Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:21][CH:22]([CH3:24])[CH3:23])=[N:12][C:13]([CH3:20])=[CH:14][C:15]=1[S:16][CH:17]([CH3:19])[CH3:18])=[O:8].[SH:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:21][CH:22]([CH3:24])[CH3:23])=[N:12][C:13]([CH3:20])=[CH:14][C:15]=1[S:16][CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(SC(C)C)c(NC(=O)CCCCCBr)c(SC(C)C)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC(C)C)c(NC(=O)CCCCCSc2nc3ccccc3o2)c(SC(C)C)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
The reaction and the treatment were conducted in the same manner as in Example 35 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (4 ml) solution of this amide (100 mg, 0.23 mmol) and 2-mercaptobenzoxazole (35 mg, 0.23 mmol) were added potassium carbonate (38 mg, 0.28 mmol) and 18-crown-6 (6 mg, 0.02 mmol), and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:1) to obtain 92 mg (yield 79%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C@H:14]([OH:20])[CH2:15]1)[CH3:7].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C:14](=[O:20])[CH2:15]1)[CH3:7]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Yield: 158.9 %

Procedure:
To a solution of 5.0 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3β-ol (E. Yoshii et al., Chem. Pharm. Bull., 1976, 24, 3216) in 70 ml of methylene chloride, 2.5 g of 4-methylmorpholine N-oxide, 0.25 g of tetrapropylammonium perruthenate and 4.0 g of powdered 4A molecular sieves were added at room temperature. After 4 hrs the solvent was evaporated to dryness under reduced pressure and the crude product purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 70/30 as eluant to give 7.9 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CCCCCC1(CCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCC(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 89 g (0.352 mol) of 2-(4-chlorophenylethyl)-2-pentyl-oxirane, 26.5 g (0.384 mol) of 1,2,4-triazole, 3.5 g (0.0875 mol) of sodium hydroxide, 1.2 ml of water and a spatula tipful of α,α'-azoisobutyronitrile in 175 ml of N-methylpyrrolidone is heated at 120° C. for 4 hours. After this the mixture is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in ethyl acetate and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=1:1). In this manner 53.2 g (47.0% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl-methyl)-3-octanol are obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[NH:6][C:5]2=O.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CNC2
Temperature: 0 °C

Procedure:
To a solution of 5-bromo-1H-isoindole-1,3(2H)-dione (4 mmol) in THF (10 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0° C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0° C. The reaction mixture was quenched by the slow addition of MeOH (10 mL) and then 2N HCl (10 mL). The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water (10 mL) was added to the residue. Remaining starting material was removed by extraction with DCM. To the aqueous solution was added 4N NaOH until pH>9. The solution was extracted with DCM. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 5-bromoisoindoline, which was dissolved in THF (20 mL). To this solution was added potassium carbonate (8 mmol) in water (1 mL), and BOC2O. The reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (2.5 mmol, 60%).
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:21])[N:9]([CH2:11][C@@H:12]3[CH2:14][C@H:13]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[N:7]3[C:8](=[O:21])[N:9]([CH2:11][C@@H:12]4[CH2:14][C@H:13]4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: O=c1n(C[C@@H]2C[C@H]2c2ccccn2)nc2cccc(Br)n12
Reactant: C1COCCN1
Product: O=c1n(C[C@@H]2C[C@H]2c2ccccn2)nc2cccc(N3CCOCC3)n12
Temperature: 120 °C
Yield: 62.3 %

Procedure:
In a 1 mL microwave vial were placed 13-5 (22 mg, 0.064 mmol) and morpholine (1.00 g, 1.00 mL, 11.5 mmol). The vial was sealed and heated at 120° C. under microwave irradiation for 10 min. The reaction mixture was directly purified by reversed phase chromatography to give 14.0 mg (62%) of 13-6. 1H NMR δ (500 MHz, DMSO-d6): δ 8.44 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.01 (dd, J=9.3, 7.0 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 5.75 (d, J=7.0 Hz, 1H), 3.90 (dd, J=6.9, 3.9 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.12-3.03 (m, 4H), 2.25 (dt, J=8.5, 4.6 Hz, 1H), 1.84 (s, 1H), 1.23-1.15 (m, 2H). HRMS (ES) 352.1761 (M+H) found, 352.1768 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.[NH2:20][C@@H:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23]>>[OH:23][CH2:22][C@@H:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@@H:13]3[CH2:16][C@@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-3-methylbutan-1-ol. LCMS m/z=361.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.43-0.48 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.20-1.27 (m, 1H), 1.98-1.20 (m, 1H), 2.20-2.27 (m, 1H), 2.74-2.79 (m, 1H), 2.80-2.86 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 2.99 (dd, J=16.5, 6.2 Hz, 1H), 3.74-3.90 (m, 3H), 7.02 (d, J=8.2 Hz, 1H), 7.20 (dd, J=5.3, 1.9 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][N:8](C)[CH2:9][CH:10]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1>C1C=CC=CC=1>[CH3:7][N:8]([CH2:9][CH:10]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)[C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CN(C)CC1C=Cc2cc([N+](=O)[O-])ccc2CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N(C)CC1C=Cc2cc([N+](=O)[O-])ccc2CC1

Procedure:
50 ml of ethyl chloroformate were added dropwise over 5 minutes at 20° C. under nitrogen to a mixture of 7.9 g of N,N-dimethyl-2-nitro-6,7-dihydro [5H] benzocycloheptene-7-methanamine in 50 ml of benzene and the mixture was refluxed for 2 hours and then evaporated to dryness. The residue was extracted with ether and the ether phase was washed with N hydrochloric acid solution and then with water, was dried and distilled to dryness under reduced pressure to obtain 9 g of ethyl methyl-[(2-nitro-6,7-dihydro [5H] benzocycloheptene-7-yl) methyl]-carbamate in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (6 g; 21.2 mmol; 1 eq.), o-tolylboronic acid (3.17 g; 23.3 mmol; 1.1 eq.), potassium carbonate (14.65 g; 106 mmol; 5 eq.) and Pd(PPh3)4 (2.45 g; 2.12 mmol; 0.1 eq.) in toluene (30 mL) and water (30 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of CELITE which was further washed with toluene (20 mL). The filtrate was concentrated in vacuo, the residue taken up in ethyl acetate (200 mL) and washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (5 g, 80%) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[O:27]CC1C=CC=CC=1)=[O:5])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1O
Reaction time: 7 h
Yield: 101.7 %

Procedure:
A mixture of 7-benzyloxy-2-phenyl-4-piperidin-1-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (47 mg, 0.10 mmole) and 10% Pd/C (20 mg) in a mixture of ethanol and ethyl acetate (3 ml, 1:5) was hydrogenated at room temperature for 7 h before it was filtered, washed with ethyl acetate and concentrated in vacuo to give the title compound as a yellow oil (39 mg). MS: (+) m/z 384.34 (M+1), MS: (−) m/z 382.37 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].O.[OH-].[Na+:20].[S:21]([O-:24])([O-:23])=[O:22].[Na+].[Na+]>C(O)CC>[Na+:20].[S:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16])([OH:24])(=[O:23])=[O:22]
Reactant: O=S([O-])[O-]
Reactant: O=C(O)CCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: O=C([O-])CCCCCCCCCCCCCS(=O)(=O)O

Procedure:
Above prepared 14-bromo-tetradecanoic acid (8.34 g, 26.0 mmol) was dissolved in n-propanol (10 mL), water (25 mL) and 1M aqueous solution of sodium hydroxide (32 mL) and sodium sulfite (5.00 g, 39.7 mmol) was added. Reaction mixture was heated to reflux for 22 hrs. After cooling down white precipitate was filtered off. Conc. hydrochloric acid was added to give acidic pH and precipitate was centrifuged and decantated two times with water (2×50 ml). After lyophilization 14-sulfo-tetradecanoic acid sodium salt was obtained as a white solid.
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:9]4[C:4]=3[CH2:5][CH2:6][CH2:7][CH2:8]4)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1[nH]nc2c1CCCC2
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1CCCC2
Yield: 65.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by flash chromatography. Yield 65.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 1.55-1.71 (m, 4H), 2.53-2.60 (m, 4H), 4.27 (dd, 1H), 4.35 (dd, 1H), 4.38-3.46 (m, 1H), 7.00 (d, 1H), 7.83-7.87 (m, 2H), 7.90-7.97 (m, 2H), 12.66 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].I>>[C:18]([C:5]1[CH:6]=[C:2]([CH3:1])[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[C:4]=1[CH3:7])(=[O:20])[CH3:19]
Reactant: CCOc1ccc(-n2c(C)ccc2C)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: I
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)c(C)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (2.29 g, 10 mmol), acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 6.99 (d, 1H), 6.85 (d, 1H), 6.79 (dd, 1H), 6.32 (s, 1H), 4.06 (q, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.44 (t, 3H); MS (ESI) 272 (M +H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:34][CH:35]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(N)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 44.5 %

Procedure:
A solution of 0.38 g of diethyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 4.6 mL of 0.5N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Acetic acid (5 mL) was added, and the resulting white precipitate collected by filtration. The filter cake was washed well with water, methanol, and ether and was dried under reduced pressure to yield 0.15 g (44%) of the title compound, which can be alternatively names as 5,10-dideazaaminopterin; mp >250° C.; NMR (TFA-d1) delta 2.2-2.7 (m, 2H), 2.28; 2.7-2.95 (m, 2H), 5.0-5.2 (m, 1H), 7.35 and 7.85 (AB q, 4H, J=9 Hz), 8.7 (s, 1H), 9.1 (s, 1H).
Reaction SMILES: S([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:11][C@@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1
Reactant: OCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
Using the procedure of Davis, J. Chem. Soc. 178-181 (1962), cholesterol tosylate and 1,6-hexanediol were condensed in refluxing dioxane to provide 52% yield of the title ether as colorless plates from hexane, m.p. 79.5°-81° C.; [α]D25 -28.1°±0.5° C.; IR 3500-3200 (OH), 1100 and 1080 cm-1 (ether); NMR (CDCL3): δ2.8-3.3 (br, 1H, H-1), 3.3-3.75 (2t,4H), 5.4 m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:20]=[C:19]3[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=1)=[CH:8][C:7]([NH:29]C(=O)OC(C)(C)C)=[CH:6][CH:5]=2.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:29][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])/[C:10]/2=[CH:11]/[C:12]1[CH:20]=[C:19]2[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Reaction time: 1 h

Procedure:
tert-Butyl(E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)-methyl-ene)indolin-5-ylcarbamate (13 mg, 0.027 mmol) was dissolved into CH2Cl2 (1.0 mL) and then trifluoroacetic acid (0.1 mL) was added and the reaction stirred for 1 hour. The solvent was removed and the residue titurated with ether/EtOAc to give after drying 4.6 mg, 29% of the title compound as an orange powder. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J=5.8 Hz, 2H), 8.31 (d, J=8.7 Hz, 1H), 8.21-8.12 (m, 3H), 7.97 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=16.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H); MS ESI 380.1 [M+H]+, calcd for [C23H17N5O+H]+ 380.15.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C@@H:6]([N:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N+:20]=[N-:21])=[CH:15][CH:14]=1.CO.Cl>C1(C)C=CC=CC=1>[N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]([OH:36])=[O:4])=[O:22])=[CH:18][CH:17]=1)=[N+:20]=[N-:21]
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1)n1c2ccccc2c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 60 °C
Yield: 87.5 %

Procedure:
Methanolic KOH (0.075 g, 1.32 mmol) was added to a stirred solution of (S)-6-(4-azido-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 13 (0.200 g, 0.44 mmol) in a mixture (2:1) of methanol (6 mL) and toluene (3 mL) at room temperature. The reaction mixture was refluxed at 60° C. for 3.5 h. After cooling to 0° C., 1M HCl solution was added drop-wise for the acidification up to pH=3-4 and extracted with EtOAc (30 mL×2). The combined organic extract was washed with water (20 mL×2) and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure provided (S)-6-(4-azido-benzoylamino)-2-carbazol-9-yl-hexanoic acid 14 (0.170 g, 88%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[O:17])=[N:4][NH:3]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[N:18]1([C:16]([C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:2](=[O:1])[NH:3][N:4]=2)=[O:17])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 55A (480 mg, 1.76 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 353 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.68-1.74 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.19-3.29 (m, 3H), 3.67-3.97 (m, 5H), 4.04 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.36 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (t, J=7.48 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:16]=[CH:15]4)[CH:11]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)CBr
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (example 60) (0.35 g) in dry DMF (5 ml) was treated with sodium hydride (60% oil dispersion, 0.08 g) at room temp under nitrogen then stirred for 20 min. A solution of methyl bromoacetate (0.2 ml) in dry DMF (0.5 ml) was added and stirring was continued for 1 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (×2). The organic extracts were washed with water (×3) and brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified using a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with cyclohexane:ethyl acetate (4:1 to 1:1) to give the title compound as a yellow foam (0.26 g).