Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]2[N:13]=[C:12]([Cl:14])[N:11]=[C:10]([Cl:15])[N:9]=2)=[CH:5][C:4]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:3]=2[CH:2]=1)=[O:17].CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C([N:57](CC)CC)C>>[CH:1]1[C:6]([NH:7][C:8]2[N:13]=[C:12]([Cl:14])[N:11]=[C:10]([Cl:15])[N:9]=2)=[CH:5][C:4]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:3]=2[CH:2]=1)=[O:17].[NH2:57][C@H:4]([C:16]([OH:18])=[O:17])[CH2:3][CH2:2][CH2:1][CH2:6][NH2:7]
Reactant: CCN(CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(Nc3nc(Cl)nc(Cl)n3)cc21
Solvent: CCOC(C)=O
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
α-t-BOC-lysine (1.39 g, 5.64 mmol) was dissolved in 50 ml of 9:1 water-triethylamine, and the solution was cooled to 0° with an ice-water bath. A single portion (1.00 g, 1.88 mmol) of DTAF was added, and the reaction mixture was allowed to stir at 0° for 1.0 hr. The solution was poured into 200 ml of EtOAc, and aqueous citric acid solution was added until the pH of the aqueous phase was approximately 4. The layers were separated, and the aqueous layer was extracted with 100 ml of EtOAc. The combined organic layers were washed with 100 ml of water, dried (MgSO4) and evaporated affording 1.22 g of the DTAF-lysine derivative as an orange foam. The crude product was dissolved in a small volume of MeOH and precipitated by the addition of ether-hexane.
Reaction SMILES: NC(N)=[S:3].S(=O)(=O)(O)O.Br[C:11]1[S:12][C:13]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:23]=[CH:24][C:25]=3[O:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31]C[CH2:29]3)[CH:17]=[CH:16][C:14]=2[N:15]=1.[OH-].[Na+]>C(#N)C.O>[CH:28]1([CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:21][C:20]=2[C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11](=[S:3])[S:12][C:13]=3[CH:19]=2)[CH2:33][CH2:32][CH2:31][CH2:29]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCc1ccc(OCC2CCCC2)c(-c2ccc3[nH]c(=S)sc3c2)c1
Temperature: 90 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
A solution obtained beforehand by adding thiourea (52 mg, WAKO) to 1 M sulfuric acid (5 ml) and mixing them was added with a solution of Intermediate 76 (101 mg) in acetonitrile (5 ml), and stirred at 90° C. for 20 hours. The reaction mixture was poured into water (20 ml), neutralized by addition of 1 N aqueous sodium hydroxide under ice cooling, and then extracted with ethyl acetate (80 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, methylene chloride:ethanol=30:1) to obtain the title compound (Compound No. V-91, 46 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][C:5]=1[C:16]([O:18][CH3:19])=[O:17].S(OC)(O[CH3:24])(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:14])(=[O:15])[N:6]([CH3:24])[C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 30 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a suspension of 3.5 grams (.086 moles) of sodium hydroxide in 68 ml DMF, a solution of 20 grams (.078 moles) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is added in 34 ml DMF over a period of about 5 minutes at about 25° C. 11.9 Grams (.094 moles) of dimethyl sulphate is added over a period of about 30 minutes at a maximum temperature of 30° C. The reaction is stirred for 3 hours at 30° C. and diluted with about 150 ml of water. It is cooled to 15° C., filtered and washed well with water. After drying, there is obtained 20 grams (95%) of product, m.p. 163°-165° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.[C:26](Cl)(Cl)=[O:27].[CH3:30][N:31](C)[C:32]1C=CC=CC=1.ClC([O-])=O.CNC>>[CH3:25][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:26](=[O:27])[N:31]([CH3:32])[CH3:30])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CN(C)c1ccccc1
Reactant: O=C(Cl)Cl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: CNC
Agent: O=C([O-])Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)N(C)C)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran with an equimolar amount of phosgene in the presence of dimethylaniline in a procedure similar to that described above in Example 20 and reacting the resulting chloroformate with dimethylamine, there is obtained 1,2-dihydro-4,4-dimethyl-9-(N,N-dimethylcarbamyloxy)-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.O>CN(C=O)C>[SH:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccncc1)c1ccc(Cl)cc1
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccncc1)c1ccc(S)cc1
Yield: 48.5 %

Procedure:
A suspension of sodium hydrogen sulfide (6 g) in DMF (100 ml) was heated to reflux for 1 h, then cooled and 4-(4-chlorobenzoyl)pyridine (5 g) was added. The mixture was heated at reflux for 2 h, then cooled and added to water. The brown solution was washed with ether, then acidified with citric acid and extracted with dichloromethane (2×100 ml). The solvent was dried and evaporated to give the title compound as beige powder (2.4 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][CH2:17][S:18][CH2:19][CH3:20])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1C=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C.C(OCC)(=O)C>[CH2:19]([S:18][CH2:17][CH2:16][C@@H:9]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]([CH3:23])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)OC
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: CCSCC[C@@H]1C(C(=O)OC)OC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
A mixture of Example 21A (1.12 g, 3.65 mmol) and catalytic 4-methylbenzenesulfonic acid (15 mg) in 2,2-dimethoxypropane (35 mL) at ambient temperature was stirred for 36 hours, diluted with ethyl acetate, washed sequentially with aqueous NaHCO3 and pH 7 buffer, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 10% acetone/hexanes) provided the desired product. MS (ESI) m/e 348 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:31](Cl)(=[O:34])(=[O:33])[NH2:32].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:31](=[O:34])(=[O:33])[NH2:32])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl-2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 15d, 8.65 g. 26.1 mmol) in dimethyl acetamide (48 mL) were added pyridine (8.44 mL, 104 mmol) and sulfamoyl chloride (6.03 g. 52.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a clear oil, which was used immediately in the next step. MS 311 (MH+-boc).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[O:6])=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: C1CCNC1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCCC3)CC2)c(C)c1

Procedure:
Using methyl 2-bromo-4-nitrobenzoate (1.7 g), pyrrolidine (0.54 mL) and 1-(2,4-dimethylphenyl)piperazine (999 mg) and by the reaction and treatment in the same manner as in Preparation Example 151, the title compound (268 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:18][CH3:19])[CH2:9][C@H:10]([CH2:15][CH:16]=[CH2:17])[C:11](OC)=[O:12])=[CH:4][C:3]=1[CH3:20].C1COCC1.[NH2:26][OH:27].[C-]#N.[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:18][CH3:19])[CH2:9][C@H:10]([CH2:15][CH:16]=[CH2:17])[C:11]([NH:26][OH:27])=[O:12])=[CH:4][C:3]=1[CH3:20]
Reactant: NO
Reactant: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)OC
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-Methyl 2-((R)-2-(4-fluoro-3-methylphenyl)-2-methoxyethyl)pent-4-enoate (50 mg) was dissolved into 1 mL of a mixture of THF, methanol, and 50% NH2OH in H2O (2:2:1) and to this solution was added 2 mg KCN. The reaction was stirred for 3 days at room temperature and then quenched by the addition of 1M HCl (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) before being concentrated under reduced pressure. The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to obtain the title compound (34 mg) as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)=O)(C)(C)C.[ClH:25].C(OCC)C>O1CCOCC1>[ClH:25].[CH3:24][O:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of (S)-2-[4-((E)-2-methoxycarbonyl-vinyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (40.2 g, 115 mmol) was added 120 mL of 4 N hydrochloric acid in dioxane and the reaction mixture was stirred for 16 h. Diethyl ether (500 mL) was added to the suspension and the resulting solid was filtered and washed twice with diethyl ether to yield 29.0 g (94%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>CO>[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20](=[O:27])[C:21](=[C:24]([NH:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=2)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)C(=O)OC1=O

Procedure:
Following the procedures of Example 4, an equimolar mixture of 3,5-dinitroaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol was reacted to give 5-acetyl-4-hydroxy-3-[1-(3,5-dinitrophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione. A solution of the latter (3.0 g., 0.008 mol) in 30 ml. of dimethylformamide was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. When absorption stopped the catalyst was filtered and the filtrate poured into 200 ml. of ice-water. The resulting product was filtered, washed with water and dried to give 5-acetyl-4-hydroxy-3-[1-(3,5-diaminophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. above 350° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11]SC)[CH:3]=1.Cl[C:15]1C=CC=C(C(OO)=O)C=1.[S:25](=S)(=[O:28])([O-])[O-:26].[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][S:25]([CH3:15])(=[O:28])=[O:26])[CH:3]=1
Reactant: CSCc1cc(Cl)cc([N+](=O)[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-chloro-3-[(methylsulfanyl)methyl]-5-nitrobenzene (4.26 g) in DCM (190 mL) was treated at 0° C. with portions of m-chloroperbenzoic acid (8.77 g, 77%). The mixture was stirred at 0° C. for further 30 minutes and then 17 hours at room temperature. The reaction mixture was diluted with DCM before disodium sulfurothioate and sodium bicarbonate solution was added and extracted with DCM (2×). The combinded organic phases were washed and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 12% 100%) to give the title compound (4.80 g). An analytical sample was crystallized from acetone/hexan.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[Cl-].[Cl-].[Ca+2]>CCO.O.[Fe]>[Br:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cc(N)c1N
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of compound 4-bromo-2-methyl-6-nitroaniline (5.0 g) in EtOH (85 ml) and water (43 ml) were added iron powder (6.0 g) and CaCl2 (4.8 g) at room temperature and the resulting reaction mixture was then heated at reflux for 4 h. The mixture was then cooled to room temperature, filtered through Celite, and washed with EtOH. The filtrate was concentrated and the resulting residue was diluted with DCM. The DCM layer was successively washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (4.0 g) as a dark brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5](Cl)[C:6]([CH2:8][Cl:9])=O)[CH3:2].[CH2:12]([C:14](=[CH2:17])[CH:15]=O)[CH3:13].S(=O)(=O)([O-])[NH2:19].[NH4+]>C(O)C>[Cl:9][CH2:8][C:6]1[N:19]=[CH:15][C:14]([CH2:12][CH3:13])=[CH:17][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)C(Cl)C(=O)CCl
Reactant: C=C(C=O)CC
Reactant: NS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc(CC)cnc1CCl
Yield: 43.1 %

Procedure:
A solution of 61 g of ethyl-2,4-dichloroacetoacetate (0.306 mol) and 30 g of 2-ethylacrolein (0.357 mol) in 500 mL of absolute ethanol is mixed with 85.5 g of ammonium sulfamate (0.75 mol), and the stirred mixture is heated at reflux for 90 minutes. The reaction is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is concentrated in vacuo, and the residue is chromatographed on silica gel using hexane-ethyl acetate mixtures to give 50 g of crude product. This material is purified by extraction into aqueous hydrochloric acid, washing with hexanes, making the aqueous phase basic with cold ammonium hydroxide, and extracting with hexanes to afford 30 g of the title product as an oil (43%), having elemental analysis calculated for C11H14ClNO2 %C 58.03, H 6.20, N 6.15, Cl 15.57 found %C 58.29, H 6.30, N 6.02, Cl 15.49.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1.ClCCl>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([NH2:17])[NH:18]2)=[CH:8][CH:9]=1)=[O:21]
Reactant: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(N)[nH]c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Yield: 43.3 %

Procedure:
Zinc powder (4.9 g) was added portion-wise at 80° C. to a solution of 4-(cyano-ethoxycarbonyl-methyl)-3-nitro-benzoic acid methyl ester (4.40 g, 15 mmol) in acetic acid. The mixture was then heated for 3 hours at 95° C. and 3 hours at 100° C. before being allowed to cool to room temperature at which point the reaction mixture was filtered and the insoluble matter rinsed with acetic acid. The filtrate was concentrated to give a brown oil which was subjected to flash silica chromatography using ethyl acetate as eluent. The partially purified oil was taken up into dichloromethane and the product precipitated using hexane to give the title compound as a pale brown solid (1.71 g, 6.5 mmol). LC-MS (1) Rt 1.88 min; m/z 263.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]COCC)=[O:9])=[C:6]([O:15][CH2:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)[CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:16][C:17]2[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOCOC(=O)c1c(Cl)cccc1OCc1nc(OC)cc(OC)n1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(COc2cccc(Cl)c2C(=O)O)n1
Yield: 96.2 %

Procedure:
3.8 g of ethoxymethyl 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoate was stirred in a mixed solvent of 30 ml of methanol and 10 ml of water, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was subjected to reaction at room temperature for about 2 hours. The reaction solution was diluted with water and extracted with chloroform, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3.1 g of 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20]>C(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(F)c(F)c1
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (23.88 g, 0.2384 mol) in methylene chloride (150 mL) and pyridine (38.0 mL, 0.470 mol) was added dropwise a solution of 3,4-difluorobenzenesulphonyl chloride (25.0 g, 0.118 mol) in 10 mL of methylene chloride. After stirring for 48 hours the reaction was diluted with more dichloromethane and extracted with 1N HCl. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. LCMS Rt=1.24 minutes MS m/z 277 [MH]+
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:19][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 98 %

Procedure:
Using the general procedure for anilines with 66.8 mg (0.242 mmol) of 2-naphthyltriflate and 30.0 μl (0.329 mmol) of aniline yielded N-phenyl-2-naphthylamine as a white solid (52 mg, 98%), whose NMR spectra were identical to commercial material available from Aldrich.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:15]=[C:14]2[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[C:50]([C:51]#[N:52])=[C:49](Cl)[N:48]=[CH:47][N:46]=1>C(#N)C>[NH2:44][C:45]1[N:46]=[CH:47][N:48]=[C:49]([N:32]2[CH2:33][CH2:34][CH:29]([C:14]3[N:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=4)[N:15]=3)[CH2:30][CH2:31]2)[C:50]=1[C:51]#[N:52]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (109.27 mg; 0.23 mmol; 1.00 eq.) in acetonitrile 2 ml was added ethyl-diisopropyl-amine (0.08 ml; 0.45 mmol; 2.00 eq.) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (35.00 mg; 0.23 mmol; 1.00 eq.), the reaction mixture was stirred at RT for 1 hr, lc-ms showed desired as major product, removed off solvent, got residue, which as title compound directly using for the next step reaction.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=[O:17])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
The product of Example 1B (931 mg, 3.33 mmole) and osmium tetraoxide (28 mg, cat.) were dissolved in 30 ml THF and 15 ml water. The solution was cooled to 0° C. Sodium periodate (1.5 g, 7.0 mmole) was added in small portions. The mixture was stirred at room temperature overnight. The solution was quenched with water, and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to give the crude product, which was purified by chromatography (20% hexane in dichloromethane) to give the title compound (710 mg, 76%). 1H NMR (500 MHz, CDCl3) δ ppm 8.00 (d, J=1.87 Hz, 1H), 7.84 (d, J=8.74 Hz, 1H), 7.59 (dd, J=8.73, 1.87 Hz, 1H), 3.96-4.10 (m, 1H), 3.54-3.76 (m, 4H). MS: (M+H)+=281/283