Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C[Si](Cl)(C)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+].[NH4+].[F-]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[OH:18][C@:2]1([CH3:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH:15][C:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:13][C:11]1=[O:12]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)c(=O)n2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
2′-C-Methylcytidine (38.9 mmol) was dissolved in pyridine (270 mL) and the reaction mixture was cooled down to 0° C. TMSCl (233.4 mmol) was added and the mixture was stirred at room temperature during 4 hours. DMAP (38.9 mmol) and mMTrCl (77.25 mmol) were added and the reaction mixture was stirred at 50° C. during 2 days. The reaction was cooled down to room temperature and a saturated solution of NaHCO3 was added slowly. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4, filtered and concentrated. Co-evaporations with toluene and CH2Cl2 were done. The crude was dissolved in CH3OH (500 mL) and NH4F (194.5 mmol) was added. The reaction mixture was heated at reflux and stirred during 1 hour. The reaction mixture was cooled down to room temperature and concentrated. The crude was purified by chromatography on a silica gel column (eluent: CH2Cl2/CH3OH 0 to 10%) to give the expected compound as a yellow powder in 89% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.08 (s, 3H), 3.71-3.84 (m, 2H), 3.81 (s, 3H), 3.90-3.94 (m, 1H), 3.99-4.03 (m, 1H), 5.14 (d, J=7.63 Hz, 1H), 5.31 (s, 1H), 5.79 (brs, 1H), 6.84 (d, J=8.65 Hz, 2H), 7.13 (d, J=8.69 Hz, 2H), 7.21 (d, J=7.35 Hz, 4H), 7.27-7.34 (m, 8H), 7.51 (brs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][N:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:56]=[N+:57]=[N-:58])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.CCOC(C)=O>[N:56]([CH:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:2]([CH3:1])[C:8]1=[O:9])=[N+:57]=[N-:58]
Reactant: CN1C(=O)Cc2ccccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])c2ccccc2CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a well stirred solution of 2,3,4,5-tetrahydro-3-methyl-4-oxo-1H-2,3-benzodiazepine-2-carboxylic acid, 1,1-dimethylethyl ester (1.0 g, 3.62 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. was added a solution of 0.5 M potassium bis(trimethylsilyl)amide in toluene (9.0 mL, 4.5 mmol). The reaction mixture was stirred for another 15 min followed by addition of a pre-cooled solution (−78° C.) of 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (1.23 g, 4.0 mmol) in THF (0.4M) via a cannula over a period of 1 min (Evans, et al., J. Amer. Chem. Soc., 1990, 112, 4011-4030; Butcher, et al., Tetrahedron Lett., 1996, 37 (37), 6685-6688). After 5 min, acetic acid (1.0 mL, 18 mmol) was added and stirring continued for another 6 h. The reaction mixture was diluted with EtOAc (300 mL), washed with water (300 mL), aqueous NaHCO3 (2×150 mL), 0.5 N HCl (200 mL) and brine (150 mL). The solvent was removed and the 5(R,S)-azido-2,3,4,5-tetrahydro-3-methyl-4-oxo-1H-2,3-benzodiazepine-2-carboxylic acid, 1,1-dimethylethyl ester was purified by flash chromatography (silica) using 10% EtOAc in hexane. The azide was obtained in 60% yield.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH2:24].[Cl-].[NH4+]>CN(C)C=O>[F:14][C:2]([F:1])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[O:4][CH2:24][CH:23]=[CH2:22]
Reactant: N#Cc1cc(C(O)C(F)(F)F)ccn1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
To 5 ml of dimethylformamide were added 0.5 g of 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carbonitrile, 0.45 g of potassium carbonate and 0.39 g of 3-bromo-1-propene, and the mixture was stirred at room temperature for 20 hours. Thereafter, an aqueous saturated ammonium chloride solution was added to the reaction solution, the resultant solution was extracted with ethyl acetate, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-[2,2,2-trifluoro-1-(2-propenyloxy)ethyl]pyridine-2-carbonitrile.
Reaction SMILES: [Na].C(O)C.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1.[C:18]1([CH2:24][C:25](OCC)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:5][C:6]([F:16])([F:17])[C:7]1[CH:8]=[C:9]([CH:13]([C:25]([CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N#CC(C(=O)Cc1ccccc1)c1cccc(C(F)(F)F)c1
Yield: 73.5 %

Procedure:
In this example, 4.91 g of metallic sodium was added to 110 ml of anhydrous ethanol at room temperature and stirred until all of the sodium dissolved. A mixture containing 18.76 g of (3-trifluoromethylphenyl)acetonitrile and 21.73 g of ethyl phenylacetate was then added dropwise and the resulting mixture was stirred at reflux for about 18 hours. The mixture was then poured into 300 ml water and extracted three times with ethyl ether. The pH of the extracted aqueous layer was adjusted to a pH of about 1 with aqueous 10 wt. % hydrochloric acid and again extracted three times with ethyl ether. The organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under vacuum affording 22.6 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=2[O:23][CH2:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH:31][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCc2ccc3c(c2)OCO3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-benzo[1,3]dioxol-5-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C20H21NO7 [M+H]+: 388.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(S(C)(=O)=O)cc3)c2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (17 mg, 0.044 mmol) in Acetonitrile (0.4 mL) was treated with Cs2CO3 (57.9 mg, 0.178 mmol), 4-methylsulfonylbenzyl bromide (44.3 mg, 0.089 mmol), and stirred at 70° C. for 1.5 hours. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-1-(4-(methylsulfonyl)benzyl)-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (22 mg, 0.040 mmol, 90% yield) as yellow oil. The ester intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with 2M LiOH (0.120 mL, 0.24 mmol), and stirred at 60° C. for 2 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (9.3 mg, 0.017 mmol, 37.6 yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 (s, 9H), 2.44 (s, 3H), 3.02 (s, 3H), 3.64 (s, 3H), 5.47 (s, 1H), 5.81 (d, J=15.7 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.43 (m, 3H), 7.47-7.58 (m, 1H), 7.89 (d, J=8.4 Hz, 2H). LCMS (m/z) ES+=537 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:21]#[N:22])=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:20])([CH3:19])[CH2:7]1)C.[C:24]([CH2:26][C:27](NCC#C)=O)#[N:25].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:21]([C:5](=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:20])([CH3:19])[CH2:7]1)[C:4]([NH:25][CH2:24][C:26]#[CH:27])=[O:3])#[N:22]
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Reactant: C#CCNC(=O)CC#N
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C#CCNC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Yield: 49.9 %

Procedure:
A 50 ml reaction flask equipped with a water separator and a reflux condenser was charged with 2.2 g of 2,3-dihydro-5,6-dimethoxy-3,3-dimethyl-1H-inden-1-one (see Example 1), 1.2 g of 2-cyano-N-prop-2-ynyl-acetamide (see above), catalytic amounts of pyrrolidine, and benzoic acid in 20 ml of toluene. The reaction mixture was refluxed for 24 hours with simultaneous separation of water. Then, the product in the cold reaction mixture was filtered off and recrystallized in ethylacetate to yield 1.13 g of white crystals, m.p. 202° C.-205° C. UV 362 nm (ε=24′992). Solubility: 0.04% in CÉTIOL LC
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:28]1([O:18][C:17](=[O:19])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 22 h
Yield: 68.4 %

Procedure:
To a solution of (S)-3-(4-Benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (10 g, 26.9 mmol) in DMF (100 ml) was added cyclopentanol (4.6 g, 53.8 mmol) and DMAP (329 mg, 2.69 mmol). The solution was cooled down to 0° C. and EDC.HCl (5.4 g, 28.2 mmol) was added. The reaction mixture was then stirred at r.t. for 22 hours. Water (100 ml) and EtOAc (100 ml) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2×80 ml). The organics were washed with water (3×50 ml) and brine (50 ml), then dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified on column (Heptane/EtOAc 7:3) to yield the title compound (8.09 g, 68.4%). LCMS purity 96.6%, m/z 462 [M++Na]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[N:21]=[CH:20][C:19]=3[C:28]([O:30]CC)=O)=[C:14]([N+:33]([O-])=O)[CH:13]=2)=[C:7]([CH3:36])[CH:6]=1)([CH3:3])[CH3:2].O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[CH:1]([O:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[C:18]4[N:22]([C@H:23]5[CH2:27][CH2:26][O:25][CH2:24]5)[N:21]=[CH:20][C:19]=4[C:28](=[O:30])[NH:33][C:14]=3[CH:13]=2)=[C:7]([CH3:36])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OC(C)C)nc2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OC(C)C)nc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn([C@H]3CCOC3)c12
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of ethyl 5-[4-(6-isopropyloxy-2,4-dimethylpyridin-3-yl)-2-nitrophenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (65.1 mg) in acetic acid (1.5 mL)-water (0.15 mL) was stirred at 80° C. for 15 minutes. Iron powder (45.1 mg) was added to the solution, and the mixture was stirred at the same temperature for two hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature, and ethyl acetate (5 mL) was added to the reaction mixture. The insoluble matter was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. A solution of the residue in ethyl acetate was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was suspended and triturated by adding MTBE. The precipitated solid was collected by filtration to give the title compound (35.1 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Cl:28])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:11]([CH:25]([F:27])[F:26])=[CH:10]2)(=O)=O.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:28][C:8]1[C:7]([C:31]#[N:32])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([CH:25]([F:26])[F:27])[N:12]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: O=S(=O)(c1ccccc1)n1c(C(F)F)cc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(cc(C(F)F)n2S(=O)(=O)c2ccccc2)c1Cl
Temperature: 120 °C
Yield: 62 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indol-5-yl trifluoromethanesulfonate (0.75 g, 1.53 mmol) in anhydrous DMF (10 mL) under N2, was added Zn(CN)2 (0.093 g, 0.80 mmol) and Pd(PPh3)4 (0.088 g, 0.077 mmol) and the resulting mixture was heated at 120° C. for 2 h. Upon cooling, the mixture was partitioned between Et2O and water. The organic phase was washed with water. The combined aqueous phases were reextracted with Et2O. The combined organic phases were washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc-hexanes gradient) to afford 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile (0.35 g, 62% yield) 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.8 Hz, 1H), 7.94 (d, J=7.8 Hz, 2H), 7.67-7.63 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.35 (t, J=54 Hz, 1H), 7.25 (s, 1H, overlapping CHCl3 signal); MS (ES) m/z 365 (M−1)) and 2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-4,5-dicarbonitrile (0.054 g, 10% yield) (1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=8.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.38 (t, J=54 Hz, 1H), 7.35 (s, 1H); MS (ES) m/z 356 (M−1)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:15][CH2:16][CH2:17][N:18]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]1[CH3:24]>COCCOC>[CH3:24][C:19]1[N:18]([CH2:17][CH2:16][NH:15][C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[S:14])[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Reactant: Cc1ccc(C)n1CCN
Solvent: COCCOC
Product: CCOC(=O)c1ccc(NC(=S)NCCn2c(C)ccc2C)cc1

Procedure:
8.3 g (0.04 mol) of 4-ethoxy carbonylphenyl isothiocyanate in 20 ml of ethylene glycol dimethyl ether are added dropwise at room temperature to 5.5 g (0.04 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole in 20 ml of ethylene glycol dimethyl ether. The precipitated product is filtered off with suction and recrystallized from methanol. Yield: 5.1 g (37% of theory) Melting point: 155°-156° C. Elemental analysis: C18H23N3O2S (345.47) calculated: C 62.6 H 6.7 N 12.2 0. 9.3 S 9.3 found: C 62.0 H 6.7 N 11.6 0 10.0 S 9.2
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].C(N)(=[O:13])C=C.OO.[Na]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:13])=[O:5].[Na+:9].[Na+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(N)=O
Agent: OO
Agent: [Na+]
Agent: [Na]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous solution of sodium maleate was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this product and acrylamide was effected in the presence of hydrogen peroxide at 100° C. for 6 h to obtain a dyeability-improving agent comprising sodium polymaleate containing 3% of acrylamide as a second component. The molecular weight was 4,000.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH:19]([NH2:21])[CH3:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH:19]([NH:21][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH3:20])([O-:16])=[O:15]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: CC(N)CO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.5 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.3 g of 1-(nitrooxymethyl)ethylamine nitrate, to obtain 0.35 g of the title compound as colorless crystals, melting at 112°-114° C. (after recrystallization from ethanol).
Reaction SMILES: [CH:1]1([N:4]2[C:9]3=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]3[CH2:7][N:6]([C:17]3[C:22]([F:23])=[C:21]([O:24][CH3:25])[CH:20]=[C:19]([O:26][CH3:27])[C:18]=3[F:28])[C:5]2=[O:29])[CH2:3][CH2:2]1.[CH2:30]([N:32]([CH2:38][CH3:39])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH3:31].C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>O1CCOCC1>[CH:1]1([N:4]2[C:9]3=[N:10][C:11]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH2:38][CH3:39])[CH2:30][CH3:31])=[N:12][CH:13]=[C:8]3[CH2:7][N:6]([C:17]3[C:22]([F:23])=[C:21]([O:24][CH3:25])[CH:20]=[C:19]([O:26][CH3:27])[C:18]=3[F:28])[C:5]2=[O:29])[CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CC3)C2=O)c1F
Reactant: CCN(CC)CCCCN
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CC)CCCCNc1ncc2c(n1)N(C1CC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Yield: 83 %

Procedure:
Using Procedure K, 0.63 g (1.48 mmol) of 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 4-(diethylamino)butylamine in 20 mL of dioxane were reacted. Chromatography with 9:1:0.5 ethyl acetate/ethanol/triethylamine gave 0.62 g (83%) of the title compound as a solid: mp 139° C.–141° C. MS (APCI) (m+1)/z 505.2. Analysis calculated for C25H34N6F2O3: C, 59.51; H, 6.79; N, 16.66. Found: C, 59.56; H, 6.77; N, 16.49.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:9])=[N:4][CH:3]=1.[CH2:17]([N:19]1[C:23](B(O)O)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1)[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC.[Cl-].[Na+].O>CC(N(C)C)=O.O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]([NH:7][C:5]1[S:6][C:2]([C:23]2[N:19]([CH2:17][CH3:18])[N:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:3][N:4]=1)=[O:9]
Reactant: O=C(Nc1ncc(Br)s1)c1ccccc1Cl
Reactant: CCn1nc(C(F)(F)F)cc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(C(F)(F)F)cc1-c1cnc(NC(=O)c2ccccc2Cl)s1
Temperature: 150 °C
Yield: 14.3 %

Procedure:
A mixture of N-(5-bromo(1,3-thiazol-2-yl))(2-chlorophenyl)carboxamide (47, 62 mg, 0.2 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (58) (62 mg, 0.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1:1) (24 mg) and potassium phosphate (63 mg) in 2 ml DMA and 0.5 ml water was heated under Ar in microwave reactor at 150° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to prep HPLC purification to give 11.5 mg (2-chlorophenyl)-N-{5-[1-ethyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-2-yl)}carboxamide (59) as dark brown solid (yield: 14%; purity>90%). LC-MS: calcd. for C16H12ClF3N4OS: 401 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23](OC)=[O:24])[CH:17]=[CH:16]2.C1(C([O-])=O)C2C(=CC=CC=2)C=CC=1>O>[OH:24][CH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:12])[CH:22]=[CH:21]2
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])c1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2cc(O)ccc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a 3-necked, 1-L round bottomed flask equipped with an overhead stirrer, digital thermometer and 500-mL constant-pressure addition funnel with a nitrogen inlet was added 11 g (0.29 mol) of lithium aluminum hydride and 200 mL of anhydrous THF. The addition funnel was charged with a solution of 40 g (0.2 mol) of methyl 6-hydroxy-2-naphthoate. The flask was cooled in ice/water and the naphthoate slowly added over 1 hour. The suspension was stirred overnight, recooled and cautiously treated with 100 mL of water. The white suspension was poured into 5% (v/v) HCI and extracted several times with ethyl acetate. The combined extracts were washed with water, dried, evaporated and the residue recrystallized in hexane/ethyl acetate to yield a total of 30 g (87%) of the title compound in three crops as beige plates, mp 179–181 ° C.