Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:25])[C:18]([C:19]5[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=5)=[CH:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH:8]=[C:7]1[CH2:6][C@@H:5]([OH:26])[CH2:4][CH2:3]2.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:27]([O:26][C@@H:5]1[CH2:6][C:7]2[C@@:2]([CH3:1])([C@@H:11]3[C@@H:10]([CH2:9][CH:8]=2)[C@@H:15]2[CH2:16][CH:17]=[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=4)[C@@:14]2([CH3:25])[CH2:13][CH2:12]3)[CH2:3][CH2:4]1)=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: -2.5 °C
Reaction time: 25 h

Procedure:
The crude abiraterone thus obtained (about 64 g) is taken up in methylene chloride (350 mL), and the resulting mixture, cooled to a temperature of −5 to 0° C., is added with acetic anhydride (130 mL) and then with triethylamine (190 mL), maintaining the temperature at −5 to 0° C. The mixture is stirred at room temperature for about 25 h, then washed with water and concentrated under vacuum, taking up the residue in acetone (250 mL). The resulting solid is isolated by filtration (at 0-5° C.) and dried under vacuum at 40° C. for 16 h (about 46 g; purity: 82.5%; assay: about 73%). A second fraction of crude abiraterone acetate, as an oil, is obtained by concentration of the mother liquor under vacuum (54 g, purity: 74%, assay: about 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][CH:26]=2)O1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:29][CH:30]=3)=[CH:7][N:6]=1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1

Procedure:
The product of Example 19A (160 mg, 0.57 mmol) was coupled with t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamate (Frontier, 319 mg, 1 mmol) according to the procedure of Example 18B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.20) as solid (150 mg, yield, 67%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.63 (m, 10H), 1.65-1.91 (m, 2H), 2.02-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.75-3.05 (m, 5H), 3.36-3.48 (m, 1H), 5.13-5.21 (m, 1H), 7.54 (s, 4H), 8.78 (s, 2H) ppm. MS (DCl/NH3) m/z 397 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10]([C:15]([O:17]C)=[O:16])=[C:9]([CH3:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1>CO>[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10]([C:15]([OH:17])=[O:16])=[C:9]([CH3:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=C(C)c2cccc(C)c2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)CCCc2c(C)cccc21
Yield: 70.4 %

Procedure:
A 2N-aqueous sodium hydroxide solution (10 ml) was added to a solution of methyl 4,9-dimethyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (0.85 g, 3.68 mmol) in methanol (10 ml), and the mixture was heated under reflux for 3 hours. The methanol was distilled off under reduced pressure and the residue was adjusted to pH 1 to 2 with 4N-hydrochloric acid and then extracted three times with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the thus obtained solid was washed with n-hexane to obtain 0.56 g of 4,9-dimethyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid.
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:10][C:9]2=[O:24].[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.CN(C)C=O>[Br:25][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([C:11]2[NH:10][C:9](=[O:24])[C:8]3[C:13](=[C:4]([CH3:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: BrBr
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 105 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Bromine (3.2 g, 0.020 mol) was added dropwise to a stirred solution of 8-methyl-2-(2-n-propoxyphenyl)quinazolin-4(3H)-one (3 g, 0.010 mol) in glacial acetic acid (45 ml) at 95° C. The resulting suspension was heated at 105° C. for 18 hours and then evaporated under vacuum. The resulting solid was dissolved in dimethylformamide (25 ml) and the stirred solution treated dropwise with a solution of N-bromosuccinimide (0.89 g, 0.0051 mol) in dimethylformamide (25 ml). After 1 hour at ambient temperature, the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (50 ml). This solution was washed with saturated aqueous sodium carbonate solution (50 ml), dried-(Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (30 g) using a methanol in dichloromethane elution gradient (0-100%) to give the title compound as a white solid (1.67 g, 45%), m.p. 179°-180° C.; Rf 0.7 (silica; dichloromethanemethanol; 99:1). This material was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[C:13]1([OH:19])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:8]([O:19][CH3:13])=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Oc1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc(N)c1Cl
Temperature: 100 °C
Yield: 51.1 %

Procedure:
A mixture of 2,5-dichloro-4-nitroaniline (7.0 g), phenol (3.2 g), potassium carbonate (9.7 g) and dry dimethylformamide (50 ml) is stirred and heated at 100° C. for 7.5 hours. The mixture is then poured into 500 ml of ice water and stirred. The aqueous mixture is extracted with ethyl acetate (5×200 ml), the extracts are dried and evaporated to dryness. The residual oil is stirred with methylene chloride (20 ml), the resulting solid is collected and dried to yield 3.5 g of title product, m.p. 122°-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:17]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(NCCS(=O)(=O)Cl)cc1
Product: NS(=O)(=O)CCNc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
2-[(4-Nitrophenyl)amino]ethanesulfonyl chloride (9) (0.5 g) was mixed with 4 mL of aqueous ammonia (22%) at room temperature. The mixture was left for 1 hour and the precipitate that formed was then filtered off by suction and reslurried in water. The crude product was recrystallized from ethanol to give 0.23 g of expected product with a melting point of 170° C. The results of the elemental analysis were as follows:
Reaction SMILES: [CH3:1][C:2]12[N:7]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:6]1[CH2:5][CH2:4][CH2:3]2.[N-:18]=[N+:19]=[N-:20].[Na+]>CC(O)C.O>[N:18]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[N+:19]=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)N2C3CCCC32C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-methyl-6-(4-methylbenzenesulfonyl)-6-azabicyclo[3.1.0]hexane (55 g, 219.12 mmol) in IPA (1000 ml) and water (1000 ml) was added sodium azide (57.0 g, 876.92 mmol). The reaction mixture was stirred at room temperature for 17 hours. The reaction was cooled to room temperature and water (1000 ml) was added. The aqueous layer was extracted with diethyl ether (3×500 ml). The combined organics were washed with brine (250 ml), dried over sodium sulfate, concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[C:31]([CH3:45])[O:30][N:29]=1>ClCCl>[CH3:27][C:28]1[C:32]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([NH:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([CH:9]4[CH2:13][CH2:12][N:11]([CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:10]4)=[CH:5][CH:6]=3)(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[C:31]([CH3:45])[O:30][N:29]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 70.6 %

Procedure:
To a solution of 2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinamine (150 mg, 0.561 mmol) in dichloromethane (DCM) (4 mL) and pyridine (0.045 mL, 0.561 mmol) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol). The reaction vessel was sealed and heated at 65° C. for 2 hours. Additional 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (169 mg, 0.561 mmol) and pyridine (0.045 mL, 0.561 mmol) were added and the reaction mixture was heated for a further 4 hours at 65° C. The reaction mixture was then cooled and separated between DCM (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The sample was purified by flash silica (Si) chromatography (0-25% methanol-dichloromethane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product (211 mg) as a brown gum (approx 71% pure). LCMS (2 min, formic) Rt 0.80 min, m/z (ES+) 533 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:6]=1)=[O:4].[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)c1ccnc(NC2CCNCC2)n1

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester (0.48 g, 1.43 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 237.4 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[C:6](=[O:22])[CH2:5]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[CH3:21][O:20][C:17]1[N:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH2:41][C:39]2[CH:38]=[CH:37][C:34]3[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=3[N:40]=2)[CH2:5][C:6]1=[O:22]
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(N3CCN(CCN)CC3=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)CC3=O)c2n1
Reaction time: 12 h
Yield: 37.4 %

Procedure:
To a solution of 4-(2-aminoethyl)-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone (168 mg, 0.558 mmol) in DCM-EtOH (6 mL, 5:1) at 25° C. were added Na2SO4 (158 mg, 1.11 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (108 mg, 0.558 mmol). After 12 h, Na(OAc)3BH (177 mg, 0.837 mmol) was added and following an additional 2 h, the solution was partitioned between DCM-H2O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (100 mg, 37%) as a yellow solid: LCMS (ES) m/e 480 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.81 (d, J=4.7 Hz, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.71 (d, J=4.7 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.04 (s, 3H), 3.92-3.94 (m, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 3.34 (2H), 3.00-3.03 (m, 2H), 2.82-2.84 (m, 2H), 2.77-2.79 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a suspension of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.76 mmol, 0.3 g) and 2,6-dichlorobenzoyl chloride (0.84 mmol, 0.175 g) in dichloromethane (2 mL) was added diisopropylethylamine (3.03 mmol, 0.53 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.40 g (99% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H27Cl2N3O5 (M+Na) 554.1221, found 554.1229.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:35])[NH:18][C@@H:19]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:20]([O:24][CH2:25][CH3:26])OCC)[C@@H:15]2[CH2:36][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:27][C:28](=[O:29])[O:30][C@H:20]2[O:24][CH2:25][CH3:26])[C@@H:15]2[CH2:36][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (1R,3S,4S)-3-((S)-1-tert-Butoxycarbonylmethyl-2,2-diethoxy-ethylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (635 mg) in dichloromethane (3 ml) was cooled to 0° C. under nitrogen. Trifluoroacetic acid (0.7 ml) was then added and the mixture stirred at 0° C. for 15 minutes, then warmed to ambient temperature and stirred until the reaction was complete by TLC. The mixture was then diluted with dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (14 ml). The organic phase was then removed and washed with 1:1 saturated aqueous sodium bicarbonate/brine (8 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. This afforded the sub-title compound as a mixture of epimers at the ketal centre. The epimers were separated on silica gel, eluting with 30% 2-butanone/petrol. Syn-isomer (oil) (115 mg, 23%); 1H NMR (400 MHz, d-6 DMSO) δ 0.80-1.91 (10H, m), 2.35-2.79 (2H, m), 3.56 (1H, m), 3.66-3.80 (2H, m), 4.18 (1H, m), 4.59 (1H, m), 4.94-5.11 (2H, m), 5.53 (1H, d), 7.20-7.40 (5H, m), 8.18 (0.5H, d), 8.27 (0.5H, d); MS ES+403.31 (100%), ES−401.37 (15%); Anti-isomer (oil) (103 mg, 20%); 1H NMR (400 MHz, d-6 DMSO) δ 0.80-1.85 (10H, m), 2.25-2.60 (1H, m), 2.95 (1H, m), 3.42 (1H, m), 3.5-3.75 (2H, m), 4.88-5.15 (3H, m), 7.21-7.40 (5H, m), 8.50 (0.4H, d), 8.59 (0.6H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:31])[CH2:29][CH3:30])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (1.30 g, 3.16 mmol) in pyridine (20 mL) was added propionyl chloride (330 μL, 3.80 mmol), and the mixture was stirred at room temperature for 4.5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→34/66) to give the title compound (1.30 g, 88%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:7][C:6]=2[CH:35]=1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])[CH2:7][C:6]=2[CH:35]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(Cl)ccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(Cl)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
Methyl 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 7) was dissolved in a solution THF: MeOH (1:1) (0.02 M) and to that solution 7 eq of an aqueous solution of NaOH (1N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (21%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[NH:17][C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[N:17]([CH3:27])[C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccc2c3c1CCC(c1ccccc1)n3c(=O)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated with cesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μL, 46.5 μmol) and stirred at room temperature for 16 h. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture. 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 3H), 7.03 (d, J=6.9 Hz, 2H), 6.99-6.93 (m, 1H), 6.93-6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H), 2.48-2.11 (m, 7H), 2.09-1.84 (m, 3H); LCMS calculated for C22H22N3O2 (M+H)+: m/z=360.2. found: 360.1.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[C:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:20][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:35]([CH2:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]2=[O:8]
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 14.4 g, 48.6 mmol), in N,N-dimethylformamide (120 ml) was added sodium hydrogen carbonate (12 g, 143 mmol) and 3-phenylpropylamine (38.8 g, 41 ml, 290 mmol). The mixture was heated to 150° C. for 7 h, then cooled to room temperature and poured onto water (1000 ml). The mixture was extracted with diethyl ether (2×500 ml), and the combined extracts were washed with water (2×250 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1000 g) column chromatography eluting with dichloromethane then dichloromethane/ethyl acetate 4:1. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (6.2 g, 36%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:28])[CH2:26][CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 31 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 ml (0.935 m mol) of triethylamine and 20 ml of methylene chloride were added 81 μl (0.935 m mol) of propionyl chloride with stirring at the room temperature, followed by further stirring for 6 hours. After the completion of the reaction, the mixture solution was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 77 mg (yield: 31%) of the pure intended compound.