Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C)cc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccc(C(C)(C)C)cc1
Yield: 61.3 %

Procedure:
Following general N—C coupling procedure 1, 7-(4-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) which gave 3-{6-[7-(4-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg) in 58% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H) 1.43 (s, 9H) 1.47-1.69 (m, 2H) 1.80 (br. s., 2H) 2.90 (br. s., 3H) 3.05 (br. s., 3H) 4.12 (br. s., 2H) 6.92 (s, 1H) 7.41 (m, J=8.59 Hz, 2H) 7.59 (m, J=8.59 Hz, 2H) 7.68 (dd, J=8.84, 2.27 Hz, 1H) 8.28-8.34 (m, 2H) 8.95 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([O:32][C:33]([F:36])([F:35])[F:34])[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[N:26]1([C:24]2[C:23]([O:32][C:33]([F:34])([F:36])[F:35])=[CH:22][C:14]3[NH:15][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[N:12][C:13]=3[CH:25]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N4CCCCC4)c(OC(F)(F)F)cc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnn(-c2nc3cc(N4CCCCC4)c(OC(F)(F)F)cc3[nH]2)c1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
A mixture of 1-[1-(2-methoxy-ethoxymethyl)-5-piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.300 g, 0.586 mmol), glacial acetic acid (5.9 mL), and 6M aqueous HCl (6.9 mL) was heated at 100° C. for 4.5 h in a sealed tube. The reaction mixture was cooled to 23° C. and then 0° C. The resulting precipitate was filtered and washed with cold water to yield the titled compound (60.0 mg, 26%). MS (ESI/CI): mass calcd. for C17H16F3N5O3, 395.1; m/z found, 396.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.84 (d, J=0.6 Hz, 1H), 8.27 (d, J=0.6 Hz, 1H), 7.47 (br s, 1H), 7.21 (br s, 1H), 2.98-2.89 (m, 4H), 1.71-1.59 (m, 4H), 1.58-1.47 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[CH3:32][C:33]12[CH:41]([OH:42])[C:37]([CH3:43])([CH2:38][NH:39][CH2:40]1)[CH2:36][N:35]([CH3:44])[CH2:34]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:39]5[CH2:40][C:33]6([CH3:32])[CH:41]([OH:42])[C:37]([CH3:43])([CH2:36][N:35]([CH3:44])[CH2:34]6)[CH2:38]5)=[O:22])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC2(C)CNCC(C)(C1)C2O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CN1CC2(C)CN(C(=O)c3ccc(Nc4ncc5cc(C(=O)N(C)C)n(C6CCCC6)c5n4)nc3)CC(C)(C1)C2O
Yield: 68 %

Procedure:
Following amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl and 1,3,5-trimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol were combined and gave 7-cyclopentyl-2-(5-(9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (266 mg) in 68% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.33 (s, 1H), 8.17 (br s, 1H), 7.72 (d, J=8.6 Hz, 1H), 6.49 (s, 1H), 4.81 (m, 2H), 3.74 (br m, 1H), 3.26 (s, 1H), 3.18 (s, 6H), 3.07 (br m, 1H), 2.70-2.56 (m, 4H), 2.29 (br m, 3H), 2.19 (s, 3H), 2.15-2.03 (m, 4H), 1.89 (m, 1H), 1.75 (m, 2H), 1.00 (br s, 3H), 0.83 (br s 3H)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH2:7][N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].[CH3:23][O:24][CH2:25][CH2:26]Br.[ClH:28]>O1CCCC1.C(OCC)(=O)C>[ClH:28].[NH2:8][CH:7]([CH2:26][CH2:25][O:24][CH3:23])[C:6]([O:5][CH2:3][CH3:4])=[O:22]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)CCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.8 g) is added to a solution of N-(diphenylmethylene)glycine ethyl ester in tetrahydrofuran under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for one hour. 2-Bromoethyl methyl ether (4.22 ml) is added to the mixture, and the whole is refluxed overnight. The reaction mixture is cooled to room temperature, 0.1 N hydrochloric acid is added thereto, and the whole is stirred for four hours. Ethyl acetate is added to the reaction mixture, and the whole is extracted with 0.1 N hydrochloric acid. The extract is basified with a saturated aqueous sodium hydrogencarbonate solution, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, a 4 N hydrogen chloride/ethyl acetate solution is added to the resulting residue, and the whole is concentrated under reduced pressure again to give the titled reference compound (2.67 g).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][N:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[OH:25][C:19]1([C:15]2[N:14]=[C:13]([CH2:12][N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:3]=4[NH:10][N:9]3[NH2:11])[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NN1Nc2c(Cl)ncnc2N1Cc1cccc(C2(O)CCOCC2)n1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NN1Nc2c(-c3ccccc3)ncnc2N1Cc1cccc(C2(O)CCOCC2)n1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A solution of the 7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine (0.10 g, 0.27 mmol) and phenylboronic acid (0.05 g, 0.41 mmol) and potassium phosphate (0.12 g, 0.55 mmol) in 1,4-dioxane (5 mL) was degassed by sparging with nitrogen. Tetrakis triphenylphosphine palladium (16 mg) was then added, the solution degassed again and the resultant mixture heated at 100° C. for seven hours. The mixture was then concentrated onto Isolute-HM in vacuo, purified by column chromatography (silica, eluting with 3:1 ethyl acetate:hexane and neat ethyl acetate) and triturated with diethyl ether to give the title compound (41 mg, 37%) as a pale beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)CCC2CCNCC2)cc1

Procedure:
A solution of 4-(3-(4-cyanophenyl)-3-oxo-propyl)-1-tert-butoxycarbonyl-piperidine (75 mg) in 30% TFA/CH2Cl2 was stirred for 30 min then concentrated and dried under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C)C=O>[CH2:29]([O:28][C:26]([N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:21]([Cl:22])=[CH:20][C:5]=2[N:6]=[C:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Dimethylformamide (25 mL) was added to 5,6-dichloro-2-(4-methoxy-3-nitro-phenyl)-1H-benzoimidazole (1.01 g, 3 mmol) from Step A. As the mixture stirred, sodium hydride (0.168 g, 4.2 mmol) was gradually added. After 3 hours, benzyl chloroformate (0.857 mL, 6 mmol) was added dropwise to the mixture. The reaction mixture was stirred overnight and then was partitioned between water (1,000 mL) and ethyl acetate (500 mL). The solvent was removed on the rotary evaporator and the residue triturated with 4:1 hexane:ethyl acetate to give the product (0.62 g), mp 212-214° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:7]1[NH:8][C:9]([CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+:18]>O>[OH2:3].[Na+:18].[CH:13]1([CH2:12][C:9]2[NH:8][C:7]([C:5](=[O:6])[C:4]([O-:16])=[O:3])=[CH:11][CH:10]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)C(=O)c1ccc(CC2CC2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(=O)c1ccc(CC2CC2)[nH]1
Yield: 94.4 %

Procedure:
A mixture of 5-cyclopropylmethyl-2-pyrrolylglyoxylic acid ethyl ester (6.63 g.) and sodium hydroxide (1.32 g.) was heated in water (40 ml.) as described in Example 20. The resulting solution was cooled to 5° and the solid was filtered off and crystallized from acetone to give 5-cyclopropylmethyl-2-pyrrolylglyoxylic acid sodium salt hydrate (3.3 g.), M.P. 228°-232°. Found: C, 51.50; H, 5.19; N, 5.91. C10H10NO3Na. H2O requires: C, 51.50; H, 5.19; N, 6.01%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:16][O:14][C:13]([CH:11]1[CH2:12][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH2:10]1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(N2CC(C(=O)O)C2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(c2ccc(C=O)cc2)C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
To a solution of 1-(4-Formyl-phenyl)-azetidine-3-carboxylic acid (Preparation 8, 4 g, 19.51 mmol) in DMF (50 mL) was added potassium carbonate (4.04 g, 29.77 mmol) at 0° C. and allowed to stir for 10 minutes followed by addition of methyl iodide (2.77 g, 19.51 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After consumption of starting material, reaction mixture was quenched with ice cold water (150 mL) and extracted with EtOAc (3×150 mL). Combined organic layer was washed with water (2×300 mL), brine (250 mL), dried over sodium sulphate and evaporated under reduced pressure to afford brown colored semi solid (4.7 g, crude). Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 20% ethyl acetate in hexane to afford yellow semisolid (2.6 g, 61%). 1H NMR (400 MHz, CDCl3) δ: 3.58-3.62 (m, 1H), 3.76 (s, 3H), 4.15-4.22 (m, 4H), 6.42 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=6.98 Hz), 9.74 (s, 1H); LC-MS (M+H): =220.20.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1N
Product: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Yield: 64.6 %

Procedure:
According to the procedure of example 97, the reaction mixture of 1.05 g (4.54 mmol) of methyl 3-amino-6-methoxy-2-naphthoate in 20 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours to give 840.5 mg (64.6%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate as a beige solid, mp 122–124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH:17]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)c2)c1

Procedure:
3-Bromo-benzoic acid (112 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.Cl.[N:12]([O-:14])=[O:13].[Na+].S([O-])([O-])=O>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=N[O-]
Reactant: Nc1c(F)cccc1Cl
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 17.2 g. of 2-chloro-6-fluoraniline hydrochloride and 12.5 ml. of concentrated hydrochloric acid in 150 ml. of water is added slowly a solution of 9 g. of sodium nitrite in 25 ml. of water. The temperature of the solution is kept below 5° at all times. This solution is then added to a stirred suspension of 18 g. of cuprocupric sulfite and 60 g. of sodium nitrite in 300 ml. of water at room temperature. The mixture is stirred for 1 hour then steam distilled until no trace of product is noted condensing in the distillate. The distillate is extracted with ether, dried (magnesium sulfate) concentrated and distilled to give 7.8 g. of product, b.p. 148°-152° at 30 mm. Gas chromatography analysis shows this to be greater than 95% pure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]2[S:16][N:15]3[C:17]([C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=5[CH:24]=4)=[C:18]([CH2:20][CH2:21][OH:22])[S:19][C:14]3=[N:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>O>[C:33]([O:22][CH2:21][CH2:20][C:18]1[S:19][C:14]2[N:15]([S:16][C:12](=[N:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[N:13]=2)[C:17]=1[C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=c2nc3sc(CCO)c(-c4ccc5c(c4)CCCC5)n3s2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCc1sc2nc(=NS(=O)(=O)c3ccc(C)cc3)sn2c1-c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethanol (500 mg), acetic anhydride (1 ml) and pyridine (5 ml) was stirred at room temperature for i hour. The reaction mixture was added to water, and the resulting crystal was collected by filtration and washed with water. The obtained crystal was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1:1, v/v). The separating crystal was recrystallized from dichloromethane-methanol to yield 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethyl acetate (355 mg, yield 65%) as a colorless needle.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (Compound 19, 2.6 ml, 34.0 mmol) was added to a mixture of N,N-dimethylethylenediamine (3.7 ml, 34.0 mmol) and diisopropylethylamine (5.93 ml, 34.0 mmol) in tetrahydrofuran (30 ml) at 0° C. After 1.5 hours stirring at 0°, the mixture was quenched with water and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extract gave an oil, which was purified by flash chromatography on silica using 20% methanol/chloroform to give the title sulfonamide. 1HNMR(CDCl3): 2.24 (s, 6H), 2.48 (t, 2H, J=5.9 Hz), 2.97 (s, 3H), 3.18 (t, 2H, J=5.6 Hz). 13CNMR(CDCl3): 39.3, 39.9, 44.5 and 57.8.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[N+:25]([CH3:28])([O-:27])=[O:26]>C1COCC1>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:12]([OH:13])[CH2:28][N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
102 mg (0.27 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution C1 was mixed into the solution. After stirring for 30 minutes, 82.4 mg (1.35 mmol) of nitromethane was added dropwise to the mixture. After 66-hour reactionitime, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 68% e.e. was obtained in a yield of 72%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].C(O)(C(F)(F)F)=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([NH2:10])=[O:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C#N)ccc1Br
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1nc(C(N)=O)ccc1Br
Temperature: 40 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution of 5-bromo-6-methylpicolinonitrile (1.8 g, 9.14 mmol) in a mixture of TFA and sulfuric acid (30 mL, 4:1, VAT) was stirred at 40° C. for 16 h. The reaction mixture was poured into ice water. The resulting solid was filtered off and washed with water and dried to give the desired product as a white solid (1.0 g, 4.65 mmol, 54% yield). MS (ESI) m/z 217.1 [M+2]+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([S:22]([CH2:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]([OH:35])[C:29]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:41](O)([CH3:44])([CH3:43])[CH3:42]>C1COCC1.CN(C)C1C=CN=CC=1>[C:16]1([S:22]([CH2:25][C:26]2[C:31]([C:32]([O:34][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:33])=[C:30]([OH:35])[C:29]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O

Procedure:
A solution of dicyclohexylcarbodiimide (0.124 g) in THF (1 ml) was added dropwise to a mixture of 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoic acid (Intermediate 114, 0.358 g) and 4-dimethylaminopyridine (0.0032 g) and t-butanol (3 ml) in THF (1 ml). The resultant mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and the filtrate was washed with citric acid (5% aqueous solution), sodium bicarbonate (saturated aqueous solution) and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (20%) to give t-butyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (0.19 g) as a waxy white solid.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[CH2:25]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N(C(=O)c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.006M) in DMF (25 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.3 g, 0.007M). The mixture was stirred at room temperature for 0.5 hours, and then benzyl bromide (1.2 g, 0.007M) was added dropwise. The reaction mixture was warmed to 60° C. and allowed to stir for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-benzyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:22])[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Solvent: c1ccncc1
Product: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Yield: 27703.4 %

Procedure:
A stirred mixture of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (10 g, 0.035 mol) in pyridine (300 ml), treated with P2S5 (8.0 g, 0.036 mmol) was refluxed, under N2, for 2 hours then concentrated in vacuo. To remove the remaining pyridine the residue was combined with toluene twice with concentration after each addition. The remaining material was mixed with cold NaHCO3 and extracted twice with CH2Cl2. At this point a precipitate thought to be undissolved product formed between the two layers. This was filtered and washed with CH2Cl2 and H2O. The NaHCO3 layer was extracted with CH2Cl2 again. The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from EtOAc-Skelly B to give 3.0 g of the subtitled intermediate, mp 250°. The precipitate was also recrystallized from EtOAc-Skelly B to give 3.01 g of additional subtitled intermediate, mp 255°.