Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[C:15](=O)[CH:14]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13]3)=[CH:4][CH:3]=1.[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[CH2:15][C:14]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc3c2CC(CC2CCCCC2)=C3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
30.5 g (95.7 mmole) 7-(4′-Methylphenyl)-2-cyclohexylmethyl-indan-1-one were dissolved in 89 ml toluene in a 500 ml—roundbottom flask equipped with a reflux condenser. 3.62 g (1.0 eq.) sodium borohydride were added. Then 17.9 ml (4.35 eq.) methanol were added at 50° C. and the mixture was stirred for 8 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 200 ml of toluene. After addition of 0.4 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent afforded 29 g (quant.) of the desired indene as a slightly offwhite oil. 1H-NMR (400 MHz, CDCl3): δ=7.42-7.14 (m, 7H, aromatic), 6.66 (s, 1H, C═CH), 3.36 (s, 2H, benzylic), 2.41 (s, 3H, PhCH3), 2.35 (d, 2H, CH2Cy), 1.70-0.83 (m, 11H, aliphatic) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].N1CCOCC1=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CO[C@@H](c2ccc(F)cc2)CN1Cc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: O=C1COCCN1
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Yield: 92.5 %

Procedure:
To a solution of (6S)-6-(4-fluorophenyl)-4-(benzyl)morpholin-3-one (1.16 g) in tetrahydrofuran (10 mL) was added dropwise over 15 min a solution of sodium bis(2-methoxyethoxy)aluminum hydride (70% in toluene, 3.2 mL, 11.4 mmol) in tetrahydrofuran (5 ml) at 65° C., and the reaction mixture was refluxed over 1.5 hrs. After HPLC analysis to confirm a disappearance of the morpholin-3-one, the reaction was quenched by addition of water (0.6 mL), 15% aqueous sodium hydroxide solution (0.6 mL) and water (1.8 mL) at 0° C. The reaction mixture was filtered and the filtrate was concentrated. To the residue was added ethyl acetate and wash successively with 15% aqueous sodium hydroxide solution and water. The solvent was evaporated to give (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (1.02 g, 92% yield) as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>[NH2:2][C:1]1[S:21][CH:10]=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)NC=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncsc1N
Yield: 37.9 %

Procedure:
A solution of ethyl 2-cyano-2-formamidoacetate (480 mg, 3.07 mmol) and Lawesson's reagent (746 mg, 1.84 mmol) in toluene (5 mL) was heated up to 80° C. for overnight. The reaction was then diluted with sodium carbonate aqueous solution (20 mL) and methylene chloride (50 mL). Organic phase was washed with brine (20 mL), dried over sodium sulfate and concentrated. Purified with silica gel chromatography to give a solid material of ethyl 5-aminothiazole-4-carboxylate (120 mg). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 5.98 (s, br, 2H), 4.38 (q, 2H), 1.41 (t, 3H). MS m/z 173.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:12]/[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)=[O:13]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Product: CN(C)/C=C/C(=O)c1ccc(S(C)(=O)=O)cc1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from 1-[4-(methylsulfonyl)phenyl]ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.96 (3H, s), 3.06 (3H, s), 3.19 (3H, s), 5.66 (1H, d, J=12 Hz), 7.83 (1H, d, J=12 Hz), 7.96-8.04 (4H, m).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:27])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4fluorophenyl)-5-pentylpyridine (Example 1) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.10 (m, 4 H), 4.65 (dq, J=2.8, 6.6 Hz, 1 H), 3.75 (septet, J=6.6 Hz, 1 H), 3.20 (septet, J=6.6 Hz, 1 H), 2.19 (t, J =8.1 Hz, 2 H), 1.63 (d, J=2.6 Hz, 1 H), 1.40 (d, J=7.0 Hz, 3 H), 1.31 (m, 14 H), 1.11 (m, 4 H), 0.79 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77; F, 5.11. Found: C, 77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101° C. Rf=0.2 (70% CH2Cl2/hexane).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:31]([CH2:33]Br)=O)[CH:28]=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:31]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: COc1cccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c1
Yield: 54 %

Procedure:
4-[4-(3-Methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (148 mg, 54%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3′-methoxyphenacyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.27 (dd, J=6.0, 2.0 Hz, 1H), 8.15 (dd, J=8.1, 1.1 Hz, 1H), 7.76-7.82 (m, 1H), 7.61-7.69 (m, 3H), 7.38-7.48 (m, 3H), 6.97 (dd, J=8.2, 2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH:21]([OH:24])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:20][CH:21]([O:24][C:38](=[O:40])[CH3:39])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CCC(O)CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Yield: 97 %

Procedure:
To a solution of 2-chloro-6-{3-[3-cyclohexyl-3-(2-hydroxybutyl)ureido]-propoxy}quinoline (6.3 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2.3 g) in methylene chloride (80 ml) is added dropwise with stirring acetic anhydride (1.8 g) at room temperature. The methylene chloride layer is washed successively with diluted hydrochloric acid, water and a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The resultant is concentrated under reduced pressure to remove the solvent to give 2-chloro-6-[3-[3-cyclohexyl-3-(2-acetyloxybutyl)ureido]-propoxy]quinoline (6.7 g) as a colorless oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([N+:20]([O-])=O)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C:11]1[CH:12]=[C:13]([NH2:20])[CH:14]=[C:15]([NH2:17])[CH:16]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCOC(=O)c1cc(N)cc(N)c1
Temperature: 7 °C
Reaction time: 1.67 h

Procedure:
9 g of 5% palladium carbon, 90 g (0.27 mol) of 2-(3,5-dinitrobenzoyloxy)ethyl isobutyrate (compound 3) and 900 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was increased to 5 kg/cm2. The autoclave contents were stirred at room temperature (7° C.). 10 minutes later, the autoclave inside temperature rose to 34° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Ten minutes later, the temperature became 50° C. and the pressure dropped to 1 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (4 kg/cm2), stirring was continued for 100 minutes (the temperature dropped to 18° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from 200 ml of toluene to obtain 2-(3,5-diaminobenzoyloxy)ethyl isobutyrate (compound 4). Yield: 60 g (83%) Melting point: 81-83° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[NH:6][C:5](=[O:9])[C:4](=[O:10])[NH:3]1.FC(F)(F)S(O[CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1)(=O)=O.CCN(C(C)C)C(C)C>O1CCCC1.CN(C)C=O>[CH3:1][N:2]1[CH:7]([S:8][CH2:17][C@@H:18]2[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]2)[NH:6][C:5](=[O:9])[C:4](=[O:10])[NH:3]1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: Cn1[nH]c(=O)c(=O)[nH]c1=S
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)S[C@@H]1CO[C@@H](CSC2NC(=O)C(=O)NN2C)C1

Procedure:
The title compound is prepared by the procedure of Example 23 using 0.551 gof product from Example 83 in 1 ml of tetrahydrofuran, 1.07 g of product from Example 22 in 1 ml of tetrahydrofuran, 3 ml of dimethylformamide, and605 microliter of Hunig's base to give 0.357 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[CH:27]=[CH:26][N:25]([NH2:28])[C:22]2=[N:23][CH:24]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:18][C:19]1[CH:20]=[C:21]2[CH:27]=[CH:26][N:25]([NH:28][C:15]([C:11]3[C:12]([CH3:14])=[N:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][CH:10]=3)=[O:17])[C:22]2=[N:23][CH:24]=1
Reactant: Nn1ccc2cc(F)cnc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)cnc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (529 mg, 2.28 mmol) and 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (288 mg, 1.9 mmol) in DMF (6 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (475 mg, 68%). MS: 366 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.30 (m, 2H), 8.18 (d, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 7.59 (m, 1H), 7.44 (m, 1H), 6.59 (d, 1H), 2.80 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:16][OH:17])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:17][N:16]=[C:15]([Cl:20])[C:12]1[S:11][C:10]([O:9][C:8]2[CH:18]=[CH:19][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:14][CH:13]=1
Reactant: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ncc(C(Cl)=NO)s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
To a solution of Example 1D (7.77 g, 0.028 mol) in N,N-dimethylformamide was added N-chlorosuccinimide (4.0 g, 0.029 mol) and the solution was stirred at room temperature for 6 hours. Water was added and the reaction mixture stirred for 30 minutes. The precipitate was filtered and air-dried to give 8.45 g of product as an off-white solid (96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.88 Hz, 6H) 4.53-4.70 (m, 1 H) 6.95-7.07 (m, 2H) 7.26-7.37 (m, 2H) 7.67 (s, 1H) 12.41 (s, 1H). MS (ESI) m/z 294.0 (M−18)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:17][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:19])[C@H:13]([CH2:14]O)[C@@H:12]([CH3:16])[O:11][CH2:10]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH3:16])[C@H:13]1[CH2:14][S:19][C:18]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:17]2
Reactant: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccc(F)cc2F)[C@@H]1CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: C[C@H]1OC[C@]2(c3ccc(F)cc3F)N=C(NC(=O)c3ccccc3)SC[C@H]12
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
N-(((3S*,4R*,5R*)-3-(2,4-Difluorophenyl)-4-(hydroxymethyl)-5-methyltetrahydrofuran-3-yl)carbamothioyl)benzamide (165 mg, 0.41 mmol) was dissolved in pyridine (2 mL) and the solution was cooled to −20° C. Trifluoromethanesulfonic acid anhydride (68 μl, 0.41 mmol) was added dropwise into the reaction. After 45 minutes, the reaction was incomplete so a further aliquot of trifluoromethanesulfonic acid anhydride (68 μl, 0.41 mmol) was added and the reaction stirred for a further 1 hour. The reaction was quenched with saturated NaHCO3 and extracted with Et2O (×2). The combined organics were concentrated and the residue purified by column chromatography, eluting with 0-30% EtOAc in n-hexane to leave the title compound as a yellow foam. (95 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 8.11-8.17 (m, 2H), 7.38-7.62 (m, 4H), 6.86-7.02 (m, 2H), 4.47-4.58 (m, 2H), 4.01 (dd, J=2.63, 9.48 Hz, 1H), 3.17-3.26 (m, 1H), 2.75-2.86 (m, 2H), 1.42 (d, J=6.11 Hz, 3H).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(=O)(O)[O-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:10][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1)[CH:20]=[CH2:19]
Reactant: C=CCI
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-Sulfamoyl-benzoic acid (2.0 g, 9.94 mmol) and sodium bicarbonate (0.84 g, 9.94 mmol) in DMF (20 mL) was added allyl iodide (0.91 mL, 9.94 mmol) and stirred at room temperature overnight under argon. The reaction was quenched with water, extracted with EtOAc and dried over Na2SO4. After removing the solvent under reduced pressure, the crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ8.20 (d, 2H), 8.00 (d, 2H), 6.06 (m, 1H), 5.40 dd, 2H), 5.02 (s, 2H), 4.96 (d, 2H). MH+ 243.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:3]=1.[C:14]([Cl:20])(=O)[CH2:15][C:16]([Cl:18])=O>C(#N)C.[OH-].[Na+]>[Cl:18][C:16]1[CH:15]=[C:14]([Cl:20])[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[CH:3]=[C:2]2[N:1]=1
Reactant: Cc1ccc(-c2cc(N)[nH]n2)cc1
Reactant: O=C(Cl)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
There was dissolved, in acetonitrile (40 mL), 5-amino-3-(4-methyl-phenyl)-pyrazole (2.00 g, 11.5 mM) in an argon gas atmosphere, malonyl chloride (1.34 mL, 13.8 mM) was added to the resulting solution with ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction liquid, there was added malonyl chloride (134 μL, 1.38 mM) followed by the further stirring of the mixture for 30 minutes. This reaction liquid was diluted with a 1M aqueous sodium hydroxide solution, washed with methylene chloride, and hydrochloric acid was added to the aqueous phase to make the same acidic (pH 2), followed by the extraction with ethyl acetate. The resulting extracts were combined and then concentrated, and the resulting solid was washed with diethyl ether. After the addition of phosphoryl chloride (5 mL) to the resulting solid with ice-cooling, the resulting suspension was stirred for 3 hours, while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, ethanol was added to the residue thus obtained with ice-cooling and then the mixture was stirred for 15 minutes. The reaction liquid was concentrated and then the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (153 mg, overall yield of these two steps: 4%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[CH3:26][CH2:27][O-].[Na+]>CCO.CCOC(C)=O.O>[CH3:26][C:27]1[O:1][N:2]=[C:3]([C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][C@H:12]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:11]3)=[N:7][CH:6]=2)[N:4]=1
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 80 °C

Procedure:
To a suspension of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (410 mg, 1.1 mmol) in EtOH (3 mL) and EtOAc (5 mL) was added NaOEt (1.7 mL, 4.4 mmol, 25 wt. %) at rt. The mixture was heated at 80° C. for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. Combi-Flash chromatography (10 g, 50-100% EtOAc in hexanes in 20 min, 35 mL/min, 15 mL/fraction) gave the title compound after trituration with Et2O-hexanes (1:1). 1H NMR (400 MHz, acetone-d6): δ 7.81 (s, 1 H), 7.71-7.65 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.52 (s, 1 H), 3.98 (m, 1 H), 3.84-3.67 (m, 3 H), 2.61 (s, 3H), 2.60-2.43 (m, 2 H). MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CS(Cl)(=O)=O.CCN(CC)CC.O>COCCOC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Fc1cccc(-c2cc3ccc(C(F)(F)F)cn3n2)c1
Temperature: -5 °C
Reaction time: 0.21 h
Yield: 91.9 %

Procedure:
To a suspension of 1-(3-fluorophenyl)-2-[5-(trifluoromethyl)-2-pyridinyl]ethanone oxime (5.0 g, 16.77 mmol) in DME (20 ml) at −5° C. was added MsCl (1.3 ml, 16.77 mmol). The suspension was stirred at −5° C. for 10-15 min, and then Et3N (4.8 ml, 34.37 mmol) was added at a rate to maintain the temperature at or below 0° C. After the addition was complete, the suspension was warmed to room temperature. After 1 h an additional 0.5 eq. of Et3N was added to drive the reaction to completion. After an additional 0.5 h stirring, the suspension was filtered into a clean flask. DME (10 ml) was used to wash the salt cake. To the solution was added FeCl3 (27 mg, 0.167 mmol) in one portion. The resultant dark solution was heated to 70° C. and stirred for 1.5 h. The solution was then cooled to room temperature before the addition of H2O (50 ml) and ethyl acetate (100 ml). The layers were separated and the ethyl acetate layer was washed with 1 M HCl (50 ml) followed by brine (50 ml). The solution was filtered through a short plug of silica to remove any residual iron salts. The solution was concentrated under reduced pressure to afford 4.32 g (92%) of the title compound as a tan solid.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20]([OH:22])=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]1.[H][H]>C(O)C.[Pd]>[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]1.[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([OH:23])=[O:8])[CH2:19][C:20]([OH:22])=[O:21])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: NC(=O)C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
A solution of the compound from step A above (700 mg) in ethanol (30 mL) was exposed to a hydrogen atmosphere in the presence of 10% Pd-C (70 mg) for 4 hr at room temperature. After filtration (Celite filter aid) and rotoevaporation, N-(tert-butoxycarbonyl)-L-aspartic acid 4-piperidinamide (500 mg) was obtained as a yellowish foam.