Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[O:32]>O.ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:31]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[O:32])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: CC#CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (3aS,7aS)-3-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 0.4105 g, 1.15 mmol) and potassium carbonate (0.170 g, 1.23 mmol) in water (3.00 mL) was added a solution of but-2-ynyl chloroformate (0.156 mL, 1.38 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature overnight. The mixture was poured into hydrometrix varian column chem elut catridge column and rinsed with dichloromethane (3 Column volumes). Concentrated in vacuo and the residue was purified by flash chromatography (0 to 50% MeOH/Ethyl acetate) and followed by preparative LC/MS (high pH) to give the title compound (0.036 g, 7.59%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1H NMR (400 MHz, CDCl3) δ ppm 1.30-1.47 (m, 6H), 1.49 (s, 2H), 1.62-1.76 (m, 1H), 1.76-2.00 (m, 9H), 2.34 (s, 2H), 2.72-2.98 (m, 6H), 2.99-3.09 (m, 2H), 3.49-3.85 (m, 2H), 4.11 (s, 1H), 4.27 (s, 2H), 4.49 (s, 1H), 4.61-4.72 (m, 2H) MS (M+1): 417.3.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([S:27]([OH:30])(=[O:29])=[O:28])[CH:12]=[C:13]3[C:18]=2[C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:16][C:15]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:14]3)=[O:7])=[C:4]([S:33]([OH:36])(=[O:35])=[O:34])[CH:3]=1.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:106][C:107](=O)[C:108]2[CH:113]=[CH:112][C:111]([N+:114]([O-:116])=[O:115])=[CH:110][C:109]=2[S:117]([OH:120])(=[O:119])=[O:118])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[N+:114]([C:111]1[CH:112]=[CH:113][C:108]([C:107]([NH:1][C:2]2[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]3[CH:10]=[C:11]([S:27]([OH:30])(=[O:28])=[O:29])[CH:12]=[C:13]4[C:18]=3[C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:16][C:15]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:14]4)=[O:7])=[C:4]([S:33]([OH:36])(=[O:35])=[O:34])[CH:3]=2)=[O:106])=[C:109]([S:117]([OH:120])(=[O:118])=[O:119])[CH:110]=1)([O-:116])=[O:115]
Reactant: Nc1ccc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(S(=O)(=O)O)c1
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(S(=O)(=O)O)c1)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 165.3 %

Procedure:
To an ice-cold solution of 17.2 g of 8-(4-amino-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid, tetrasodium salt, and 5.24 g of sodium acetate trihydrate in 100 ml of water was added 6.87 g of 4-nitro-2-sulfobenzoic anhydride. The mixture was stirred for 10 minutes, and filtered through diatomaceous earth. The filtrate was poured into 750 ml of absolute ethanol with vigorous stirring and cooled in an ice bath. The solid was recovered by filtration, washed with ethanol and ether and evaporated in vacuo overnight. This solid was dissolved in 100 ml of water, acidified with 3 ml of concentrated hydrochloric acid, and then poured with vigorous stirring into 500 ml of cold absolute ethanol. The solid was collected by filtration, washed with ethanol, then ether, and dried overnight at 110° C., giving 19.35 g of 8-[4-(4-nitro-2-sulfobenzamido)-2-sulfobenzamido]-1,3,6-naphthalenetrisulfonic acid, pentasodium salt as a powder.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:8][C:7]=1[N+]([O-])=O)#[N:5].O.Cl>CO>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:8][C:7]=1[O:2][CH3:1])#[N:5]
Reactant: N#Cc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1C#N

Procedure:
Sodium methanolate solution (2.8 g of a 30 percent strength solution in methanol) was added to a solution of 3-[4-cyano-3-nitrophenyl]-6-trifluoromethyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (2.4 g) in 50 ml of anhydrous methanol. The reaction mixture was subsequently refluxed for 5 hours. After cooling, water (50 ml) was added first, followed by 10% strength aqueous hydrochloric acid to a pH of 3-4. The precipitate formed was subsequently separated off, washed with water and petroleum ether and dried. Yield: 1.1 g; m.p.: >230° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), pyrrolidine (228 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is evaporated. The residue (65 mg white solid) is triturated with diethylether affording 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (24 mg, 20.9%) as a white solid. mp.: 210-215° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[NH:4]1[CH:5]=[CH:6][C:2]([NH:1][C:7](=[O:9])[CH3:8])=[N:3]1
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc[nH]n1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a 2 L glass flask was charged with 200 g (2.36 mol) of 3-aminopyrazole and 900 g of ethyl acetate. The mixture was agitated at 45° C. for 30 min to form a homogeneous solution. To the mixture was added 245 g (2.36 mol) of acetic anhydride over 1.2 h. The mixture was stirred at 60° C. for 3 h. HPLC analysis of reaction mixture indicated the presence of 3-aminopyrazole. Another 9.7 g (0.09 mol) of acetic anhydride was added into the mixture over 15 min at ca. 60° C. The resulting suspension was agitated for another 2 h at ca. 60° C. The mixture was cooled to 20-25° C. and stirred at that temperature for 15 h. The solids were collected by filtration and washed with 630 g of ethyl acetate. The solids were dried in a vacuum oven (45-50° C./P≦−0.1 MPa) for ca. 24 h to afford 295.2 g (94% yield) of N-(1H-pyrazol-3-yl)-acetamide as off-white solid. 1H-NMR (400 MHz, d6-DMSO): δ 12.26 (s, 1H), 10.33 (s, 1H), 7.57 (s, 1H), 6.47 (s, 1H), 1.99 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C(C)CCOC(C1C(=O)[O:17][C:18]2[C:23](C=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)=O>>[CH:21]1[CH:22]=[C:23]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:18]([OH:17])=[CH:19][CH:20]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)CCOC(=O)c1cc2ccccc2oc1=O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 80 °C

Procedure:
The preparation of tagged diphenol 2.4 (3,3-bis(4-hydroxyphenyl)butyl 2-oxo-2H-chromene-3-carboxylate). Phenol (200 mmol) and a catalyst (e.g., Cs2.5H0.25DEAT0.25PW12O40, 0.5 g) can be combined under nitrogen in a 250 mL three necked flask equipped with a condenser and a magnetic stirrer and heated to 80° C. with stirring. A tagged ketone (20 mmol), such as 2-oxo-2H-chromene-3-carboxylic acid 3-oxo-butyl ester, can be added and diphenol 2.4 can be produced with high (e.g., approximately 96%) selectivity for the p,p-isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Na+].[CH3:30][S:31]([O-:33])=[O:32].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O>[CH3:30][S:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3ccc(Br)cc3)nc2)CC1
Reactant: CS(=O)[O-]
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Yield: 31.2 %

Procedure:
The title compound (0.12 g, 31%) was prepared as a white solid from 1,1-dimethylethyl 4-({[2-(4-bromophenyl)-5-pyrimidinyl]oxy}methyl)-1-piperidinecarboxylate (0.385 g, 0.86 mmol), methanesulfinic acid sodium salt (0.16 g, 80%, 1.29 mmol), L-proline (20 mg, 0.17 mmol), Cul (17 mg, 0.09 mmol) and NaOH (7 mg, 0.17 mmol) in DMSO (5 mL) in a manner similar to Example 76, Step 3. 1H NMR (400 MHz, CD3OD): δ 8.60 (s, 2H), 8.57 (d, 2H, J=8.5 Hz), 8.03 (d, 2H, J=8.6 Hz), 4.20-4.10 (m, 2H), 4.08 (d, 2H, J=6.1 Hz), 3.15 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(I)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(I)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 12 h

Procedure:
4-Hydroxy-3-nitroiodobenzene (3.2 g, 12.0 mmol) was dissolved in acetone (30 mL). K2CO3 (1.8 g, 1.1 equiv) and Me2SO4 (1.23 mL, 1.1 equiv) were added to the solution. The mixture was stirred at 65° C. for 12 h. The reaction was then cooled, concentrated, and diluted with H2O (100 mL) and CHCl3 (100 mL). The mixture was shaken in a separatory funnel. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 4-methoxy-3-nitroiodobenzene as a beige solid (3.3 g, 12.0 mmol, quant.): mp: 92-93° C. 1H NMR (300 M Hz, CDCl3) δ 8.13 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.7, 2.4 Hz), 6.86 (d, 1H, J=8.7 Hz), 3.95 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1CCNCC1
Product: CC1(C)c2cc(N3CCCCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidine.
Reaction SMILES: C([NH:4][C@:5]1([C:41](=[O:47])NC(C)(C)C)[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][N:7]([CH2:22][CH:23]2[CH2:32][C:31]3[C:26](=[CH:27][C:28]([Cl:33])=[CH:29][CH:30]=3)[CH2:25][N:24]2C(OC(C)(C)C)=O)[CH2:6]1)(=O)C.[ClH:48].[OH2:49]>>[ClH:33].[ClH:48].[ClH:33].[NH2:4][C@:5]1([C:41]([OH:49])=[O:47])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:22][CH:23]2[CH2:32][C:31]3[C:26](=[CH:27][C:28]([Cl:33])=[CH:29][CH:30]=3)[CH2:25][NH:24]2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O
Agent: Cl
Product: N[C@@]1(C(=O)O)CN(CC2Cc3ccc(Cl)cc3CN2)C[C@@H]1CCCB(O)O
Temperature: 25 °C

Procedure:
In an Ace pressure tube, a solution of tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (280 mg, 0.415 mmol) was treated with concentrated HCl (8 mL) and stirred at room temperature. After 10 min the tube was sealed, and the mixture was heated to ˜118° C. for 16 h. After cooling to room temperature, the solution was carefully diluted with water (20 mL) and washed with methylene chloride (2×15 mL). The aqueous phase was concentrated under reduced pressure, and the resulting residue purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give (3R,4S)-3-amino-1-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-4-[3-(dihydroxyboryl)propyl]-pyrrolidine-3-carboxylic acid trihydrochloride (mixture of 2 diastereomers, each a racamate) (102 mg, 49%) as a faint yellow amorphous solid. 1H NMR (0.1M DCl in D2O, 400 MHz) δ 7.23 (m, 1 H), 7.15 (m, 2 H), 4.37 (s, 2 H), 4.00 (m, 3 H), 3.84 (m, 2 H), 3.69 (m, 1 H), 3.43 (m, 1 H), 3.22 (m, 1 H), 2.98 (m, 1 H), 2.68 (m, 1 H), 1.60 (m, 1 H), 1.25 (m, 3 H), 0.64 (m, 2 H). ESI+ MS found for C18H27BClN3O4 m/z 378.1 (M−18+H), 360.1 (M−36+H); ESI− MS m/z 376.2 (M−18−H).
Reaction SMILES: C1(C2CCC(N3CC[O:16]CC3)=CC2)CCCCC1.C1(N=C=S)C=CC=CC=1.[CH:28]1([CH:34]2[CH2:39][CH2:38][C:37](N3CCOCC3)=[C:36]([C:46](=[S:54])[NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH:34]2[CH2:39][CH2:38][C:37](=[O:16])[CH:36]([C:46](=[S:54])[NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: S=C(Nc1ccccc1)C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Reactant: C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Solvent: S=C=Nc1ccccc1
Product: O=C1CCC(C2CCCCC2)CC1C(=S)Nc1ccccc1

Procedure:
Using the procedure of example 1 and starting from 9.2 g of 4-cyclohexyl 1-morpholyl cyclohex-1 ene and from 5 g phenyl isothiocyanate 7.8 g of 4-cyclohexyl 2-phenylthiocarbamoyl 1-morpholyl cyclohex-1 ene are obtained, melting at 143°. Acid hydrolysis of 7 g of 4-cyclohexyl 2-phenylthiocarbamoyl 1-morpholyl cyclohex- 1 ene gives 4.5 g of 4-cyclohexyl 2-phenylthiocarbamoyl cyclohexanone which melts at 150° .
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=2)[S:16][CH2:15][C:14]1([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH3:24])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=2)[S:16][CH2:15][C:14]1([C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[CH3:24]
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCN
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Methanol (70 ml) and 10% Pd/C (137 mg) were added to (3RS,4RS)-4-(azidononyl)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman (410 mg, 0.93 mmol) and the mixture was stirred for 2 h under hydrogen (normal pressure). When the reaction was completed, the mixture was filtered through celite pad, the filtrate was evaporated in vacuo to give 380 mg (yield: 98%) of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].O1CCCC1.CC(C)([O-])C.[K+]>O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-n2ccccc2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C/C=C/c1ccc(-n2ccccc2=O)cc1
Temperature: -50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
3.00 g of 4-(1,2-dihydro-2-oxo-l-pyridyl)benzaldehyde and 6.15 of β-carboxyethyltriphenyl phosphonium chloride were suspended into 30 ml of tetrahydrofuran, cooled to -50° C. and stirred. 20 ml of a tetrahydrofuran solution of 3.72 g of potassium-tert-butoxide was dropped and the temperature was gradually raised to 0° C. After 10 hours, iced water was added and the aqueous layer was washed with ether. The aqueous layer was adjusted to about pH 3 with concentrated hydrochloric acid, and deposited crystals were collected by filtration to obtain 2.96 g of the above-captioned compound as pale brown yellow powder (yield: 77%).
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12]OS(O)(=O)=O.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:3]([S:10][NH2:12])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(=S)c1ccccc1
Reactant: NOS(=O)(=O)O
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred solution of KOH (560 mg, 10 mmol) in water (15 mL) was added thiobenzoic acid (690 mg, 5 mmol) and hydroxylamine-O-sulfonic acid (565 mg, 5 mmol). The solution was stirred for 20 min at rt. The white solid (S-benzoylthiohydroxylamine) was collected by filtration and then dissolved in CH2Cl2 (10 mL). To this mixture was added benzoic anhydride (2.26 g, 10 mmol). The resulting solution was allowed to stir overnight at rt. The crude product was purified by recrystallization (CH2Cl2/hexane) to give 2 as white solid. m.p. 138-140° C.; 1H NMR (300 MHz, CDCl3) δ 7.92 (m, 4H), 7.60 (m, 1H), 7.53 (m, 1H), 7.39 (m, 4H), 7.17 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 190.0, 159.1, 134.6, 134.4, 133.3, 132.8, 129.3, 129.0, 128.0, 127.3; IR (thin film) cm−1 3265, 3062, 1696, 1659, 1451, 1419, 1257, 1207; HRMS m/z 258.0598 [M+H]+; calcd for C14H12NO2S 258.0589; overall yield: 64% (2 steps).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9]([O:22][Si](C(C)(C)C)(C)C)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9]([OH:22])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(Cl)ncc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of 1.430 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine in 31.5 ml of dry acetonitrile is cooled to 3° C., 1.3 ml of concentrated hydrochloric acid is added dropwise thereto while maintaining the internal temperature at 4° C. or below, and the mixture is stirred in this state for 15 min. The reaction solution is diluted with 200 ml of ethyl acetate, washed with 40 ml of a 5% aqueous sodium hydrogencarbonate solution (aqueous layer pH 9) and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate) to give 1.020 g of (3R,5S)-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methyl-3-hydroxypyrrolidine as a slightly yellow viscous material.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:18])([CH3:17])[CH2:4][CH2:3]1)[O:13][CH:12]=[CH:11][C:10]3=[O:16]>[Pd].CCOC(C)=O.CO>[CH3:1][C:2]1([CH3:19])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:18])([CH3:17])[CH2:4][CH2:3]1)[O:13][CH2:12][CH2:11][C:10]3=[O:16]
Reactant: CC1(C)CCC(C)(C)c2cc3c(=O)ccoc3cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCCC3=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
A solution of 6,6,9,9-tetramethyl-6,7,8,9-tetrahydrobenzo[g]chromen-4-one (4.4 g, 17.2 mmol) in 1:1 EtOAc/methanol (250 ml) containing 10% palladium on carbon (1:1 g, 7% by weight) was stirred at room temperature under an atmosphere of hydrogen (balloon) for 14 h. TLC analysis indicated complete reaction. The mixture was filtered and concentrated to give a yellow oil. The oil was passed through a small column of silica (10% EtOAc in hexane) and concentration to give 6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-one (4.2 g, 16.3 mmol, 95%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 6.86 (s, 1H), 4.46 (t, 2H), 2.75 (t, 2H), 1.65 (s, 4H), 1.25 (s, 12H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]2=[N:17][N:18]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:19]=[C:13]2[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:18]1[CH:19]=[C:13]2[CH2:12][NH:11][CH2:16][CH2:15][C:14]2=[N:17]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCN(C(=O)OCc3ccccc3)C4)c2c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2nccc(-n3cc4c(n3)CCNC4)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(6-methoxy-quinolin-4-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid benzyl ester (300 mg, 0.7 mmol) in EtOH (3 mL) was added HCO2NH4 (70 mg, 1 mmol) and 10% Pd/C (300 mg). The mixture was stirred at RT for 16 h. The crude mixture was filtered through diatomaceous earth, washing with EtOH (10 mL), and the filtrate was concentrated to afford 203 mg (100% crude) of the title compound as a pale yellow foam. MS (ESI): exact mass calculated for C16H16N4O, 280.13; m/z found, 281.32 [M+H]+. 1H NMR (3:2 mixture of isomers; 500 MHz, CDCl3): 8.80-8.79 (m, 0.6H), 8.78-8.76 (m, 0.4H), 8.08-8.05 (m, 1H), 7.73-7.62 (m, 2H), 7.24-7.18 (m, 0.6H), 7.11 (s, 0.4H), 5.00 (s, 2H), 4.68 (s, 0.8H), 4.52 (s, 1.2H), 3.61-3.58 (m, 3H), 3.01 (td, J=6.9, 3.3, 0.6H), 2.54 (s, 0.4H), 2.38 (s, 1H), 2.02 (t, J=7.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.[CH:12]([NH2:14])=O>O>[CH3:7][C:6]1[C:2]2[N:1]=[CH:12][NH:14][C:8](=[O:10])[C:3]=2[S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: NC=O
Solvent: O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 200 °C
Reaction time: 3 h

Procedure:
Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0 g) was added to formamide (5 mL), and the mixture was stirred at 200° C. for 3 hours. After cooling to room temperature water (50 mL) was added thereto and then stirred for 15 hours at room temperature to obtain a solid. The solid was filtered, washed with water and dried with N2 gas to obtain the title compound as a white solid without further purification.