Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH3:28]I>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:22][O:23][CH3:28])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(COC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of {4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol in dry THF was added 60% NaOH in oil and stirred for 5 min. Excess of MeI was added and stirred at room temperature for 2 hr. After standard worked up procedure and purification, the title compound was obtained as a clear golden oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.06(s,1H), 4.40(s,3H), 3.72(d,1H), 3.39(s,3H), 3.36(m,1H), 2.12(s,3H), 2.11(s,3H), 2.10(s,6H), 1.4–1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:19])[C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11][CH:10]1[CH2:17][CH3:18])=[O:8])(=O)C.Cl>O.N>[CH2:17]([CH:10]1[N:9]([C:7](=[O:8])[CH:6]([CH3:19])[CH2:5][SH:4])[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11]1)[CH3:18]
Reactant: CCC1SCC(C(=O)O)N1C(=O)C(C)CSC(C)=O
Agent: Cl
Agent: N
Solvent: O
Product: CCC1SCC(C(=O)O)N1C(=O)C(C)CS
Temperature: 25 °C

Procedure:
3-(3-Acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid (1 g.) is dissolved in a mixture of water (3 ml.) and concentrated ammonia (3 ml.) under a blanket of argon. The mixture is stirred at room temperature for thirty minutes and acidified with concentrated hydrochloric acid. The organic layer is dried and concentrated to dryness to vacuo to yield 2-ethyl-3-(3-mercapto-2-methylpropanoyl)-4-thiazolidinecarboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[BrH:21]>C(O)(=O)C>[Br:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: Br
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Temperature: 25 °C

Procedure:
A solution of (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), 40% HBr (2 ml) and acetic acid (5 ml) was heated at 120° C. overnight. After cooled to room temperature, the reaction mixture was concentrated to oil, and the residue was treated with 50 ml water. The mixture was extracted by ethyl acetate (50 ml×3), and the organic layer was evaporated to give 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol as solid (80 mg). LC-MS: m/e 319 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=O)=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:37]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18])=[O:28])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (28 mg, 22%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:12]1[C:13]2[C:9](=[CH:8][C:7]([F:6])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH:3]1[O:5][CH2:4]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(ccn2CC2CO2)c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
Epibromohydrin (1.4 ml, 16.5 mmole) was added to a stirred solution of 5-fluoroindole (2.0 g, 15 mmole) and sodium hydride (0.66 g, 16.5 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 15 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×35 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a viscous yellow colored oil (2.7 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a viscous oil (2.5 g, 89% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([NH:17][CH2:18][CH2:19][N:20](C(OCC1C=CC=CC=1)=O)[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:25]=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:25]=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(CC(=O)OC(C)(C)C)NCCN(CC=Cc2cccc(NCC3CC3)n2)C(=O)OCc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(CC(=O)OC(C)(C)C)NCCNCCCc2cccc(NCC3CC3)n2)cn1
Yield: 57.2 %

Procedure:
A mixture of 2-6 (29.0 g, 47.0 mmol) and 10% Pd/C (7.25 g) in EtOH (500 mL) was stirred under a balloon of hydrogen for 18 h. Filtration through celite and evaporative removal of the solvent followed by purification on silica gel (90:10:1 CHCl3:MeOH:NHOH) afforded 13 g of 2-7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=O)[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([Cl:26])=[O:23])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)ccc1O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)Cl)cc2Br)ccc1O

Procedure:
3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (444 mg) was mixed with 10 ml thionyl chloride and heated at reflux for 3 h. The reaction mixture was co-evaporated with toluene to give the crude 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride. N,O-bis(trimethylsilyl)acetamide (670 mg) was added at 0° C., under nitrogen atmosphere, to a mixture of D-Aspargine (225 mg) and 10 ml acetonitrile. The reaction mixture was further stirred at room temperature and a solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride in 10 ml acetonitrile was added. After stirring for 16 h, the reaction mixture was poured into water and the solid filtered off. The solid was dissolved in methanol and the organic phase removed in vacuo. The residue was purified by HPLC to give 76 mg (14%) of D- N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine. LC-MS (electrospray): m/z 557 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=S)[S:10]C)[CH2:4][O:3]1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=[S:10])[NH:15][NH2:16])[CH2:4][O:3]1
Reactant: NN
Reactant: CSC(=S)NCC1COC(C)(C)O1
Solvent: O
Solvent: CCO
Product: CC1(C)OCC(CNC(=S)NN)O1
Yield: 69.4 %

Procedure:
A misture of methyl N-(2,2-dimethyl-dioxolan-4-yl-methyl)-dithiocarbamate (23,6 g) prepared according to U.S. Pat. No. 4,064,242, absolute ethanol (500 cc) and hydrazine hydrate (5.6 g) is heated under reflux for 2 hours 30 minutes. It is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in diethyl ether (100 cc). After filtration and drying, 4-(2,2-dimethyl-dioxolan-4-yl-methyl)-thiosemicarbazide (15.2 g) is obtained in the form of a cream-coloured solid melting at 145° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1cccc(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Into a solution of 2-chloro-3-fluoroaniline (2.61 g, 17.94 mmol) in 50 mL of toluene at room temperature, thiophosgene (2.1 mL, 26.91 mmol) and triethylamine (3.02 mL, 26.91 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (2.99 g, 89%). 1H NMR (CDCl3) δ 7.10 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4]3=[C:5]([C:12](=[O:15])[C:13](=[O:14])[N:3]13)[CH:6]=[CH:7][CH:8]=2.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4]3=[C:5]([C:12](=[O:15])[C:13](=[O:14])[N:3]3[CH:2]([CH3:1])[CH2:11][CH2:10]2)[CH:6]=1
Reactant: CC1CCc2cccc3c2N1C(=O)C3=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CCc2cc(Cl)cc3c2N1C(=O)C3=O
Yield: 46.7 %

Procedure:
To a suspension of 8.05 g (0.04 mole) of 5,6-dihydro-4-methyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione in carbon tetrachloride (50 ml) was added 5.74 g (0.043 mole) of sulfuryl chloride and the mixture was refluxed for 24 hours. After cooling, there was obtained 4.4 g of red crystals. Recrystallization from ethanol afforded 2.93 g (31.1%) of red prisms, melted at 152°-154° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCC(c2ncc(-c3ccccc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(-c2cnc(C3CCNCC3)o2)cc1
Temperature: 75 °C

Procedure:
A solution of 1-[4-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone (30.0 g, 110.99 mmol), prepared as part B, in MeOH (450 ml) is treated with a solution of NaOH (44.40 g, 1109.90 mmol) in water (150 ml), heated at 75° C. for 18 hours, and then the reaction mixture is concentrated to 1/3 volume. Upon addition of ca. an equal volume of water, crystallization occurred. The solids are filtered, washed with water and dried in a vacuum over at 70° C. to afford 4-(5-phenyl-oxazol-2yl)-piperidine as a white solid. 1HNMR (CDCl3): d 7.61 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.30 (t, 1H, J=7.4 Hz), 7.23 (s, 1H), 3.19 (d t, 2H, J=11.8, 3.3 hz), 2.99 (t t, 1H, J=11.8 3.9 Hz), 2.76 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26]>[Cu]I>[CH3:18][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:7]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To a pressure tube was added 4-(6-bromo-3-methylindazol-1-yl)pyrimidin-2-amine (0.5 g, 1.64 mmol), piperidine (3.5 mL) tetrakis(triphenylphosphine)palladium (113.98 mg, 0.1 mmol), copper(I) iodide (18.79 mg, 0.1 mmol) and ethynyl(trimethyl)silane (0.47 ml, 3.29 mmol). The mixture was purged with nitrogen for 2 minutes and then stirred at 65° C. for 1.5 hr. The reaction mixture was concentrated in vacuo, DCM (5 mL) was added and the concentration repeated (×2). The mixture was purified by column chromatography (Biotage, 3-8% MeOH gradient in DCM) to give the title intermediate as a white solid (116 mg): 1H NMR (250 MHz, DMSO) delta 0.28 (9H, s), 2.57 (3H, s), 7.03 (3H, d, J=5.5), 7.38 (1H, d, J=8.2), 7.84 (1H, d, J=8.2), 8.26 (1H, d, J=5.5), 8.90 (1H, s); LC-MS: m/z=+322.50 (M+H)+.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10]>O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:5][CH3:4])=[O:10]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With reference to FIG. 4, DMF (130 mL) was added to a well mixed 2-methyl-3-nitrobenzoic acid 2 (50 g, 0.28 mol) and KHCO3 (84 g, 0.84 mol) solution. Since the mixture became highly viscous, it was heated to 40° C. with manual shaking. lodomethane (79 g, 0.56 mol) was added via syringe after the gas evolution had ceased. The resulting orange colored solution was stirred for 12 hours at room temperature. The reaction mixture was poured into water (800 mL), and the resulting precipitate collected by filtration and dried over P2O5 to give pure methyl 2-methyl-3-nitrobenzoate 3 (56 g, 100%) as a white solid: mp. 64.2-65.5° C.; 1H-NMR (CDCl3) δ 8.00 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H); IR (KBr, cm−1) 1724, 1548, 1279; MS (EI): 195 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCCCCc1oc(-c2ccc(Cl)cc2)nc1CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCc1oc(-c2ccc(Cl)cc2)nc1CC(=O)O
Yield: 87.3 %

Procedure:
1.0 g of ethyl 2-[2-(4-chlorophenyl)-5-n-pentyl-4-oxazolyl]acetate, 10 ml of methanol, 3 ml of water and 0.4 g of potassium hydroxide are treated in the same manner as described in Example 8. 0.8 g of 2-[2-(4-chlorophenyl)-5-n-pentyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.2%.
Reaction SMILES: FC1(C(O)=O)CC[C:5](=[CH:8][C:9]2[C:10]([CH3:50])([CH3:49])[C@H:11]3[C@:24]([CH3:27])([CH2:25][CH:26]=2)[C@@H:23]2[C@:14]([CH3:48])([C@@:15]4([CH3:47])[C@H:20]([CH2:21][CH2:22]2)[C@H:19]2[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:18]2([NH:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:39][CH2:38]2)[CH2:17][CH2:16]4)[CH2:13][CH2:12]3)CC1.[C:54]([O:60][CH3:61])(=[O:59])/[CH:55]=[CH:56]/C=C>>[CH3:47][C@:15]12[C@@:14]3([CH3:48])[C@@H:23]([C@:24]4([CH3:27])[C@@H:11]([CH2:12][CH2:13]3)[C:10]([CH3:50])([CH3:49])[C:9]([CH:8]=[CH:5][CH:56]=[CH:55][C:54]([O:60][CH3:61])=[O:59])=[CH:26][CH2:25]4)[CH2:22][CH2:21][C@@H:20]1[C@H:19]1[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:18]1([NH:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][CH:40]([S:43]([CH3:46])(=[O:44])=[O:45])[CH2:41][CH2:42]1)[CH2:17][CH2:16]2
Reactant: C=C/C=C/C(=O)OC
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in step 1 of the preparation of 1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylic acid using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate and (E)-methyl penta-2,4-dienoate as the reactants. The crude material was used in next step without purification. MS: m/e 709.5 (M+H)+, 2.55 min (method 5).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylate (4.3 g, 11.8 mmol) in methanol:THF (4:1, 100 ml) 10 N sodium hydroxide (15 ml) was added at room temperature. It was stirred for 16 hrs and evaporated to dryness in vacuo. The residue was dissolved in 100 mL water, pH adjusted to 7 with 5N hydrochloric, acid solution. It was extracted with chloroform/methanol (3:1), washed with water, dried and concentrated to give 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylic acid. Yield 4.0 g (98%); White solid, mp. 112-4° C. Electrospray Mass Spec 349 (M−H)−.
Reaction SMILES: C(O)C.[OH-].[Na+].C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]4[O:35][CH2:36][O:37][C:31]=4[CH:30]=3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:38])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])C>O>[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]4[O:35][CH2:36][O:37][C:31]=4[CH:30]=3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:38])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Yield: 97.9 %

Procedure:
10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxide were added to 1 g of 2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 20 minutes, concentrated under a reduced pressure and neutralized with 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 920 mg of the title compound.
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:37])[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.C1COCC1.CO>>[CH3:37][C:22]1([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1
Reactant: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCN(S(=O)(=O)c2cccnc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCN(S(=O)(=O)c2cccnc2)CC1
Reaction time: 64 h
Yield: 27 %

Procedure:
A mixture of 6-benzenesulfonyl-1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (74.0 mg, 0.14 mmol) in THF/methanol containing aqueous sodium hydroxide (0.53 mmol) was stirred for 64 hr. The solvent was evaporated under vacuum to a small volume, the residue dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum and the resulting residue purified by column chromatography on silica gel (gradient: 0 to 5% [2M NH3 in methanol] in DCM) to afford 15.0 mg (27%) of 1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method A, ESI): RT=3.42 min, m+H=398.2; 1H NMR (400 MHz, DMSO): δ 12.45 (s, 1H), 8.99 (s, 1H), 8.86 (m, 2H), 8.13 (ddd, 1H), 7.65 (m, 2H), 6.91 (dd, 1H), 3.49 (m, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 2.31 (m, 2H), 1.75 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[B:9]([OH:14])[OH:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccncc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirring solution of 3-bromo-4-methylpyridine (5.9 g, 34.3 mmol) in toluene (30 mL) and THF (7.5 mL) was added triisopropyl borate (10.3 mL, 44.6 mmol). The resulting mixture was cooled to −78° C. under a nitrogen atmosphere followed by the addition of n-butyllithium (17.83 mL, 44.6 mmol, 2.5 M in hexanes) over a period of 1 hour. The reaction mixture was allowed to stir for an additional 30 min and then the dry ice bath was removed. The reaction mixture was quenched by the addition of 2N HCl (60 mL). Upon reaching room temperature, the resulting yellow solution was transferred to a 500 mL separatory funnel and the layers were separated. The aqueous layer was neutralized to pH 7.0 with sodium hydroxide and then extracted with THF (3×60 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid material was vigorously stirred with acetonitrile and filtered to yield Intermediate 1A (2.2 g, 16.06 mmol, 48.8% yield) as an off-white solid. MS (ES): m/z=138.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.45 (1 H, s), 8.33 (1 H, d, J=5.77 Hz), 7.50 (1 H, d, J=5.27 Hz), 2.62 (3 H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](=O)[CH2:29]Br>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:29]=[C:28]([C:27]3[CH:32]=[CH:33][CH:34]=[C:25]([C:24]([F:23])([F:35])[F:36])[CH:26]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3cccc(C(F)(F)F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 18 %

Procedure:
2′-Nitro-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (53 mg, 18%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-(trifluoromethyl)phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H), 8.53-8.58 (m, 2H), 8.38 (s, 2H), 8.27-8.31 (m, 1H), 8.13-8.18 (m, 1H), 7.63-7.82 (m, 4H), 7.41-7.49 (m, 2H).