Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CC(=O)OCCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A solution of 4,4′-dihydroxybiphenyl (3.72 g, 20 mmol), acrylic acid 6-iodohexyl ester (4.21 g, 15 mmol) and potassium carbonate (2.07 g, 15 mmol) in DMF (50 ml) was stirred overnight at room temperature and under argon atmosphere. The reaction mixture was then poured into HCl 3N (100 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with saturated NaCl solution (200 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The crystalline residue obtained was purified on silica-gel column (CH2Cl2, CH2Cl2/Et2O:19/1). This gave acrylic acid 6-(4′-hydroxybiphen-4-yloxy-)hexyl ester as white crystalline material. Yield 2.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[Br:12]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:12])=[C:3]([O:2][CH3:1])[C:4]=1[F:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc(Br)c(OC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2-fluoro resorcinol (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL×2), and brine (200 mL×1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1.[C-:23]#[N:24].[K+]>C1COCC1.CCOC(C)=O.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.[Cu]I>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:23]#[N:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1
Reactant: [C-]#N
Reactant: O=C(N1CC(CCl)c2c1ccc1c(I)cccc21)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 125 (148 mg, 0.34 mmol), KCN (120 mg, 1.9 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and CuI (50 mg, 0.26 mmol) in dry THF (30 mL) was heated to reflux under N2 with vigorous stirring for 30 min. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and then filtered through Celite. The filtrate was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with EtOAc/petroleum ether (from 1:5 to 1:2) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (126) (97 mg, 85%): mp (EtOAc/petroleum ether) 158-160° C.; 1H NMR (CDCl3) δ 8.63 (d, J=9.1 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.90 (dd, J=7.2, 1.0 Hz, 1H), 7.64 (dd, J=8.2, 7.2 Hz, 1H), 4.70-4.63 (m, 1H), 4.51-4.43 (m, 1H), 4.28-4.20 (m, 1H), 3.95-3.89 (m, 1H), 3.64-3.55 (m, 1H); 13C NMR S 154.7 (q, JC-F 38.3 Hz), 141.5, 132.0, 130.7, 129.0, 127.7, 127.5, 126.7, 119.7, 117.2, 115.9 (q, JC-F 288 Hz), 111.7, 52.7, 45.4, 42.6. Anal. (C16H10ClF3N2O.⅓H2O) C, H, N.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nnsc2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nnsc2-c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 76.9 %

Procedure:
Boron tribromide (102 ml of a 1 M solution in CH2Cl2) was added dropwise to a solution of thiadiazole 7 (8.0 g, 26.84 mmol) in CH2Cl2 (30 ml) at -78° C. After 2 hours the resulting dark green solution was warmed to 0° C. and quenched with 5% HCl. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, and the solvent was removed under reduced pressure. The crude yellow solid was dissolved in EtOAc and extracted twice with 5% NaOH. The aqueous layer was acidified with 10% HCl, and extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, and the solvent was removed under reduced pressure. The resulting white solid was recrystallized from MeOH/H2O to afford 28 (5.58 g, 77.1%), m.p. 221.0°-222.0°60 C.
Reaction SMILES: [CH:1]1([C:7]([S:9]C)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:11]=[C:12]1[N:17]2[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]2[CH2:15][NH:14][CH2:13]1.O>CN(C)C=O>[CH:1]1([C:7]([N:14]2[CH2:13][C:12](=[O:11])[N:17]3[CH2:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:16]3[CH2:15]2)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Reactant: CSC(=S)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(C(=S)C2CCCCC2)CC2c3ccccc3CCCN12

Procedure:
Methyl cyclohexanecarbodithioate (0.24 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.3 g) in dimethylformamide (5 ml). The mixture was refluxed for 4 h, cooled and poured into water. This was extracted with diethyl ether; the ether solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:54]1([CH2:57][NH:58][CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH2:56][CH2:55]1>CN(C=O)C>[CH:54]1([CH2:57][N:58]([CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:56][CH2:55]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (306 mg, 0.85 mmol) in DMF (3 mL) was added with HATU (485 mg, 1.28 mmol) and DIEA (0.37 mL, 275 mg, 2.12 mmol). This was sonicated, stirred for 30 min and then 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (200 mg, 0.85 mmol) in 1 mL DMF was added to the mixture. Then it was stirred at room temperature for 16 hours and the mixture was concentrated to dryness. This was purified by silica gel column (eluted with 0-10% methanol in dichloromethane) followed by trituration with methanol to give a white solid as the title compound (93 mg, 0.19 mmol, 22% yield). m/z=495.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cn1cc(-n2ccc(C(=O)O)n2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cnn(C)c2)n1
Yield: 66 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1′-methyl-1′H-[1,4′-bipyrazole]-3-carboxylic acid (0.921 mmol, 177 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.767 mmol, 200 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated. The residue was purified by flash chromatography. The product was further purified by dissolving it in DCM and washing three times with 1 M NaHCO3 and evaporating the separated DCM phase. 220 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 3.89 (s, 3H), 4.27-4.42 (m, 2H), 4.42-4.53 (m, 1H), 6.76 (d, 1H), 6.95 (d, 1H), 7.83-7.87 (m, 3H), 7.94 (dd, 1H), 8.06 (d, 1H), 8.16 (d, 1H), 8.18 (s, 1H), 8.21 (d, 1H).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:12][CH2:13][CH2:14][OH:15].CO>ClCCl>[OH:15][CH2:14][CH2:13][NH:12][CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: NCCO
Reactant: C[Si](C)(C)C#CC[C@H](O)CCl
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)C#CC[C@H](O)CNCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2S)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol (80 g, 420 mmol) and 2-aminoethanol (110 g, 1.8 mol) was stirred at 80° C. for 18 hours. Silica gel chromatography (Gradient: 1% to 10% methanol in dichloromethane) provided the product as a yellow oil. Yield: 30 g, 140 mmol, 33%. 1H NMR (400 MHz, CD3OD) δ 3.80-3.88 (m, 1H), 3.61-3.72 (m, 2H), 2.84 (dd, J=12.3, 3.3 Hz, 1H), 2.69-2.81 (m, 2H), 2.64 (dd, J=12.0, 8.5 Hz, 1H), 2.45 (dd, half of ABX pattern, J=16.6, 5.5 Hz, 1H), 2.37 (dd, half of ABX pattern, J=16.6, 7.0 Hz, 1H), 0.12 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:18][C:17]=3[CH3:28])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:33][C:34]1[CH:56]=[CH:55][C:37]([O:38][CH2:39]/[CH:40]=[CH:41]/[C:42]2[CH:54]=[CH:53][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:17]([CH3:28])=[CH:18][C:19](/[CH:23]=[CH:24]/[C:25]([N:50]4[CH2:49][CH2:48][N:47]([CH2:46][C:45]5[CH:53]=[CH:54][C:42](/[CH:41]=[CH:40]/[CH2:39][O:38][C:37]6[CH:36]=[CH:35][C:34]([CH3:33])=[CH:56][CH:55]=6)=[CH:43][CH:44]=5)[CH2:52][CH2:51]4)=[O:26])=[CH:20][C:21]=3[CH3:22])=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(OC/C=C/c2ccc(CN3CCNCC3)cc2)cc1
Reactant: COc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)O)cc3C)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(/C=C/COc6ccc(C)cc6)cc5)CC4)cc3C)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.3 %

Procedure:
To a solution of (E)-3-[4-({5-[(4-methoxybenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]prop-2-enoic acid (0.122 g) and 1-{4-[(E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazine dihydrochloride (0.119 g) in DMF (2 mL) were added Et3N (0.08 mL), WSC (0.070 g), and HOBT (0.055 g) at room temperature under an Ar atmosphere. The mixture was stirred at room temperature for 14 hours, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt). The resulting powder was crystallized from EtOH (10 mL) to give (2E)-3-[4-({5-[(4-methoxybenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(4-{4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.195 g) as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCCCS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-hydroxypropanesulfonyl)thiophene-2-sulfonamide (1.2 g, 4.2 mmol) in 75 ml of THF was added 0.5 ml of pyridine and 0.5 ml of acetyl chloride. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oily residue was dissolved in ethyl acetate and the ethyl acetate was washed with aqueous sodium bicarbonate solution and then brine. After drying over sodium sulfate the ethyl acetate was concentrated under vacuum, giving a solid residue. This solid was recrystallized from dichloroethane to give 1.0 g of product; m.p. 103°-104.5°. 1H-NMR,δ (DMSO, d6) 7.97 (2H, S); 7.75 (1H, d, J=3); 7.57 (lH, d, J=3); 4.00 (2H, t, J=6); 3.50 (2H, m); 1.90 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([S:17]([NH:20][C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:14]2[CH2:15][CH2:16][N:11]([S:17]([NH:20][C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-chlorophenylisocyanate (0.33 g, 2.14 mmol) in diethyl ether (30 ml) was added methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (0.42 g, 1.8 mmol) [prepared as described in Step 1 above]. The reaction was stirred at RT for 2 h and filtered. The solid was washed with additional ether and the solid was collected to give methyl 2-(R)-{[4-(4-chlorophenylamino-carbonyl)piperazine-1-sulfonyl]amino}propionate (55%). This material was converted to N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide by following Example 13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 418 (200 mg, 0.59 mmol) in a mixture of anhydrous toluene/ethanol (15mL/15mL) was slowly added a solution of 2-phenylacetyl isothiocyanate (522 mg, 2.95 mmol) in a mixture of anhydrous toluene/ethanol (5mL/5mL). The reaction mixture was stirred at room temperature for 4 hrs under nitrogen, concentrated, and adsorbed on silica gel. The crude material was purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2 from 5/95 to 10/90) followed by trituration with AcOEt (with traces of acetone)/hexanes, to afford title compound 415 (183 mg, 60% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H), 11.81 (s, 1H), 8.82 (bs, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.91 (dd, J=12.4, 2.3 Hz, 1H), 7.79 (d, J=1.1 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.40-7.24 (m, 6H), 6.42 (dd, J=5.55, 2.22 Hz, 1H), 3.83 (s, 2H), 3.71 (s, 3H). LCMS: 517.0 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[Cl:15].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>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(Oc2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenol (0.1 mL, 0.903 mmol) was added to 10 mL of tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (150 mg, 0.452 mmol) and triphenylphosphine (237 mg, 0.903 mmol) dissolved in distilled tetrahydrofuran solution, and diisopropyl azocarboxylate (0.18 mL, 0.903 mmol) was slowly added at 0° C., and the mixture was stirred at room temperature for one day. The solvent of the reaction mixture was removed by reduced pressure evaporation to obtain a yellow liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][S:11](=[O:15])(=[O:14])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCS(=O)(=O)CC2)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an ice cold solution of 4-(6-aminopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (140 mg, 0.62 mmol) in DCM (15 mL) was added NBS (110 mg, 0.62 mmol) in two portions. The reaction mixture was stirred at 0° C. for 20 min. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give 4-(6-amino-5-bromopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (190 mg, 0.62 mmol). LCMS (m/z): 305/307 (MH+), 0.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.Cl.[NH2:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([NH:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])=[O:9]
Reactant: CCc1ccc(C=CC(=O)O)cc1Cl
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C=CC(=O)NN2CC(=O)NC2=O)cc1Cl

Procedure:
3-Chloro-4-ethylcinnamic acid (50 g, 0.24 mole) in SOCl2 (100 ml) was heated under reflux for about 1 hour. The excess SOCl2 was removed in vacuo and the residue flushed with benzene. The acid chloride was treated with 1-aminohydantoin hydrochloride (40 g, 0.26 mole) and pyridine (300 ml) and the reaction mixture heated on a steam bath for 4 hours. The reaction mixture was poured onto HCl/ice to precipitate the product. (40 g, 55%). Several recrystallizations from CH3NO2 provided analytical material which melted at 231°-234°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].Cl[C:10]([O:13]C(Cl)=O)(Cl)Cl>O1CCOCC1>[CH3:2][O:3][C:4](=[O:8])[CH:5]([N:6]=[C:10]=[O:13])[CH3:7]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(C)N=C=O
Temperature: 55 °C
Yield: 83.6 %

Procedure:
L-Alanine methyl ester hydrochloride (6.00 g., 42.99 mmole) was slurried in anhydrous 1,4-dioxane (125 ml.), treated with trichloromethylchloroformate (7.8 ml., 64.66 mmole) and heated at 55° C. for 20.5 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was subjected to distillation to afford the desired intermediate 2-isocyanatopropionic acid methyl ester (4.64 g., 83.6% yield) as a clear colorless liquid. B.P. 58° C. (15-20 mm Hg.). 1H-NMR (200 MHz, CDCl3) δppm =1.54, d, J=8 Hz., 3H (--CH3), 3.87, s, 3H (--OCH3), 4.13, q, J=8 Hz., 1H(--CH--CH3), IR(neat) 3000, 2960, 2270, 1745, 1455, 1445, 1385, 1305, 1230, 1110 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([S:16]([N:19]=[C:20]=[S:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20](=[S:21])[NH:19][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: O=S(=O)(N=C=S)c1ccccc1
Reactant: Cc1cc(C)nc(N)n1
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2)n1

Procedure:
To a dry suspension of 12.4 g of 2-amino-4,-6-dimethypyrimidine in 60 ml of acetonitrile was added 19.9 g of benzenesulfonyl isothiocyanate. The heavy white precipitate which formed was removed by filtration and washed with anhydrous ethyl ether. It melted at 165°170°. The product was N-[(4,6-dimethylpyrimidin-2-yl)-aminothioxomethyl]benzenesulfonamide.