Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[O:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.030 g (11.76%). 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.61-1.65 (m, 2H), 2.29 (d, 3H, J=0.8 Hz), 2.37 (s, 3H), 2.96 (s, 3H), 4.06 (s, 3H), 6.69 (s, 1H,), 7.14 (s, 1H), 7.28 (apparent t, 2H), 7.34 (dd, 1H, J=1.6, 8.4 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.88 (s, 1H), 7.96-8.00 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH:41]2[CH2:45][CH2:44][N:43]([CH3:46])[C:42]2=[O:47])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:37]1[CH:38]=[C:39]([O:40][CH:41]2[CH2:45][CH2:44][N:43]([CH3:46])[C:42]2=[O:47])[CH:48]=[C:49]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:13]=[CH:14][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:24]=2[CH:25]=1
Reactant: Cc1cc(OC2CCN(C)C2=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCN(C)C6=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-1-methylpyrrolidin-2-one following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.60 min; Mass spectrum (ESI+): m/z=560 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC#N.O>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([Cl:20])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC#N
Solvent: O
Product: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-hydroxy-phenyl)-propionic acid benzyl ester (13.36 g, 52.1 mmol) in MeCN (100 ml) was cooled to 0° C. Trichloroisocyanuric acid (4.00 g, 17.2 mmol) was added, and the resulting white suspension was gradually allowed to warm to RT and stirred overnight. The reaction mixture was diluted with water (200 ml) and the product was extracted into EtOAc (250 ml) and dried (MgSO4). Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, s), 7.32 (3H, m), 7.29 (2H, d), 7.18 (1H, d), 6.97 (1H, dd), 6.85 (1H, d), 5.07 (2H, s), 2.76 (2H, t), 2.64 (2H, t). LC-MS Rt 1.46 mins; 313.2 [M+H]+, Method 2minLC_v002.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][C@@H:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Si:20]([O:21][C@@H:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: N#Cc1cc(-c2nnc(Br)s2)ccc1F
Reactant: CC1(C)OB(c2cccc3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Prepared using General Procedure 1: A 20 mL microwave vial was charged with 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (30 mg, 0.1 mmol), (S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (43.6 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol) and a 3:1 mixture of DME/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and mixture degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EA (10 mL), and washed with water and brine. The organic layer dried over MgSO4, concentrated, and purified by silica gel chromatography (EA/hexanes) to provide 25 mg (44%) of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C24H26FN3OSSi: 451.15; found 452.1 [M+H]+, tR=4.53 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.34-8.25 (m, 2H), 7.85 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.44-7.34 (m, 2H), 5.34 (t, J=7.1 Hz, 1H), 3.46 (ddd, J=16.8, 9.0, 2.8 Hz, 1H), 3.13 (dt, J=16.8, 8.3 Hz, 1H), 2.61-2.50 (m, 1H), 2.08-1.96 (m, 1H), 0.98-0.95 (m, 9H), 0.22-0.17 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.[S].C(=S)=[S:19]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:9]1[S:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: S=C=S
Reactant: c1ccc2scnc2c1
Agent: [S]
Solvent: Nc1ccccc1
Product: Sc1nc2ccccc2s1

Procedure:
The distillates containing aniline and benzothiazole, can be reacted with carbon disulphide and sulphur, if appropriate together with fresh aniline and/or benzothizole, in a known manner to give highly pure 2-mercaptobenzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3ccc(Cl)cc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4ccc(Cl)cc4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (117 mg, 0.430 mmol) in EtOH was added hydantoin (43 mg, 0.430 mmol) and piperidine (43 μL, 0.430 mmol). The mixture was heated at 70° C. overnight. Solvent was removed under reduced pressure and the remaining solid was washed with EtOAc to yield 5-((5-(4-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[CH2:20])=[C:14]([OH:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[CH2:20])=[C:14]([O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCCCCCCCCI
Reactant: C=CCc1ccc(Oc2ccc(C(=O)OCC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCc1ccc(Oc2ccc(C(=O)OCC)cc2)cc1OCCCCCCCCCC
Yield: 48.1 %

Procedure:
Following the general procedure of Example 1H above, 7.11 g of 4-[3-hydroxy-4-(2-propenyl)phenoxy]benzoic acid ethyl ester was allowed to react with 6.38 g of decyl iodide in the presence of 3.3 g of potassium carbonate to provide 5.02 g of the desired subtitle intermediate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[N:18]([CH3:31])[C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: CI
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by dissolving the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione from Example 10 (1.8 g, 4.6 mmol) in 10 ml of dimethylformamide at 0° C. After treating this solution with NaH (203 mg, 5 mmol) followed by 720 mg (5 mmol) of methyl iodide, the mixture was stirred at room temperature for 24 hours. The reaction was poured into water and extracted with CH2Cl2. The combined extracts were washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using 2% MeOH/CH2Cl2. The title compound was crystallized from CH2Cl2 /hexane to give a white solid (1.04 g, 54% yield), mp 176°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[Br:22].C(OCC)(=O)C.[H][H]>[C].[Ru].C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Br:22]
Reactant: Brc1ccc2ccccc2c1-c1c(Br)ccc2ccccc12
Reactant: [H][H]
Agent: [Ru]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2
Temperature: 30 °C
Reaction time: 20 h

Procedure:
A 500 ml capacity stainless steel autoclave was charged with 35 g (0.085 mol) of 2,2'-dibromo-1,1'-binaphthyl, 5.25 g of 5%-ruthenium-carbon (manufactured by NECHEMCAT), 130 ml of ethyl acetate and 130 ml of 95% ethanol. After carrying out 20 hours of hydrogenation at a temperature of 100° C. under a hydrogen pressure of 50 kg/cm2, absorption of 4 mols of hydrogen per mol substrate was confirmed. The reaction mixture was cooled to 30° C. to remove the catalyst by filtration, the resulting filtrate was allowed to stand overnight at room temperature and then 30.6 g of the thus precipitated crystals were collected by filtration (yield, 85.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1ccnc(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(O)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 2-hydroxyisonicotinic acid (1.4 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 40 mmol) at 0° C., the mixture was stirred overnight. The solvent was evaporated in vacuo and water was added. The mixture was extracted with ethyl acetate (100 mL×3), the organic phase was dried sodium sulfate and evaporated in vacuo to give methyl 2-hydroxyisonicotinate (1.2 g, 78%). LRMS (M+H+) m/z: calcd 153.04. found 153.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5].S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27]>O>[OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:12][C:13]=1[N+:26]([O-:28])=[O:27])(=[O:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(CCO)Cc1ccc(CS(=O)(=O)CCO)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)CCO)ccc1CS(=O)(=O)CCO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
80.5 parts of 1,4-bis(hydroxyethylsulfonylmethyl)benzene are stirred into 612.5 parts of 100% strength sulfuric acid, and the mixture is heated at 35° to 40° C. until a sample shows quantitative esterification in the HPLC chromatogram (about 4 to 5 hours). 57 parts of a mixture of 30 parts by weight of 100% strength nitric acid and 70 parts by weight of 100% strength sulfuric acid (so-called "M3 acid") are then added dropwise over a period of 4 hours at 30° to 40° C., stirring is continued for 2 hours at 45° C. until the nitration is completed (checked by HPLC chromatogram), and the reaction mixture is then decomposed by pouring it into 2,500 parts of cold water. The resulting aqueous acidic solution is then refluxed (about 110° C.) for 5 hours to hydrolyze the sulfuric ester groups, 5 parts of activated carbon are then added, the mixture is clarified and the clarified filtrate is cooled to 0° to 5° C. with stirring. The resulting precipitate is filtered off with suction, washed neutral and dried in vacuo at 80° C. This gives 89.0 parts of 2,5-bis(hydroxyethylsulfonylmethyl)nitrobenzene of the formula ##STR20## in the form of colorless crystals of melting point 125° to 126.5° C., the purity of which (HPLC) is 98.8%.
Reaction SMILES: Cl[C:2]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[N:3]=1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[CH:10]1([C:9]2[C:2]([O:29][C:27]3[CH:26]=[CH:25][C:24]4[B:20]([OH:30])[O:21][CH2:22][C:23]=4[CH:28]=3)=[N:3][C:4]([O:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[C:5]([CH:8]=2)[C:6]#[N:7])[CH2:12][CH2:11]1
Reactant: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(C2CC2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinonitrile (360 mg, 1.29 mmol), compound benzo[c][1,2]oxaborole-1,5(3H)-diol (232 mg, 1.55 mmol) and Cs2CO3 (505 mg, 1.55 mmol) in DMSO (20 mL) was stirred at 40° C. overnight. The mixture was diluted by water, extracted by EtOAc, the separated organic layer was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1˜3:1) to afford 5-cyclopropyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile. (200 mg, 40%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.20 (s, 1H), 7.86 (s, 1H), 7.75 (d, J=8.0, 1H), 7.24 (d, J=2.0, 1H), 7.16 (dd, J=8.0, 2.0, 1H), 4.97 (s, 2H), 3.94 (t, J=7.8, 2H), 3.29 (t, J=7.8, 2H), 2.02 (m, 4H), 1.65 (t, J=7.8, 2H), 0.92 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)(=O)C>[Br:20][CH2:17][C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(CO)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(CBr)c1

Procedure:
12 g of the N-(4-chloro-3-hydroxymethylphenyl)-2-methyl-3-furancarboxamide prepared in Step 5 above, was dissolved in 180 ml ethyl acetate. 1.8 ml of phosphorus tribromide was then added. The resultant mixture was stirred for 90 minutes at room temperature. 100 ml of water was then added to the mixture. The resultant organic phase was separated, washed with water, aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. The solvent was evaporated off to produce 12.97 g of N-(3-bromomethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide as a solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=O)[O:9]CC.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([S:28]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[N+:36]([O-])[CH:35]=[CH:34]3)(=[O:30])=[O:29])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([S:28]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37]([O:9][CH3:8])=[N:36][CH:35]=[CH:34]3)(=[O:30])=[O:29])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c[n+]([O-])ccc3c2)CC1
Reactant: CCOC(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1nccc2cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 mL of triethylamine and 0.1 mL of ethyl chlorocarbonate were added dropwise with stirring at 0° C. to a methanol (5 mL) solution of 300 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide, and the mixture was then stirred at room temperature for 3 hours. After the completion of reaction, the reaction solvent was distilled off under reduced pressure. To the obtained residue, 20 mL of ethyl acetate was added, and the deposited insoluble matter was removed by filtration. The filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 110 mg of the compound of interest as a white crystal (36%).
Reaction SMILES: O.O=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[C:10]1([NH:16][N:17]=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C(=O)C(=O)O
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(O)C(=NNc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a vigorously stirred solution of ketomalonic acid monohydrate (29.33 g) in ethanol (140 ml) and water (300 ml) at ambient temperature was added phenylhydrazine (23.3 g) dropwise over a 40 minute period. The resultant slurry was stirred overnight at ambient temperature. The solid was separated by filtration, washed sucessively with cold water (100 ml) and ethanol (25 ml) and air dried. Subsequent drying was performed at 75° C. overnight in a vacuum oven to give the title compound as a yellow solid (42.38 g). 1H (300 MHz, DMSO-d6): d 7.12(t, 1H), 7.35-7.48(m, 4H); m.p.: 155°-157° C. (dec).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.CN(C)C=O.[C:12]1([N:18]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=CC(=O)[NH:21][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:6][C:1]1[CH:2]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[N:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(=O)[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1nc(Cl)cc(-c2ccccc2)n1-c1ccccc1
Yield: 34.9 %

Procedure:
Oxalyl chloride (3.1 g, 24.4 mmol) was added to a mixture of N,N-dimethylformamide (1.8 g, 24.6 mmol) in dichloromethane (30 ml) at −5° C. to 0° C. under stirring. After the completion of addition the reaction temperature was allowed to reach 20° C. to 25° C. 1,6-Diphenyluracil (4.0 g, 15.2 mmol) was added in portions to the resulted suspension for 2.5 hrs. The reaction mixture was heated to reflux for 4 hours under stirring and continued stirring for 12 hours at room temperature. The reaction mass was poured onto sodium hydroxide solution (150 ml, 0.25 N) and collected the dichloromethane layer. The dichloromethane layer was washed with hydrochloric acid (200 ml, 0.025N), water and saturated sodium chloride solution successively. The organic extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (1.5 g, 35%, HPLC purity 99.8%), mp: 141-143° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[CH:16]=[O:17].S(=O)(=O)(O)O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[OH:17])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: c1ccsc1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccs2)cc([N+](=O)[O-])c1OC
Reaction time: 0.5 h

Procedure:
18.8 ml of n-butyllithium solution (1.6M in hexane) are added dropwise at -50° within 10 minutes to 4.03 g of thiophene dissolved in 40 ml of tetrahydrofuran. After stirring at -50° for 30 minutes 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -50° for 1 hour at 0° for 30 minutes and poured into 100 ml of 2N sulphuric acid. The mixture is extracted three times with 100 ml of ether each time; the combined ether phases are washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol of m.p. 79°-81° (from methylene chloride/hexane).