Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][N:26]=[CH:27]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][N:26]=[CH:27]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cccc2cnccc12
Product: O=C(Nc1cccc2cnccc12)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 5-aminoisoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (23.0 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.85 (1H, br), 9.36 (1H, s), 9.00 (2H, s), 8.83 (1H, m), 8.54 (1H, m), 8.08 (1H, m), 7.84 (2H, m), 7.71 (1H, m). MS m/z: 475.17, 477.12 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[CH:10]1(CO)[CH2:12][CH2:11]1>>[C:1]([O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=[O:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6]
Reactant: CC/C=C/CC(=O)OC
Reactant: OCC1CC1
Product: CC/C=C/CC(=O)OCC1CC1

Procedure:
Prepared from (E)-methyl hex-3-enoate and cyclopropanemethanol according to the ester preparation method B described above.
Reaction SMILES: [H-].[Na+].[C:3](=O)([O:7]CC)[O:4][CH2:5][CH3:6].[C:11]([C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])(=[O:13])[CH3:12].Cl>C(OCC)(=O)C.C(O)C.C(OCC)C>[CH2:5]([O:4][C:3]([CH2:12][C:11]([C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13])=[O:7])[CH3:6]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(C)=O)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(CC(CC)C(=O)OCC)ccc1OC
Yield: 58.2 %

Procedure:
To anhydrous diethyl ether (20 mL), sodium hydride (60% oil dispersion, 1.27 g, 52.9 mmol) was added under stirring and cooling with ice. Successively, after diethyl carbonate (2.25 g, 19.0 mmol) was added, the mixture was stirred for 30 minutes at room temperature. Following this, a mixture of ethyl 3-(3-acetyl-4-methoxyphenyl)-2-ethylpropanoate (3.53 g, 12.7 mmol), anhydrous diethyl ether (10 mL) and absolute ethanol (0.24 mL) was added dropwise over 20 minutes, and then the mixture was refluxed for 6 hours. After cooling, the reaction mixture was added slowly to a mixed solution of 2 mol/L hydrochloric acid (45 mL) with ethyl acetate (80 mL) under stirring and cooling with ice. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=9:1 v/v) to afford 2.59 g (58%) of the title compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([CH:21]1[CH2:23][CH2:22]1)[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH:21]1([N:10]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]2[CH:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:23][CH2:22]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (85 mg, 0.19 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (10 mL) and then 1.2 ml of LiOH 1N was added to it. After 60 min of stirring at room temperature, solvant was removed and then partitioned between 15 ml of H2O, 4 ml of KHSO4 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 22 mg (27%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): rotamer: 7.75 ppm (m, 2H, Haro); 7.68 ppm (m, Haro, minor rotamer); 7.62-7.55 ppm (m, 2H, Haro); 7.52 ppm (m, Haro, minor rotamer); 7.48-7.27 ppm (m, 5H, Haro); 3.14 ppm (m, minor rotamer); 3.04 ppm (m, 1H, major rotamer); 0.87-0.42 ppm (m, 4H). The following compounds were prepared in a similar manner: Compound #403, Compound #404
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O1CCOCC1.[I-].[K+]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: OCCCBr
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A suspension of 4-phenylpiperidine (3.00 g, 18.6 mmol, 1.00 equiv), 3-bromopropan-1-ol (2.12 mL, 22.3 mmol, 1.20 equiv), potassium carbonate (12.8 g, 93.0 mmol, 5.00 equiv), and potassium iodide (124 mg, 0.74 mmol, 0.04 equiv) in n-butanol (50 mL) and 1,4-dioxane (50 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×100 mL). The combined organic solutions were dried over MgSo4 and concentrated. The residue was crystallized from ethyl acetate to give 3.36 g (82%) of tan solid, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2ccc(O)cc12
Product: CC(=O)Nc1cccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
100 g (0.55 mol) of 8-aminonaphth-2-ol are poured into 125 ml (135.25 g or 1.325 mol) of acetic anhydride cooled in an ice bath, and the mixture is stirred under cold conditions for 1 h. The mixture obtained is poured into 375 ml of ice-water and stirred for several hours. The violet solid is collected by filtration, washed three times with 30 ml of diethyl ether and dried under reduced pressure. 108.8 g of a product melting point: 193°-195° C. are obtained which is used as it is in the following step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Li]>O1CCCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:15]2[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:28])[CH3:2])=[CH:9][CH:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:26][CH:25]=1
Reactant: [Li]C
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
To a 2-(4-Acetyl-phenyl)-N-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-acetamide (0.270 grams, 0.741 mmole) in tetrahydrofuran (15 ml) at −78° C. 1.0 M methyl lithium in tetrahydrofuran (1.63 ml, 1.63 mmole) was added via syringe and stirred at −78° C. for 75 minutes. Another 0.8 ml methyl lithium was added and the mixture was warmed to 0° C. for 10 minutes and cooled to −78° C. The mixture was quenched with water, allowed to warm to room temperature and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to a white solid which was purified by chromatography on silica eluting with 2% methanol/methylene chloride to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.032 g). M.P. 135-137° C.; Anal. calcd. for C22H21N2O3F: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.46; H, 5.92; N, 7.73.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C[O-].[Na+]>CO>[Cl:13][C:14]1[C:15]([F:22])=[C:16](/[CH:17]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[O:11][CH3:12])\[C:7]#[N:8])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(Cl)ccc1CC#N
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Yield: 65.2 %

Procedure:
Step C In a manner similar to the method described in Example 1b, 4-chloro-2-methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50° C. for 2 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)-acrylonitrile as a white powder (2.1 g, 65%).
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.S([O-])([O-])=O.[Na+].[Na+].[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:22][C:21]([OH:25])([CH3:24])[CH3:23])[C:6]([CH3:14])([CH3:13])[CH2:5]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C

Procedure:
A solution of 50% aqueous hydrogen peroxide is added to a mixture of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed with aqueous sodium sulfite. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford a sample of 4-hydroxy-1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 31.2 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester (Intermediate 50, 0.195 g, 0.53 mmol), triethyl amine (2 mL), copper(I)iodide (0.040 g, 0.2 mmol), trimethylsilyl acetylene (0.3 mL, 2.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.13 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.064 g, 32%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[CH:15](OC)(OC)OC.B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[CH3:15][O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: COC(OC)OC
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1C2CCC(C)(OC)C1CCC2(C)C
Yield: 85.4 %

Procedure:
120 g (0.563 mol) of dihydro-α-ionone, 65 g (0.612 mol) of trimethyl orthoformate and 200 ml of methylene chloride are treated dropwise while stirring during 15 minutes with a solution of 8 g of boron trifluoride etherate in 60 ml of methylene chloride and the mixture is subsequently held under reflux for 105 minutes. The reaction mixture is cooled and poured into 500 ml of a 5% aqueous potassium hydroxide solution. After the addition of 500 ml of methylene chloride and vigorous intermixing the phases are separated, the organic phase is washed with water and the solvent is distilled off. The residue (197.1 g) is fractionated in a vacuum over a 15 cm Widmer column. There are obtained 100.2 g of product of b.p. 44°-47°/0.06-0.07 mbar (yield 87% of theory based on pure dihydro-α-ionone) as a colorless liquid which contains 72.3% of exo isomer and 20.1% of endo isomer of the desired bicyclo-nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:35][C:36]1([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:39]1[CH2:40][CH2:41][C:36]([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)([F:35])[CH2:37][CH2:38]1)=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1Cl
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(F)(c3ccc(C#N)cc3)CC2)cc1-c1[nH]ncc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 5, except 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 13.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 423 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].Cl.[CH:14]1([C:18](=[NH:20])[NH2:19])[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[CH:14]1([C:18]2[N:19]=[C:5]([CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:4]=[CH:3][N:20]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: N=C(N)C1CCC1
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(OC)c1ccnc(C2CCC2)n1
Yield: 12.5 %

Procedure:
To a solution of 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (2.0 g, 11.5 mmol) in ethanol was added cyclobutanecarboximidamide hydrochloride (3.0 g, 22.3 mmol) and triethylamine (2.33 g, 23.0 mmol) under nitrogen at room temperature. The reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography to afford 2-cyclobutyl-4-(dimethoxymethyl)pyrimidine as a colorless liquid (300 mg, 12%). MS (ES+APCI) (M+H) 209.2; LCMS retention time: 3.257 minutes (Method J).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].F[C:9]1[C:10]([CH3:29])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16]([C:19]1[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=1)[CH:15]=[CH:14][CH:13]=2.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>CN(C=O)C.CS(C)=O>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:29][C:10]1[C:9]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:27][C:26]2[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=2[CH:20]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a slurry of NaH (60% in mineral oil; 0.064 g, 1.606 mmol) in 1 mL DMF at 0° C. was added methanesulfonamide (TCI America, Portland, Oreg.; 0.153 g, 1.606 mmol) in portions. The ice/water bath was removed and the reaction warmed to RT. 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 0.068 g, 0.229 mmol) was added. After 30 min, the reaction was cooled to 0° C., TFA (0.177 ml, 2.295 mmol) was added (dropwise via syringe), and 1 mL DMSO was added. The solution was filtered through a 0.45 micron syringe filter and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo, to give N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)methanesulfonamide 2,2,2-trifluoroacetate (0.020 g, 0.041 mmol, 18% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br. s.), 10.98 (1H, br. s), 8.11 (1H, d, J=7.6 Hz), 7.74 (1H, dt, J=8.0, 0.8 Hz), 7.54-7.66 (1H, m), 7.05-7.15 (1H, m), 7.01 (1H, br. s.), 3.44 (2H, t, J=7.0 Hz), 3.39 (3H, s), 2.91 (2H, t, J=6.9 Hz), 2.68 (3H, s). m/z (ESI, +ve) 372.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[N:27]=[N:26]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:34])[N:27]=[N:26]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride (50 mg, 0.137 mmol) and 4-(1H-1,2,3-triazol-4-yl)butanoic acid (25.6 mg, 0.165 mmol) were suspended in EtOAc (5 mL) and triethylamine (0.067 mL, 0.481 mmol) was added. After 5 mins at RT, T3P, 50% in EtOAC (0.164 mL, 0.275 mmol) was added and the mixture allowed to stir at RT for 20 hours. EtOAc (30 ml) was added and the mixture washed with a 10% solution of citric acid and a saturated solution of brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. Purification via silica chromatography eluting with 0-10% MeOH/DCM gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[C@@H:12]([CH3:15])[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: C[C@H](N)CO
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](C)CO)cc1

Procedure:
Into a 10000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed 4-methoxybenzaldehyde (500 g, 3.67 mol), (S)-2-aminopropan-1-ol (276 g, 3.68 mol), 4-methylbenzenesulfonic acid (31.7 g, 184.09 mmol) and toluene (5000 mL). The resulting solution was maintained at reflux overnight. The reaction mixture was cooled and concentrated under vacuum. The residue was washed with 3000 mL of hexane and filtered to afford the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=3)[CH2:38][CH2:37]2)=[O:10])[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to yield the title compound as a colorless solid. MS (m/e): 491.2 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].NN.O.CCOCC>C(O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Yield: 86.2 %

Procedure:
A solution of taxol (0.026 g, 0.030 mmol) and 98% hydrazine (0.035 g, 1.1 mmol) in 95% ethanol (1.0 mL) is stirred at room temperature for 2 hr. The solution is poured into water and ether, the mixture is shaken well, and the layers separated. The aqueous layer is extracted with additional ether. The combined ether extracts are dried over Na2SO4, filtered and concentrated, giving 0.021 g of the title compound: 1H NMR spectrum in CDCl3 is identical to the spectrum reported for 10-deacetyltaxol (Ringel, I.; Horwitz, S. B. J. Pharmacol. Exp. Ther. 1987, 242, 692) and is identical to the spectrum of an authentic sample.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:7]=1)=[O:5].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:1][C:2]1[C:3]([C:4]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:7]=2)=[O:5])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3N)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)c1nc(N2CCNCC2)cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 4-(1-(2-aminonicotinoyl)isoquinolin-3-yl)piperazine-1-carboxylate (6 mg, 0.014 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.5 ml). The solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and triturated twice with ether and dried to leave the compound as an orange solid (2 mg, 26% yield).