Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[OH2:15]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][OH:15])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O
Reactant: C=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(CCO)cc([N+](=O)[O-])c1
Yield: 25 %

Procedure:
3,5-Dinitrostyrene (0.28 g, 1.43 mmol) was dissolved in acetonitrile (150 ml) and water (300 ml) was added. The mixture was poured into a photolysis apparatus and irradiated with an UV-lamp (HPK 125, Phillips) for 3 h. The organic solvent was evaporated and the aqueous phase extracted with methylene chloride (2×100 ml). The solvent was evaporated and the residue was purified by flash chromatography o n a column of silica using heptane/ethyl acetate (1/1) as eluent. Evaporation of solvent gave 76 mg (25%) of a crystalline product.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][P:4]([C:9]([C:35]#[N:36])([CH3:37])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reaction time: 0.33 h
Yield: 14.2 %

Procedure:
To a solution of {1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodium bis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz, 2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s, 3H), 2.17 (s, 3H), 2.23 (m, 1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H), 5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.26 ppm; MS (m/z) 574 [M+Na]+.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:28])[CH3:27])[N:5]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:20])(=[O:34])=[O:19])=[CH:14][CH:13]=2)[C:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:27])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(S(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 28.7 %

Procedure:
2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methysulfinyl)phenyl]-5-(pent-1-enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0° C. under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic acid (“mCPBA”) (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0° C. and quenched with the addition of a saturated aqueous solution of NaHO3 (3 mL). The reaction mixture was further diluted through the addition of water (5 mL) and then extracted with methylene chloride (3×10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (31.1 mg, 29%). 1H NMR (300 MHz, CDCl3): δ 0.69 and 0.79 (t, J=7.2 Hz, 3 H), 1.08-1.37 (m, 14 H), 1.45 (t, J=4.2 Hz, 1 H), 1.86-1.93 (m, 2 H), 3.10 and 3.11 (s, 3 H), 3.2-3.50 (m, 2 H), 4.34-4.36 (m, 2 H), 5.20-5.50 (m, 1 H), 5.93-6.00 (m, 1 H), 7.41 (d, J=8.4 Hz, 2 H), 7.96 (d, J=8.4 Hz, 2 H). Anal. calc. for C24H33NO3S: C, 69.28; H, 7.91; N, 3.18; S, 7.50. Found: C, 69.36; H, 8.00; N, 3.37; S, 7.71.
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([CH:35]=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([CH:35]([C:2]2[C:3]([O:14][CH3:15])=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[OH:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1c(Br)cccc1-c1ccccc1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cccc1C(O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2 (0.91 g, 3.46 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (1.38 mL, 3.46 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr when a solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (1.0 g, 3.46 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min, then for 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude 3 was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19]([C:18]3[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:17]=3[O:16][CH:13]([CH3:15])[CH3:14])=[O:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1Cl)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(Cl)c(Cl)c2C1

Procedure:
Prepared in analogy to example 1.1 from 7,8-dichloro-1,2,3,4-tetrahydro-isoquinoline (CA [61563-24-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH2:30]>O1CCOCC1>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:29][CH2:28][OH:27])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: NCCO
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(NCCO)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
20.3 gm (0.05 mol) of 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 188°-190° C.) were refluxed for about 45 minutes with 8 gm (0.13 mol) of 2-hydroxyethyl-amine in 400 ml of dioxane. Most of the solvent was distilled off in vacuo, and the residue was taken up in about 500 ml of water. The reaction product, which precipitated after standing for a little while, was filtered off, washed with water and dried at about 70° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (73 mg, 0.2 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.3 mmole, 1.5 eq) and NaH (1.2 mmol, 6 eq) were dissolved in THF (3 mL) and then stirred at room temperature overnight. THF solvent was removed in vacuo and the oily solid residue was re-dissolved in water and extracted with ethyl acetate provided compound A46 as greenish yellow oil (111 mg, 90%). 1H NMR (CDCl3, 400MHz) δ 1.48 (s, 9H), 1.88-1.84 (m, 2H), 2.09 (m, 2H), 3.35-3.29 (m, 2H), 3.87-3.80 (m, 2H), 5.62-5.59 (m, 1H), 7.81 (s, 1H), 8.26 (s, 1H), 8.69 (s, 1H), 8.96 (s, 2H). Exact mass calculated for C23H23F6N5O3 531.17, found 532.2 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]([O:26][C:20]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(NC(=O)c1cccc(C)c1OC(C)C)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5-methoxy-indan-2-carboxylic acid ethyl ester (92) (410 mg, 1 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (93) as white solid (400 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([C:19]([NH2:22])([CH3:21])[CH3:20])[CH2:15]1)=[N:9][C:8]([O:23][CH3:24])=[CH:7][CH:6]=2.CCO.[O:28]=[C:29]1[CH2:34][S:33][C:32]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[N:38][C:31]=2[NH:30]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([C:19]([NH:22][CH2:39][C:37]3[CH:36]=[CH:35][C:32]4[S:33][CH2:34][C:29](=[O:28])[NH:30][C:31]=4[N:38]=3)([CH3:21])[CH3:20])[CH2:15]1)=[N:9][C:8]([O:23][CH3:24])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@@H](C(C)(C)N)C3)c2n1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](C(C)(C)NCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 12 h
Yield: 36.8 %

Procedure:
To a solution of the hydrochloride salt of 2-((3R)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2-propanamine (100 mg, 0.25 mmol) in DCM:EtOH (6 mL, 1:1) were added NaHCO (210 mg, 2.5 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (47 mg, 0.25 mmol). After 12 h at 25° C., NaBH (10 mg, 0.28 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM and water. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 0-1% MeOH in DCM (1% NH OH)) yielding the title compound (47 mg, 37%) as an off-white solid: LC/MS (ES) m/e 512 (M+H)+; H NMR (CDCl, 400 Hz) δ 8.59 (s, 1H), 8.17 (d, J=9.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.07 (s, 3H), 3.76 (s, 2H), 3.39-3.43 (m, 4H), 2.76-2.96 (m, 4H), 2.55-2.64 (m, 2H), 2.39-2.44 (m, 1H), 1.85-1.88 (m, 1H), 1.72-1.78 (m, 1H), 1.09 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 90.6 %

Procedure:
To a solution of 2-chloro-5-nitrobenzoic acid (3.0 g, 0.14 mol) in methanol (500 mL) was added sodium methoxide (28.1 g, 0.520 mol). The reaction mass was refluxed for 15 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with water and acidified with dilute HCl to obtain solid which was filtered off to afford 25.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 7.36 (d, J=9.3 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 13.32 (br s, 1H)); MS (m/z): 198.25 (M+H)+.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[C:5]([Cl:22])=[CH:6][C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1>O1CCOCC1.O.[Cu](I)I>[Cl:22][C:5]1[C:4]([I:1])=[CH:9][N:8]=[C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=1
Reactant: [I-]
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Agent: I[Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 110 °C
Reaction time: 120 h

Procedure:
Under a nitrogen atmosphere 1.3 g (8.4 mmol) sodium iodide, 80 mg (0.42 mmol) copper iodide and 90 μL (0.84 mmol) N,N-dimethylene-ethylenediamine were added to 1.5 g (4.2 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 15 mL 1,4-dioxane and the mixture was stirred for 5 days at 110° C. The reaction mixture was diluted with water, the precipitate formed was suction filtered and dried.
Reaction SMILES: C(OC([NH:8][N:9]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[C:10]([N:9]([C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 112.7 %

Procedure:
To a mechanically stirred solution of N-t-butoxycarbonyl-N'-benzoyl-N'-t-butylhydrazine (52 g, 0.18 mol) in methanol (100 ml) was added concentrated hydrochloric acid (35 ml). The resulting mixture was stirred at room temperature for 4 days and then neutralized with saturated aqueous sodium bicarbonate. The resulting white solid was filtered, washed with water and dried under vacuum to afford N'-t-butyl-N'-benzoylhydrazine (39 g): m.p. 124°-125° C.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:33]2[CH:42]=[CH:41][CH:40]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[CH:34]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[C:12]=2[Cl:21])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 18 h
Yield: 26 %

Procedure:
A solution of N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine (186 mg, 0.42 mmole) and methyl 3-hydroxybenzoate (63 mg, 0.42 mmole) in 15 mL of THF was treated with Ph3P (110 mg, 0.42 mmole) and diisopropylazodicarboxylate (93 mg, 0.46 mmole). The reaction was stirred for 18 hours, diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent evaporated. The residue was chromatographed on a silica gel column, and elution with 10% EtOAc in hexane gave the titled product, 64 mg (26% yield). MS (ESI) 583 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]([CH2:21]Br)=O)=[O:18]>CCO.CCOC(C)=O>[CH2:15]([O:16][C:17]([C:19]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[S:7][CH:21]=1)=[O:18])[CH3:14]
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc(C)cc2[N+](=O)[O-])n1
Temperature: 70 °C

Procedure:
4-Methyl-2-nitro-thio benzamide (60 mgs, 0.30 mmol, prepared as described in compound 5, Step 2, was stirred in 1 mL absolute EtOH at room temperature under N2. Ethyl bromo pyruvate (65 mgs, 0.33 mmol) was added, and the resulting solution was heated to 70° C. for 3 h. The reaction was diluted to 30 mL with EtOAc and washed with saturated NaHCO3, and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to a yellow oil, which was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: COc1cccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)c1

Procedure:
from 9-(3-methoxyphenyl)-9H-fluoren-9-ol (Example 3f) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11]
Reactant: O=C1CCc2c(Br)cccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1-indanone (1.0 g) in a mixture of ethanol (6 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (0.09 g) at an ice temperature. The reaction mixture was stirred at the same temperature overnight and poured into dilute hydrochloric acid, and the aqueous layer was saturated with saline and extracted with ether. The organic layer was washed with a saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (1.02 g) thus obtained was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:71][C:72]1[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][CH:73]=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:76][C:75]2[CH:77]=[CH:78][C:72]([F:71])=[CH:73][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:39]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.1 mg, 58%). LC-MS m/z 633 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([C:6]1[CH:11]=C[CH:9]=[CH:8][N:7]=1)[OH:5].C(C1C=NC=C[N:16]=1)(=O)C>>[CH3:1][NH:2][CH2:3][C@H:4]([C:6]1[CH:11]=[N:16][CH:9]=[CH:8][N:7]=1)[OH:5]
Reactant: CNC[C@@H](O)c1ccccn1
Reactant: CC(=O)c1cnccn1
Product: CNC[C@@H](O)c1cnccn1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol, 2-acetylpyrazine is converted to the title compound, isolated as a light orange liquid that solidified on standing.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]=[O:9]>ClCCl.[OH-].[Na+]>[OH:9][CH2:8][NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(N)=O
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a mixture of 2,2-dimethylpropanamide (5.0 g, 49.4 mmol, 1.0 equiv) and aqueous sodium hydroxide (1 M, 0.494 mL, 0.494 mmol, 0.01 equiv), add aqueous formaldehyde (13.31 M, 3.71 mL, 49.4 mmol, 1.0 equiv). Stir at room temperature for 2 h, and concentrate under reduced pressure to give a white solid. Dilute the crude material with dichloromethane, dry over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (6.4 g, 99%). 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (br s, 1H), 5.40 (t, 1H, J=6.7 Hz), 4.46 (app t, 2H, J=6.6 Hz), 1.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:5][N:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:5][N:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nnc(SCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nnc(SCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1

Procedure:
1-[3-(2-Amino-1,3,4-thiadiazol-5-ylthio)-2-(2,4-dichlorophenyl)-2-hydroxy-propyl]-1,2,4-triazole (0.5 g, 0.00124 m) was stirred at room temperature with a mixture of acetic anhydride (0.5 ml) and pyridine (5 ml) for one hour. The resulting solid was collected by filtration, washed with water and dried to give the title compound, 0.44 g (80%); m.p. 132° C.