a black solid.
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][S:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][CH:12]=4.[H-].[Na+]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[N:10]([CH3:1])[C:11]4[C:16]([C:17]=3[CH2:18][S:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][CH:12]=4
Reactant: COc1ccc2c(c1)SCc1c-2[nH]c2ccc(OC)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)SCc1c-2n(C)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CH3I (108 mg, 0.758 mmol, 1.5 eq.) was added to a mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (150 mg, 0.505 mmol) and NaH (61 mg, 60% in mineral oil, 1.515 mmol, 3.0 eq.) in DMF. The reaction mixture was then stirred at 25° C. for 2 hours. The reaction mixture was partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (Hexanes to EtOAc 4:1) to yield the title compound as a brown solid.