Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][N:10]=[C:4]2[C:3]=1[CH2:11][CH2:12][CH3:13].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][N:10]=[C:4]2[C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1c(C)ncn2ncnc12
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1c(CBr)ncn2ncnc12
Temperature: 110 °C

Procedure:
A mixture of 168 (523 mg, 2.75 mmol) and bromine (1.12 g, 7 mmol) in acetic acid (15 mL) is heated in a sealed tube at 110° C. over the weekend. The solvent is removed and the residue is neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. On drying, the solvent is removed and the crude is purified by PTLC (ethyl acetate:hexanes 1:1) to give the product (169).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[Li+].[Br-:22].[BH4-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][C@@:2]12[C:18](=[O:19])[C@H:17]([Br:22])[CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: [Br-]
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](Br)C2=O

Procedure:
16α-Bromoestrone was prepared by bromination of the enol acetate of estrone and then epimerized with LiBr (as described by Fishman et al., J. Org. Chem. 23, 1190 (1958) and Mueller et al., supra, which are hereby incorporated by reference). The resulting mixture of 16α- and 16β-bromoestrone was reduced with NaBH4. All four of the possible bromohydrins were isolated from the reaction mixture by chromatography on silica gel in 5 percent ethyl acetate in benzene. The second compound eluted from the column (60 percent of the reaction mixture) melted at 176° to 178° C., where-upon a new crystalline structure formed (melting point, 255° to 256° C.). It was identified as 16β-bromoestradiol by reaction with KOH to form estrone (cis-bromohydrin); epimerization with LiBr to form 16α-bromoestradiol (compared to an authentic sample); and its mass spectrum. 16α-Iodoestradiol (melting point, 190° to 191° C.) was synthesized from 16β-bromoestradiol by exchange with NaI. Its nuclear magnetic resonance (NMR) and mass spectra were consistent with the predicted structure.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc2N(C)C1=O
Yield: 156.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.014 g (0.0001 mole) of 4-aminobenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-benzoic acid (I-5) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([C:16]([OH:18])=[O:17])=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([C:16]([O:18][C@H:21]4[CH:22]5[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]5)[CH2:20]4)=[O:17])=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1cnc(-c2ccc3c(C(=O)O)n[nH]c3c2)s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc3c(C(=O)O[C@@H]4CN5CCC4CC5)n[nH]c3c2)s1
Temperature: 25 °C
Yield: 1 %

Procedure:
To a solution of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid (0.50 mmol), (3R)-quinuclidin-3-ol (0.57 mmol), and triphenylphosphine (0.57 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a solution of diisopropyl azodicarboxylate (0.57 mmol) in tetrahydrofuran (1 mL). The mixture was allowed to warm to rt over 2 hours and was maintained for 16 h. The mixture was loaded on a SCX column (5 g) and was washed with methanol. Product was eluted with methanol/dimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 1% yield. 1H NMR (CD3OD) δ 8.65 (s, 1 H), 8.51 (s, 1 H), 8.04 (d, J=6.0, 1H), 7.74 (d, J=6.0, 1 H), 7.55 (s, 1 H), 5.45 (m, 1 H), 3.81 (m, 1 H), 3.45-3.20 (m, 5H), 2.55 (s, 3 H), 2.55 (m, 1 H), 2.36 (m, 1 H), 2.21-1.93 (m, 3 H); LC/MS (EI) tR 4.7 min, m/z 369 (M++1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[C:21]([OH:26])(=[O:25])[CH2:22][CH2:23][CH3:24].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.O>[CH2:27]([CH:22]([CH2:23][CH3:24])[C:21]([OH:26])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC(=O)O
Reactant: ClCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Diisopropylamine (3.2 ml) was dissolved in 20 ml of tetrahydrofuran, cooled to 0° C. and treated with 14.2 ml of 1.6M n-butyllithium. After 30 minutes, the lithium diisopropylamide was added to 1 g of n-butyric acid in 75 ml of tetrahydrofuran at -78° C. After 10 minutes the reaction was warmed to -20° C. After 10 more minutes the reaction was warmed slowly to room temperature. The solution was then heated to approximately 35° C. for 30 minutes and then cooled back to room temperature and 1.3 ml of benzyl chloride was added. After 1.5 hours the reaction mixture was heated to 35° C. for 2.5 hours. The solution was then cooled, diluted with 300 ml of water, rinsed with diethyl ether (2×200 ml), and the aqueous phase was acidified with 1M hydrochloric acid and extracted with diethyl ether (3×200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by radial chromatography (50% ethyl acetate in hexane, 2 mm plate) to yield 1.56 g of 2-benzylbutyric acid (77% yield).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])C.C[N:6](C)[CH:7]=[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH:9]=O.C(#N)C[C:20]#[N:21]>O>[C:20]([C:3]1[C:1](=[O:4])[NH:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:9]=1)#[N:21]
Reactant: CN(C)C=C(C=O)c1ccncc1
Reactant: CC(C)O
Reactant: N#CCC#N
Solvent: O
Product: N#Cc1cc(-c2ccncc2)c[nH]c1=O
Temperature: 3 °C

Procedure:
To 2500 ml of isopropyl alcohol heated to reflux was added with stirring 300 g of 3-dimethylamino-2-(4-pyridinyl)-2-propen-1-one [same as α-(4-pyridinyl)-β-(dimethyl-amino)acrolein]. To the resulting mixture was added 500 ml of a solution containing 138 g of malonontrile, 1500 ml of isopropyl alcohol and 100 ml of water. The temperature was brought back to reflux in about 10 minutes and then the remainder of the malononitrile solution was added from a dropping funnel over a period of about 25 minutes. The reaction mixture was stirred at reflux for additional 35 minutes and the resulting orange suspension was cooled to 3° C. The precipitated solid was collected by filtration and the filter cake was washed with four 100 ml portions of cold isopropyl alcohol. The solid was then dried at 40° C. in vacuo overnight (about 15 hours) and then for two hours at 60° C. to yield 245 g of 5-cyano[3,4'-bipyridin]-6(1H)-one [same as 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile], m.p.>300° C. The nuclear magnetic resonance spectrum of this product was consistent with that of the same product prepared by another method. The filtrate was concentrated in vacuo to about 500 ml volume and cooled in an ice bath. A total of 40 g of a second crop material was obtained, m.p.>300° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH:13]([OH:15])=[O:14].[CH2:16](N(CC)CC)C>>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH2:1][CH2:16][C:13]([OH:15])=[O:14])[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: O=CO
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
4.80 g (0.025 mol) of 2,2-pentamethylene-1,3-dioxane-4,6-dione (m.p.: 94° C.) and 4.15 g (0.025 mol) of veratraldehyde were added to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction was carried out according to Example 1.
Reaction SMILES: N[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.N([O-])=O.[Na+].O.[BrH:22]>C(O)(=O)C.OS(O)(=O)=O>[Br:22][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: CC1(C)C=Cc2cc(N)c([N+](=O)[O-])cc2O1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C=Cc2cc(Br)c([N+](=O)[O-])cc2O1
Reaction time: 0.5 h

Procedure:
A suspension of 6-amino-2,2-dimethyl-7-nitro-2H-1-benzopyran (5.0 g, the preparation of which was described in J. Med. Chem., 26, 1582 (1983)) in glacial acetic acid (19 mL) was added dropwise to a stirred solution of sodium nitrite (1.6 g) in conc. H2SO4 (19 mL) while maintaining the temperature below 10° C. After an additional 0.5 h, the dark brown solution was added to a stirred solution of CuBr (6.5 g) in 47% HBr (53 mL). After 1 h, water was added to the solution and it was extracted with ethyl acetate. The organic extract was washed with water, saturated sodium bicarbonate solution, and dried over anh. MgSO4. The organic layer was filtered, evaporated, and chromatographed on silica gel. Elution with 3% ethyl acetate--60°-80° C. petroleum ether gave the compound of description 1 as a crude solid (3.5 g). Mass spectrum (E.I.) M+ at m/z 282.9848. Calcd. for C11H10NO3Br: 282.9845.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methy ester hydrochloride salt, of Preparation 44, and 2,3- dihydro-benzo[1,4]-dioxine-6-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.26-7.16 (m, 3H), 7.07 (d, 1H), 6.85-6.78 (m, 3H), 4.24 (s, 4H), 3.75 (s, 2H), 3.68 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.62 (t, 2H); MS 342 (M+1).
Reaction SMILES: [CH2:1]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH2:1]([C:7]1[S:8][C:9]([Sn:18]([CH3:20])([CH3:19])[CH3:17])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Hexylthiophene (23.0 g, 0.137 mol) was dissolved in 250 ml THF and n-BuLi (94 ml, 1.6 M in hexanes, 0.150 mol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then cooled down to −78° C. A solution of trimethyltin chloride (32.8 g, 0.164 mol) in 100 ml THF was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 h. After quenching with ice water and aqueous work-up, the product was distilled at 108° C. under high vacuum. 5-Hexyl-2-trimethylstannylthiophene was obtained as a colourless liquid (40.8 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[C:40]([N:37]1[CH2:36][CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:39][CH2:38]1)(=[O:42])[CH3:41]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(=O)N1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CC(=O)N1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanone. MS (ESI): mass calcd. for C22H22FN5O3S, 455.14; m/z found, 456.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=6.0, 2H), 8.11-8.08 (m, 1H), 8.00 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.37-7.29 (m, 2H), 3.43-3.34 (m, 4H), 2.96-2.81 (m, 4H), 2.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[CH2:14][C:15]([O:17]C)=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:8][C:6]1[CH:5]=[C:4]2[C:3]([CH2:14][C:15](=[O:17])[NH:11]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c2c(c1)NC(=O)C2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of methyl (2-chloro-4,6-dinitrophenyl)acetate, ammonium chloride, iron powder, ethanol and water was stirred at 120° C. for 3 hours. The reaction liquid was filtered, trifluoroacetic acid was added to the filtrate, followed by stirring overnight at room temperature. The reaction liquid was concentrated under a reduced pressure, 1 M sodium hydroxide was added to the residue, and this was post-treated to obtain 6-amino-4-chloro-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13](O)([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)(Cl)Cl>[N:27]([C:13]([C:11]1[CH:10]=[CH:9][C:8]([NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:12]=1)([CH3:15])[CH3:14])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(N=[N+]=[N-])c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in example 12, 15.0 mg, 0.0428 mmol) and NaN3 (27.8 mg, 0.428 mmol) in 1 mL of chloroform at 0° C. under Ar was added TFA (49 μL, 0.642 mmol). The resulting mixture was stirred at 0° C. for 1 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with saturated NaHCO3 aqueous solution (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0-5% EtOAc/DCM) gave 13.6 mg (84%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C20H21N7O, 376.2 (M+H), found 376.0.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:8]>O.CO>[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:21])=[O:1])[N:15]=1)#[N:8]
Reactant: CSc1nccc(-c2[nH]ncc2C#N)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1nccc(-c2[nH]ncc2C#N)n1
Reaction time: 20 h

Procedure:
A solution of Oxone (475 mg, 0.77 mmol, 1.2 equiv) in water(10 mL) was added to a solution of 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (4-3, 670 mg, 2.86 mmol, 1 equiv) in methanol (150 mL), and the resulting mixture was stirred under ambient condition for 20 hours. The reaction was concentrated and the resulting residue was sonicated in water and filtered to provide 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidine (4-4) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 9.11(dd, 1H, J=5 Hz), 8.83 (br s, 1H), 8.10 (dd, 1H, J=5 Hz), 3.04 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].CO.[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:12]([CH:17]=O)[C:13]=1[C:14]([NH2:16])=[O:15])=[O:7].[BH4-].[Na+]>O1CCCC1.CC(C)=O>[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:12]([CH2:17][NH:2][CH3:1])[C:13]=1[C:14]([NH2:16])=[O:15])=[O:7]
Reactant: CN
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(C=O)c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: CNCc1c(-c2cccc(Cl)c2)[nH]c(NC(N)=O)c1C(N)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
40% Methylamine in methanol (1 mL, 9.8 mmol) was added to a suspension of 2-aminocarbonylamino-5-(3-chlorophenyl)-4-formylpyrrole-3-carboxamide (Compound No. 17-1, 45 mg, 0.15 mmol) in tetrahydrofuran (1 mL), and the mixture was sealed and stirred at 40° C. for 3 hours. Moreover, sodium borohydride (25 mg, 0.66 mmol) was added thereto and the whole was stirred at room temperature for 3 hours. Acetone (5 mL) was added to the reaction solution and concentrated in vacuo. Water (10 mL) was added to the obtained residue, and the precipitated solid was filtered off. The solid was washed with water (10 mL) and the mixed solvent (5.5 mL), which consists of chloroform and ethanol (10:1), dried under reduced pressure to give the target compound (17 mg) as an orange solid (Yield 36%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1C2C(=CC=C(I)C=2)N=[CH:13][C:12]=1[C:22]([NH2:24])=[O:23]>>[Cl:10][C:11]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([Cl:9])=[CH:7][CH:6]=2)[N:4]=[CH:13][C:12]=1[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: Cc1c(N)cccc1Cl
Product: Cc1c(Cl)ccc2c(Cl)c(C(N)=O)cnc12

Procedure:
Intermediate 68 was prepared from 2-methyl-3-chloroaniline (Aldrich) in a similar manner to Intermediate 13.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17](CBr)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[OH:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].[CH3:32]N(C=O)C>>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([O:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])=[N:16][C:15]3[C:10]2=[N:11][C:12]([CH3:32])=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CCOP(=O)(CO)OCC
Reactant: Nc1ncnc2c1nc(CBr)n2CCC1CCCCC1
Agent: [Na]
Product: CCOP(=O)(COc1nc2c(N)nc(C)nc2n1CCC1CCCCC1)OCC

Procedure:
A solution of N9-cyclohexylethyl-8-bromomethyladenine (1 mmol) in DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium salt (1 mmol) in DMF at 25° C. for 1 h. Extraction and chromatography gave N9-cyclohexylethyl-8-diethylphosphonomethoxy-methyladenine as a white solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(C)=CC=1.BrBr.O>C(O)(=O)C.[Co]>[CH3:13][O:8][C:6](=[O:7])[CH3:5].[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)cc1
Agent: [Co]
Agent: BrBr
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: COC(C)=O

Procedure:
In a process for the synthesis of terephthalic acid, comprising the oxidation of para-xylene in acetic acid solution, at a temperature of from 100° to 230° C. and at a pressure from 1 to 30 kg/cm2, and in the presence of a catalytic system based on manganese, bromine and cobalt, whereby water is formed and methyl-acetate is by-produced during the oxidation, whereby solid terephthalic acid is separated from the mother liquor and whereby one withdraws from the oxidation zone a liquid which is obtained by condensing the vapors released during the oxidation and which are mainly consisting of acetic acid and water, the improvement for the recovery of the acetic acid solvent, the catalyst and the methyl acetate, comprising:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=590.2 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and benzoyl chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:16]=1[CH2:17][N:18]1[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]1=[O:25]>ClCCl.O>[CH3:1][S:2]([O:24][CH2:23][CH:21]1[CH2:20][C:19](=[O:25])[N:18]([CH2:17][C:16]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:15]=2[O:14][CH3:13])[CH2:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2CC(CO)CC2=O)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2CC(COS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
MsCl (3.3 g, 28 mmol) and Et3N (3.8 g, 38 mmol) were added to a mixture of 1-(2,4-dimethoxybenzyl)-4-(hydroxymethyl)pyrrolidin-2-one (5.0 g, 19 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 10 hours then diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford [1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]methyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 7.13-7.15 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 4.09-4.14 (m, 2H), 3.79-3.82 (m, 6H), 3.36-3.42 (m, 1H), 3.12-3.19 (m, 1H), 2.98 (s, 3H), 2.62-2.75 (m, 2H), 2.21-2.25 (m, 1H). MS ESI calc'd. for C15H22NO6S [M+H]+ 344. found 344.