Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[Cl-].[CH3:19][O:20][C:21]1([O:42][CH3:43])[CH2:25][NH2+:24][C@@H:23]([C:26](=[O:41])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:22]1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][C:21]([O:42][CH3:43])([O:20][CH3:19])[CH2:22][C@@H:23]2[C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)=[O:41])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC1(OC)C[NH2+][C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)C1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(OC)C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 0.12 ml of triethylamine and 127 mg (0.830 mmol) of 4-chlorophenyl isocyanate are added to a solution of 250 mg (0.658 mmol) of (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride in 10 ml of dichloromethane. After stirring at room temperature for one hour, the reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent, giving 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide (“A7”) as a colourless solid; ESI 497.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1cccc(CCO)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanol (0.23 g, 1.50 mmol), 4-dimethylaminopyridine (0.028 g, 0.23 mmol), triethylamine (0.63 mL, 4.50 mmol) and p-toluenesulfonyl chloride (0.34 g, 1.80 mmol) in dry dichloromethane (5 mL) was stirred at rt over night. The solvent was removed in vacuo. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%). Yield: 0.18 g (38%).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[PH:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[P:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)PC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)P(C1=Cc2ccccc2C1)C(C)C

Procedure:
Following the procedure described for the synthesis of 3 (method A), 15.81 g (0.081 mol) of 2-bromo-1H-indene, 9.54 g (0.081 mol) of iPr2PH, 13.9 ml (10.09 g, 0.100 mol) of Et3N, and 2.95 g (2.55 mmol) of Pd(PPh3)4 in 60 ml of toluene gave 1H-Inden-2-yl(diisopropyl)phosphine. The crude product was distilled in vacuum (104–106° C./2 mm). Yield 14.8 g (80%) of colorless oil of 1H-Inden-2-yl(diisopropyl)phosphine, 4.
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=[O:10]>CO>[CH3:1][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([NH2:5])[CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(N)n1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(C)nc(N)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 50 ml of MeOH is added drop wise acetyl chloride (3 ml) at room temperature. After 15 min, 2-amino-6-methylisonicotinic acid (2.3 g) is added and the mixture is stirred overnight at 50° C. After concentrating the solution, the resulting residue is suspended in acetone and then filtered and dried at 50° C. in vacuum, to yield 2-amino-6-methylisonicotinic acid methyl ester (4.1 g). HPLC: Rt=0.91 min (method D)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:16][N:15]=[N:14][N:12]=2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 4-cyanomethyl benzoic acid methyl ester (2.63 g, 15 mmol) in anhydrous toluene (100 mL) was added sodium azide (1.95 g, 30 mmol) and triethylamine hydrochloride (4.13 g, 30 mmol). The reaction mixture was stirred at 100° C. for 24 hours under nitrogen. The reaction mixture was cooled to room temperature, then extracted with water (2×100 mL). The aqueous layer was acidified with concentrated HCl to pH approximately 4. The white solid was filtered off, washed with water, and dried under vacuum at 40° C. overnight, to give methyl-4-(1H-tetrazol-5-ylmethyl)benzoate (2.88 g, 88%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>CO.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccc(Cl)cc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 47.2 mg, 0.150 mmol) in methanol (6.0 mL) was added neat 2,4-dichlorophenyl isocyanate (56.4 mg, 0.300 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a colorless film. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (74.8 mg, 99%) as a colorless film. MS cald. for C26H26Cl2FN2O3 [(M+H)+]: 503, obsd. 503.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1HNMR (DMSO-d6): δ 4.06 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.77-7.68 (m, 5H), 7.84 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.67 (d, J=6.9 Hz, 1H), 10.38 (s, 1H), 12.79 (br s, 1H); MS (m/z): 540.92 [M+H]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1.[Li+].[OH-].O.Cl>C1COCC1>[C:4]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)O)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate prepared above (529 mg, 2.10 mmol) in THF (20 mL), 1N aq. LiOH (7.0 mL, 7.0 mmol) was added. After the mixture was stirred at 40° C. overnight, it was poured into water. The aqueous solution was acidified with 1N HCl to pH 1. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentared in vacuo to give 5-ethynyl-thiophene-2-carboxylic acid (316 mg). MS 153 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cnn(-c2ccccc2N)c1N
Temperature: 25 °C

Procedure:
1.28 g (5.27 mmol) of 5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxamide (Example 21A) are introduced into 30 ml of ethyl acetate and stirred with 5.8 g (25.8 mmol) of tin(II) chloride dihydrate at 70° C. for 16 hours. After cooling to room temperature, the solution is adjusted to pH 9-10 with saturated sodium bicarbonate solution. The tin salts precipitated thereby are filtered off through kieselguhr. The filtrate is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over sodium sulphate, the solvent is removed in vacuo. 0.82 g (72% of theory) of the desired product is obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:17]1C=CC=C[CH:18]=1.CN>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:15])[NH:17][CH3:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: c1ccncc1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
A solution of 1-Boc-4-(chlorocarbonyl)piperazine (300 mg, 1.22 mmol), pyridine (288.4 mg, 3 equiv), and methylamine (1.83 mmol, 1.5 equiv) in dichloromethane was refluxed overnight. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜70% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=O.C([NH2:20])C1C=CC=CC=1.ClCCl.CO.[OH-].[NH4+]>>[OH:1][CH2:2][C:3]1([NH2:20])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Typical procedure from fructose: 18.0 g (100 mmol) of D-(−)-fructose was treated at 0° C. with freshly distilled benzyl amine (3-8 equiv.). The reaction mixture was allowed to warm to room temperature and was then heated at 40° C. for 20 h. The TLC (dichloromethane:methanol:ammonium hydroxide 2:1:1) showed the disappearance of the starting material. The excess of benzyl amine was removed by repeated washings with petroleum ether according to the following method: 150-500 mL of petroleum ether was added into the reaction mixture and subsequently cooled to between −25 and −20° C. (dry ice-alcohol bath) until the carbohydrate-rich phase was frozen. The organic layer was then decanted, and the procedure was repeated 4-5 times. The obtained crude fructosyl amine was diluted with methanol (200-300 mL) and treated with glacial acetic acid (15-20 mL) at room temperature for 2-4 h. TLC (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) showed consumption of the ketosylamine and the formation of N-benzyl-2-amino-2-deoxy-D-mannose together with N-benzyl-2-amino-2-deoxy-D-glucose in a ratio of 2:8-4:6 as the main products. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) to give N-benzyl-2-amino-2-deoxy-D-mannose as an amorphous solid (4.1-8.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:44]=[CH:43][C:27]([CH2:28][CH2:29][NH:30][C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35](Cl)=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[CH:26][CH:25]=1>CS(C)=O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH2:29][NH:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[O:42])=[CH:43][CH:44]=1
Reactant: COC(=O)C1CCOc2cc(O)c(Cl)cc21
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3[N+](=O)[O-])c(Cl)cc21
Temperature: 62 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Methyl 6-chloro-7-hydroxychroman-4-carboxylate (100 mg, 0.412 mmol) (Preparation 4, substituting methanol for ethanol in Step C) was diluted with DMSO (1 mL) followed by the addition of K2CO3 (68.3 mg, 0.495 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (140 mg, 0.412 mmol). The reaction was heated to 62° C. and stirred for 3 hours. The reaction was cooled, loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (60 mg, 26.7% yield).
Reaction SMILES: C(O)C.[NH2:4][OH:5].[CH3:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25](OC)=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>O1CCCC1>[OH:5][NH:4][C:25](=[O:26])[CH:24]([N:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH3:6])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)=[O:33])[CH3:23])[C:29]([NH:31][CH3:32])=[O:30]
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Reactant: NO
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Ethanol (5.0 mL) and a 50% aqueous solution (5.0 mL) of hydroxylamine were added to a tetrahydrofuran (5.0 mL) solution of 4-(methoxymethyl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.40 g) as obtained in Example 3-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure, and purified by preparative silica gel thin-layer chromatography (chloroform/methanol=85/15). IPE was added, and the precipitated solid was filtered off and dried to obtain N-hydroxy-2-[{[4′-(methoxymethyl)biphenyl-4-yl]carbonyl}(methyl)amino]-N′-methylpropanediamide (Compound 4, pink solid) (0.18 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:12][C:13]1[CH:14]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)c(F)c2)c(C)s1
Yield: 39.3 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 155.5 mg (2 equiv, 0.72 mmol) of 3-fluoro-4-phenylphenyl boronic acid to give 50.6 mg (41.6%) of methyl 4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.44 (s, 3H), 3.91 (s, 3H), 6.19 (s, 1H), 6.78-6.86 (m, 2H), 7.32-7.39 (m, 2H), 7.73-7.47 (m, 2H), 7.55 (d, 1H, J=6.9 Hz), 7.82 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][NH2:24].O>C1(C)C=CC=CC=1>[NH2:23][NH:24][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccccc1Cl)c1ccncn1
Reactant: NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=Nc1ccccc1Cl)c1ccncn1

Procedure:
To a suspension of N-(2-chlorophenyl)pyrimidine-4-carboxamide 3 (0.2 g, 0.86 mmol) in 20 mL of PhMe was added 0.65 g of PCl5. The mixture was stirred at reflux for 3 h. To this solution was added 3 mL of NH2NH2.H2O. The mixture was stirred at ambient temperature for 2 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5 as a solid. Yield: 0.15 g, 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([CH2:27][CH2:26][CH2:25][CH2:24][OH:28])[CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(CCCCO)ccc2c1O
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-7-iodo-3-quinolinecarboxamide from Example No. 39 (0.646 g), 3-butyn-1-ol (0.16 mL), PdCl2 (PPh3)2 (26.0 mg), and 0.93 mL DMF was heated at 90° C. for 1 hr. The reaction mixture was cooled to room temperature and partitioned between EtOAc and H2O. An orange solid precipitated from the organic layer and was filtered and collected to obtain pure product as indicated by NMR. The aqueous layer was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4 and condensed to obtain an orange-brown residue. The residue was adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC were combined, condensed, and recrystallized from EtOAc/hexanes to obtain a white solid. The two crops yielded 0.412 g (74%) of the desired product as an orange and white solid. A mixture of the acetylene from above (300 mg) and Pd/C (10%, 60.0 mg) was dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture was placed under the Parr hydrogenator and monitored with the OAMS for complete reduction of the acetylene. After 1 hr OAMS showed that complete reduction had not been achieved. The old palladium catalyst was replaced with fresh palladium catalyst (60.0 mg) and placed under the Parr hydrogenator for another hour. The reaction was completed in a total of 2 hrs and filtered over celite to remove the palladium. The filtrate was condensed to obtain a yellow solid. The crude product was adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC were condensed and recrystallized with EtOAc/hexanes to yield 186.2 mg (61%) of the desired product as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][Cl:48].BrCC1OC(C(F)(F)F)=CC=1>>[Cl:48][CH2:47][CH2:46][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: ClCCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(CCCCl)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-bromo-3-chloropropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 144-146° C.; 1H NMR (300 MHz, CDCl3) δ 7.31 (dt, 1H), 7.14-7.12 (m, 2H), 7.01(t, 1H), 6.65 (s, 1H), 6.23 (s, 1H), 5.89 (s, 2H), 4.68 (ABq, 2H), 3.85-3.79 (m, 2H), 3.67 (t, 2H), 2.06 (t, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 155.8, 148.7, 142.9, 142.2, 132.4, 129.3, 124.1, 123.3, 120.3, 109.3, 103.6, 101.7, 80.3, 57.8, 43.4, 30.6; MS(ES+) m/z 358.2 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25]([O:27][C:28](=[O:37])[C@@:29]([CH3:36])([C:32]([NH:34][CH3:35])=[O:33])[NH:30][CH3:31])[CH3:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:37])[C:29]([N:30]([CH3:31])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:21])([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH3:26]
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
DIPEA (1.0 mL) and 4-phenylbenzoyl chloride (0.50 g) were added in this order to a chloroform (10 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.69 g), and the mixture was stirred for 5 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=60/40→25/75) to obtain 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (colorless oil) (0.79 g, 66%).