Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][OH:18])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(Cl)Cl>[C:30]([O:18][CH2:17][CH2:16][C@@H:15]1[C@@H:7]([O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C@H:8]([CH3:29])[O:9][C:10](=[O:28])[C@@H:11]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:12][O:13][C:14]1=[O:19])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.3 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6 methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (200 mg, 0.479 mmol) in pyridine (0.5 mL) and CH2Cl2 (1 mL) was added benzoyl chloride (195 mg, 0.958 mmol) at room temperature (about 22° C.), and the reaction mixture was stirred at room temperature for 12 h. The solvents were removed under vacuum and the residue was purified by column chromatography (SiO2, hexanes/EtOAc gradient) to give the title compound (268 mg, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, J=8.5, 1.0 Hz, 2H), 7.56-7.40 (m, J=10.6, 3H), 5.39-5.15 (m, 2H), 5.10 (t, J=9.9 Hz, 1H), 4.97-4.73 (m, 2H), 4.42-4.29 (m, 1H), 4.25 (m, 1H), 3.57-3.35 (m, 1H), 2.73 (t, J=9.5 Hz, 1H), 2.62 (dt, J=14.0, 7.0 Hz, 1H), 2.36-2.18 (m, 1H), 1.90-1.71 (m, 1H), 1.46 (s, 9H), 1.28 (d, J=6.4 Hz, 3H), 1.21 (dd, J=7.0, 1.0 Hz, 6H); ESIMS m/z 544 ([M+Na]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:8]([C:24](OCC)=[O:25])[N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[H][H]>C(O)C>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[C:8]([CH2:24][OH:25])[N:7]=[C:6]([CH2:4][OH:3])[CH:11]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1cc(CO)nc(CO)c1
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of 4-(3-tert-butoxycarbonylamino-propoxy)-pyridine-2,6-dicarboxylic acid diethyl ester (150 mg) in absolute ethanol (5 mL) was added sodium borohydride (43 mg) and calcium chloride (128 mg). After stirring for 4 h, hydrogen evolution ceased, and reaction was quenched with water. Solvent was evaporated under reduced pressure. The residue was then washed into separatory funnel using dichloromethane and water. The layers were separated, and the aqueous layer was extracted three times with dichloromethane. The combined organic solutions were dried over magnesium sulphate, and concentrated in vacuo to give 4-(3-tert-butoxycarbonylamino-propoxy)-2,6-bis-(hydroxymethyl)pyridine (80 mg):
Reaction SMILES: [Al].[C:2]([C:6]1[C:7](=[O:28])[C:8](C(C)(C)C)=[CH:9][C:10](O[Si](CC)(CC)CC)([C:12]([F:15])([F:14])[F:13])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]>O>[C:2]([C:7]1([OH:28])[C:6]([C:2]([CH3:4])([CH3:5])[CH3:3])=[CH:11][C:10]([C:12]([F:14])([F:13])[F:15])=[CH:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Agent: [Al]
Solvent: O
Product: CC(C)(C)C1=CC(C(F)(F)F)=CCC1(O)C(C)(C)C
Temperature: 70 °C
Yield: 87 %

Procedure:
A strip of aluminum foil weighing 264 mg (9.8 mmol) was amalgamated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ehtanol followed by diethyl ether, cut into small pieces, and added to a solution of 412 mg of 96% pure (0.98 mmol) 2,6-di-tert-butyl-4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 25 mL of 10% water - 90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with tetrahydrofuran. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with petroleum ether), affording 247 mg of 95% pure (87% yield) 1,6-di-tert-butyl-4-trifluoromethylphenol. An analytical sample was obtained by crystallization from methanol: mp 78°-80° C.; 1H NMR (CDCl3)δ1.45 (s, 18H), 5.56 (broad s, 1H), 7.50 (s, 1H); 19F NMR (CDCl3, relative to CFCl3)-61.7 ppm (s); IR (KBr) 3632, 2963, 1337, 1319, 1241, 1167, 1141, 1109, 893, 668 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 274 (20, M+), 259 (100), 231 (28), 57 (57), 41 (54). Anal. Calcd. for C15H21F3O: C, 65.67; H, 7.72. Found: C, 65.46; H, 7.94.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9]3[C:10](=[CH:16][CH:17]=[CH:18][C:8]=3[C:7]1=[O:19])[C:11](Br)=[CH:12][CH:13]=2.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+].Cl>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:22]1([C:11]2[C:10]3[C:9]4[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:20])[F:1])[C:7](=[O:19])[C:8]=4[CH:18]=[CH:17][CH:16]=3)[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: O=C1c2cccc3c(Br)ccc(c23)N1CCCC(F)(F)F
Reactant: C1CNCCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cccc3c(N4CCCNCC4)ccc(c23)N1CCCC(F)(F)F
Temperature: 85 °C
Yield: 108.5 %

Procedure:
To a mixture of 1-(4,4,4-trifluorobutyl)-6-bromo-benzo[cd]indol-2(1H)-one (1.225 g, 3.42 mmol), homopiperazine (6 g, 60 mmol) and toluene (100 ml) in a round bottomed flask was added BINAP (42 mg, 2%) and Pd2(dba)3 (30 mg, 1%) and sodium tert-butoxide (333 mg, 3.46 mmol). The reaction mixture was heated at 85° C. for 18 hours and was then poured into 500 ml concentrated HCl solution in water. The organic layer was seperated and the aqueous layer was extracted with more toluene (2×500 ml). The combined organic layers were neutralized with 10 N NaOH (aqueous ) and extracted with a one to one mixture of dichloromethane and toluene (3×500 ml). The combined organic layers were dried and filtered and concentrated to give the crude product (1.4 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[NH:17][N:18]=1)=[O:13])[CH3:2].[CH3:25]N(C=O)C.CI>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[N:17]([CH3:25])[N:18]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (1.04 g, 3.211 mmol) in DMF (12 mL) Cs2CO3 (1.255 g, 3.85 mmol) and methyl iodide (0.22 mL, 3.532 mmol) were added. The reaction was stirred at room temperature for 1 h, then AcOEt (60 mL) was added and the organic phase washed with water (3×50 mL). The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 1/9) provided 0.99 g (91% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:34])([Cl:33])[CH2:3][O:4][C:5](=[O:32])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25]C3CCCCO3)[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Cl:33][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:32])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Yield: 99 %

Procedure:
A colourless solution of Intermediate 39b (120 mg, 0.224 mmol) and pyridinium p-toluenesulfonate (169 mg, 0.673 mmol) in MeOH (5 mL) was stirred at 40° C. for 90 min. The solution was concentrated in vacuo, suspended in water (3 mL) and sat. aq. NaHCO3 solution (3 mL), then extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit, concentrated in vacuo and azeotroped with toluene (2×5 mL) to leave the title compound as a white solid (100 mg, 99%). LCMS (Method 3): Rt 4.01 min, m/z 450, 452 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][CH:3]=1.IC.[C:20](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:20])=[CH:13][CH:12]=2)=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc(Cl)cnc1Oc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(Oc2ncc(Cl)nc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
In 8 mL of dimethylformamide was dissolved 0.4 g of 6-chloro-3-(4-hydroxyphenoxy)-2-pyrazinecarbonitrile. After adding 0.5 ml of iodomethane and 0.89 g of potassium carbonate, the mixture thus obtained was stirred at room temperature for 30 minutes. The reaction mixture was added to a mixture of 10 mL of ethyl acetate and 30 mL of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.43 g of 6-chloro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile was obtained as a yellow-brown colored solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[O:42][CH2:41][CH2:40][C@H:39]2[NH2:47].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:47][C@H:39]2[C:38]3[C:43](=[C:44]([F:46])[CH:45]=[C:36]([F:35])[CH:37]=3)[O:42][CH2:41][CH2:40]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: N[C@@H]1CCOc2c(F)cc(F)cc21
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cc(F)cc43)n2)c(OC)c1
Reaction time: 24 h
Yield: 67.8 %

Procedure:
A partial suspension of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile (415 mg) in 40 mL of acetonitrile was treated with a solution of (R)-6,8-difluorochroman-4-amine HCl salt (320 mg) in DMSO (10 mL) followed by potassium carbonate (1.0 g). The mixture was stirred for 24 hours, and then diluted with EtOAc (200 mL). The mixture was washed once with saturated aqueous ammonium chloride (200 mL) and 3 times with saturated aqueous NaCl (200 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20→40% EtOAc/hexanes) provided 358 mg of the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:37])[CH2:34][O:35][CH3:36])[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:37])[CH2:34][O:35][CH3:36])[C:17]([OH:19])=[O:18])[C:13]1=[O:38])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCCCCC
Product: COCC(C)=C(C(=O)O)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-methoxy-2-butenoate (200 mg) was dissolved in 1 ml of 1:1 mixture of anisole and trifluoracetic acid at 0°. After 30 min. at 0°, 50 ml of hexane was added and the solvents were removed under reduced pressure. The residue thereby obtained was washed thoroughly with ether and dried. A total of 53 mg of the title product was isolated: nmr (CDCl3) δ 2.07 (s, 3, CH3), 3.33 (s, 3, --OCH3), 4.33 (s, 2, --CH2OCH3), 3.77 (m, 2, C4 --H), 5.00 (m, 1, C3 --H), 4.52 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.N1C=CC=CC=1.[CH3:53][N:54]([CH3:59])[S:55](Cl)(=[O:57])=[O:56]>O1CCCC1>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][S:55]([N:54]([CH3:59])[CH3:53])(=[O:57])=[O:56])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)N(C)C)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(S)-2-(1-((5-(4-Amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with pyridine (19 μL, 0.23 mmol) and dimethylsulfamoyl chloride (23 mg, 0.16 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at 50° C. overnight. The title compound was obtained (76 mg, 74% yield, 57% purity) without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:19])[CH3:18])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12](/[CH:15]=[CH:16]/[CH:17]([OH:19])[CH3:18])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC(O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the product from Example 7C (1.4 g 4.6 mmole) in methanol (45 mL) at 0° C. was added a methanolic solution of 0.4 M cerium(III)chloride (13.8 mL, 5.5 mmole) followed by portion-wise addition of sodium borohydride (175 mg, 4.6 mmole). The reaction mixture was allowed to warm up to room temperature, stirred at room temperature for 15 minutes and quenched with acetone for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water (×2) and brine. The reaction mixture was dried over magnesium sulfate filtered and evaporated. The crude product (1.4 g, quantitative) was carried on to the next step without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (d, J=6.62 Hz, 3H) 1.34 (d, J=6.25 Hz, 6H) 1.56 (d, J=4.04 Hz, 1H) 4.33-4.46 (m, 1H) 4.47-4.59 (m, 1H) 5.82 (dd, J=15.63, 6.07 Hz, 1H) 6.56 (d, J=16.18 Hz, 1H) 6.83-6.97 (m, 2H) 7.05 (s, 1H) 7.11-7.22 (m, 2H). Mass spectrum DCI 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1F

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 L, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=CC=C[CH:2]=1.O1CCC[CH2:16]1>>[C:9]1([C:8]#[C:7][C:1]([CH3:2])([CH3:6])[CH3:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: C(#Cc1ccccc1)c1ccccc1
Product: CC(C)(C)C#Cc1ccccc1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution containing W(CCMe3)(Cl3)(OPEt3) (0.43 g, 0.866 mmol) and diphenylacetylene (0.18 g, 1.0 mmol) in 2 ml of tetrahydrofuran was heated to 60° C. for 2 hours. During this time, the color of the reaction mixture changed from blue to green. Phenyl-t-butylacetylene (100% yield versus tungsten) was observed in the reaction mixture by gas chromatography. The reaction mixture was filtered and PMe3 (0.30 ml, 3.0 mmol) was added by syringe. The color of the solution turned yellow, and after the addition of 2 ml pentane, yellow crystals precipitated from solution. The product was collected by filtration and was recrystallized from a mixture of tetrahydrofuran and pentane at -30° C.; total yield 0.47 g (89%) W(CPh)Cl3 (PMe3)3.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:7]=[C:8]3[CH:14]=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)[CH:3]=[N:2]1.C1C(=O)N([I:22])C(=O)C1>CC(C)=O>[I:22][C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[N:7]=2)[NH:12][CH:13]=1
Reactant: c1cc2nc(-c3cn[nH]c3)cnc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: Ic1c[nH]c2ncc(-c3cn[nH]c3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 28 (0.27 g) and acetone (20 mL) was added in one portion NIS (0.36 g). The mixture was stirred at RT for 30 min and then concentrated to afford 0.55 g of crude material which was purified by SiO2 chromatography using an EtOH/EtOAc gradient (1 to 15% EtOH over 15 min) to afford 0.29 g of pure 7-iodo-2-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (30).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[OH:23][CH2:24][CH2:25][SH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:23][CH2:24][CH2:25][S:26][CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2
Reactant: OCCS
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n(C)c(CSCCO)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (125 mg, 0.349 mmol) in 5 mL of dimethylformamide was added 2-hydroxyethanethiol (0.027 mL, 0.38 mmol) and cesium carbonate (227 mg, 0.698 mmol). After one hour, the reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane to provide the titled product. 1H-NMR (500 MHz, CDCl3) δ 8.41 (d, J=9.0 Hz, 1H), 7.45-7.54 (m, 3H), 7.34-7.36 (m, 2H), 7.04 (dd, J=9.0, 2.5 Hz, 1H), 6.35 (d, J=2.5 Hz, 1H), 3.83, (s, 3H), 3.68 (s, 3H), 3.63 (s, 2H), 3.41 (m, 2H), 2.58 (t, J=5.6 Hz, 2H) ppm. ESI+ MS: 356.14 [M+H]+.
Reaction SMILES: [SH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH2:8][CH2:9][N:10]=2)[CH2:3]1.C1(P(O[C:26]2[C@H:27]([CH3:50])[C@@H:28]3[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]3[C:30]=2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(SC1CN(C2SCCN=2)C1)(=O)C>C(#N)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[S:7]1[CH2:8][CH2:9][N:10]=[C:6]1[N:4]1[CH2:5][CH:2]([S:1][C:26]2[C@H:27]([CH3:50])[C@@H:28]3[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]3[C:30]=2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: SC1CN(C2=NCCS2)C1
Agent: CC(=O)SC1CN(C2=NCCS2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(C4=NCCS4)C3)[C@H](C)[C@H]12
Yield: 65 %

Procedure:
770 mg of 28% sodium methoxide-methanol solution was added to a mixture solution of 862 mg of Compound (18) obtained in the step (b) in 20 ml of anhydrous methanol under ice-cooling and nitrogen gas atmosphere. Then the reaction mixture was stirred for 10 minutes under the same conditions. After reaction, 4 ml of 2N--HCl was added to the reaction mixture and the solvent was removed under reduced pressure to give crude 3-mercapto-1-(thiazolin-2-yl)azetidine [Compound (19)]. Then the crude Compound (19) was dissolved in 15 ml of a mixture solution of anhydrous acetonitrile-chloroform and to this solution were added 2430 mg of p-nitrobenzyl (1R,5R,6S)-2-(di-phenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (20)] and 2.8 ml of diisopropylethylamine under ice-cooling and nitrogen gas atmosphere. After stirring the reaction mixture for 2 hours under the same conditions, ethyl acetate was added and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution. The solvent was removed and the resulting residue was purified by silica gel column chromatography (chloroform: acetone =1:2) to give 1339 mg [65% yield from Compound (18)] of p-nitrobenzyl (1R,5S,6S)-2-[(1-(thiazolin-2-yl)azetidin-3-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [Compound (21)].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+:19]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[O-:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+:19]
Reactant: Oc1ccccc1
Agent: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: [O-]c1ccccc1

Procedure:
Parahydroxybenzoic acid has been used for manufacturing a wide variety of products including liquid crystalline polymers and preservatives for cosmetics and medicines. Generally, parahydroxybenzoic acid is prepared by a method in which phenol is reacted with potassium hydroxide to give potassium phenoxide, and the obtained potassium phenoxide is reacted with carbon dioxide under pressure to give potassium parahydroxybenzoate and then, parahydroxybenzoic acid is isolated by means of aciding out procedure, i.e. by adding a mineral acid to the salt.