Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH:11]([F:16])[C:12]([F:15])([F:14])[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]([CH2:10][CH:11]([F:16])[C:12]([F:14])([F:15])[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC(F)C(F)(F)Cl)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)CC(F)C(F)(F)Cl
Yield: 72.2 %

Procedure:
Thereafter, 4.76 g (0.018 mol) of ethyl 2-azido-4,5,5-trifluoro-5-chloropentanoate was dissolved in 20 ml of ethanol. The resultant solution was placed in a three-neck round-bottom flask and 0.50 g of 5% palladium-containing activated carbon was added to the solution, and hydrogen was passed through the resultant mixture at a flow rate of 20 ml/min at room temperature for 22 hours. The catalyst was separated by filtration and the ethanol was expelled by distillation. By vacuum distilling the residual liquid, there was obtained 293 g (0.013 mol, yield of 69%) of ethyl 2-amino-4,5,5-trifluoro-5-chloropentanoate having b.p. 69° to 70° C./3 mm, nD20 1.4102, νNH2 3386 and 3318 cm-1 and νC=O 1733 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=5)[C:14]4=[O:31])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.Cl.[CH3:33][NH:34][CH3:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3([C:8]4[C:9](=[CH:10][C:5]5[O:4][N:3]=[C:2]([CH3:1])[C:6]=5[CH:7]=4)[O:11][CH2:12]3)[C:14]2=[O:31])[O:24][CH:25]=1)=[O:30]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2nc(C(=O)O)co2)c2ccccc21
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2nc(C(=O)N(C)C)co2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
A mixture of 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.32 g, 0.76 mmol), dimethylamine hydrochloride (0.13 g, 1.52 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.21 g, 1.07 mmol), 4-methylmorpholine (0.23 mL, 2.07 mmol) and anhydrous N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue recrystallized from diethyl ether to afford N,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide (0.23 g, 68%) as a colorless solid: mp 87-89° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.48-7.5 (m, 1H), 7.31-7.25 (m, 1H), 7.14-7.11 (m, 1H), 7.05-6.95 (m, 3H), 5.28-5.06 (m, 3H), 4.87-4.84 (m, 1H), 3.32 (s, 3H), 3.06 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.8, 164.0, 161.7, 158.2, 157.1, 154.9, 143.7, 141.3, 137.2, 130.1, 129.5, 124.0, 123.9, 123.2, 118.0, 109.3, 108.6, 107.9, 81.3, 56.3, 38.4, 37.5, 36.2, 9.8; MS (ES+) m/z 444.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][NH2:31])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:31][CH2:30][CH2:29][N:28]([CH2:32][CH3:33])[CH2:26][CH3:27])[N:13]=1
Reactant: CCN(CC)CCN
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN(CC)CC)nc21
Yield: 80 %

Procedure:
The product of Example 44, and N,N-diethylethylenediamine were reacted by the procedure of Example 60 to afford 4-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 80% yield. LC MS (m/e)=442 (MH+). Rt=1.77 min.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:25])=[O:24]
Reactant: CCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 99 %

Procedure:
To 3.0 mL of anhydrous triethylamine (23.04 mmol, 30 equiv.) at 0° C. was added 1-octanol (0.10 g 0.77 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride in one portion. The mixture was kept at 0° C. for 3 hours followed by the addition of water (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL), then the organic extracts were combined and washed with aqueous NaHCO3 solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (2% EtOAc/Hex) afforded 15 (99%): 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=7.0 Hz, 1H, ArH), 7.94 (p, J=8.8 Hz, 2H, ArH), 7.54 (t, J=6.4 Hz, 1H, ArH), 4.26 (t, J=6.7 Hz, 2H, CH2OSO2R), 1.61 (p, J=7.9 Hz, 2H), 1.13 (m, 10H), 0.76 (t, J=7.0 Hz, 3H); MALDI-FTMS 294.1130 (C13H21NO3S+Na+ requires 294.1134).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:10][NH2:11].O>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[NH:11][N:10]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)[nH]n1
Yield: 97 %

Procedure:
A solution of 4,4-dimethyl-3-oxopentanenitrile (Compound [CCLII]) (7 g, 55.9 mmol, 1.00 equiv) and NH2NH2.H2O (4.5 g, 140 mmol, 2.00 equiv) in EtOH (100 mL) was stirred for 7 h at 110° C. under nitrogen. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). After cooling, the resulting solution was concentrated under vacuum and diluted with 50 mL of water. The resulting solution was extracted with CH2Cl2, dried and concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether as the eluent to Compound [CCXXXIV] as a yellowish oil: LCMS (m/e) 140 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 5.18 (s, 1H), 1.19 (s, 9H). Amount obtained: 7.6 g, 97% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl.[N+](C)([O-])=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=3[CH3:21])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 6-bromo-1H-indole-2-carboxylate (4.40 g, 16.41 mmol) in dichloromethane (70 mL) at 0° C. was added tin (IV) chloride in dichloromethane (20.51 mL, 20.51 mmol) over 15 min. The resulting yellow heterogeneous mixture was stirred at room temperature for 30 min before a solution 2-methyl-3-nitrobenzoyl chloride (4.42 g, 22.16 mmol) in nitromethane (70 mL) was added over 20 min. The mixture was stirred at room temperature for 4 hr and then poured into ice-cold water (200 mL). The resulting mixture was stirred at room temperature for 20 min and diluted with ethyl acetate (800 ml). The mixture was washed with water (100 mL), saturated NaHCO3 solution (2×100 ml), water (100 mL), and brine (100 mL). The organic solution was dried over anhydrous MgSO4. Removal of solvent under vacuum gave the desired product (7.04 g, 16.33 mmol, 99% yield) as yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1.OC1C=C(C=CC=1)C=CC1(/C=C/C2C=CC=CC=2)N(C2C=CC=CN=2)C2C=CC(C(F)(F)F)=CC=2N1.C(O)(=O)C(O)=O>C(OCC)(=O)C>[OH:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Agent: Oc1cccc(C=CC2(/C=C/c3ccccc3)Nc3cc(C(F)(F)F)ccc3N2c2ccccn2)c1
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from (E)-5-methoxy-1-(2-pyridyl)-2-styryl-1H-benzimidazole according to the preparation of (E)-2-(3-Hydroxystyryl)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 32). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][C:15]1([CH3:19])[O:14][C@@H:13]([CH2:12][N:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[CH:8]=[N:9]2)[CH2:17][O:16]1
Reactant: Ic1ccnc2cn[nH]c12
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](Cn2ncc3nccc(I)c32)O1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.204 mmol), (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (30.7 mg, 0.204 mmol), and cesium carbonate (133 mg, 0.408 mmol) in DMF (1.0 mL) was heated in a microwave at 80° C. for 15 minutes. Additional (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (61.4 mg, 0.204 mmol) and cesium carbonate (67 mg) was added the reaction was heated in microwave at 80° C. for 2 hour. Additional (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (30.7 mg, 0.204 mmol), tetrabutylammonium iodide (301 mg, 0.816 mmol) and cesium carbonate (133 mg, 0.408 mmol) was added and the reaction was heated in microwave at 80° C. for 60 minutes, then the reaction was transferred to an oil bath and heating was continued overnight at 75° C. The reaction was cooled and poured into water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer were dried over sodium sulfate, filtered, and concentrated to give (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-1H-pyrazolo[4,3-b]pyridine MS [M+H] found 360.2.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].[CH2:33]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:33]/[P:42](=[O:49])([O:43][CH2:44][CH3:45])[O:46][CH2:47][CH3:48])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 62.8 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (9:1, v/v) to give diethyl (E)-2-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.41 g, yield 65%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 82-84° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([OH:28])[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][C:45]([C:47]1(Br)[CH2:50][CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][C:47]3([C:45]([O:44][CH2:42][CH3:43])=[O:46])[CH2:50][CH2:49][CH2:48]3)[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-4-methanesulfonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 127 mg of cesium carbonate and 81 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)CCl.[NH2:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: N[C@@H]1CCNC1
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(NC1CCNC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A solution of 3-bromobenzoic acid (4.0 g, 20 mmol) and EDC (3.83 g, 20 mmol) in 50 mL acetonitrile was added dropwise to a solution of (3R)-(+)-3-aminopyrrolidine (1.72 g, 20 mmol) in 100 mL acetonitrile. The reaction mixture was stirred at room temperature for 2 h and the solvent was removed. The residue was dissolved in 50 mL CH2Cl2 and washed with brine (50 mL). The organic phase was dried (MgSO4) and the solvent was removed. The crude product was purified by silica gel column chromatography (Rf=0.22, CH2Cl2/MeOH, 75:15) to give 3-bromo-N-pyrrolidin-3-yl-benzamide as a colorless solid (2.0 g, 37%). To a solution of the above precursor (1.14 g, 4.24 mmol) in 30 mL CH2Cl2 were added di-tert-butyldicarbonate (925 mg, 4.24 mmol) and triethylamine (596 μl, 4.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the crude product was purified by silica gel column chromatography (Rf=0.66, CH2Cl2/MeOH, 90:10) to afford the title intermediate compound 106, as a viscous, colorless oil (1.1 g, 70%). MS (ESI+) m/z=369/371.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[CH3:34][NH:35][CH3:36].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:35]([CH3:36])[CH3:34])=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
After the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 338, a tetrahydrofuran solution (2.0M, 0.21 ml, 0.42 mmol) of dimethylamine, 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) was added to the resulting solution at room temperature. The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with hexane:ethyl acetate=2:1 was concentrated under reduced pressure, whereby the title compound (35 mg, 0.066 mmol, 90%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14]C>>[C:1]([O:5][C:6]([NH:7][N:8]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)NN
Product: CCCCC=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of valeraldehydede (2.0 g; 23 mmoles) and t-butylcarbazate (3.1 g; 23 mmoles) in hexane (25 mL) is heated under reflux conditions for 30 minutes. At the end the solution is cooled at room temperature. The solvent is removed under vacuum and the obtained residue purified by chromatography on silica gel eluting with chloroform. 4.1 g of t-butyl-2-pentylidenhydrazinecarboxylate (white solid; yield 89%) are obtained. Rf=0.32 chloroform; 1H NMR (CDCl3) δ (ppm): 8.02 (s broad, 1H, NH), 7.19 (t, 1H, CH), 2.29 (m, 2H, CH2), 1.46 (m, 11H, CH2 and CH3), 1.36 (m, 2H, CH2), 0.91 (t, 3H, CH3); 13C NMR (CDCl3) δ (ppm): 147.6, 146.7, 80.8, 31.9, 28.8, 28.3, 22.3, 13.8.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[CH2:8][CH2:7][S:6]2>C(#N)C.O.[O-2].[O-2].[Mn+4]>[S:6]1[CH2:7][CH2:8][N:9]2[CH:10]=[C:3]([CH:2]=[O:1])[N:4]=[C:5]12
Reactant: OCc1cn2c(n1)SCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: CC#N
Product: O=Cc1cn2c(n1)SCC2
Reaction time: 1.5 h

Procedure:
2,3-Dihydro-6-hydroxymethylimidazo[2,1-b]thiazole (1.47 g, 9.4 mmol) was dissolved in acetonitrile (30 ml) by addition of water (minimum volume). Manganese dioxide (4.41 g, 3 wt. equivalents) was added and the mixture stirred at ambient temperatures for 1.5 h. The mixture was filtered through Keiselguhr, the filter pad washed with water and the combined filtrate and washings evaporated to dryness under reduced pressure. The residue was triturated under diethyl ether, the solid collected by filtration and dried in air (1.33 g, 92%); nmax (CH2Cl2) 1685, 1528, 1272, 1260 and 1152 cm-1 ; dH (90 MHz; CD3OD) 3.84-4.10 (2H, m), 4.20-4.50 (2H, m), 7.97 (1H, s), 9.52 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N:17]=[C:18]=[S:19])[CH2:3][CH2:2]1.[NH3:20]>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([NH2:20])=[S:19])[CH2:5][CH2:6]1
Reactant: FC(F)(F)c1ccc(N2CCOCC2)c(N=C=S)c1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
Reaction of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with 33% ethanolic ammonia solution (50 ml) at room temperature for 2 hours gave 1-(2-morpholino-5-trifluoromethylphenyl)thiourea (m.p. 196°-197° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N+:5]=1[O-:18])#[N:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(C#N)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 4-methylpicolinonitrile (5 g, 42.3 mmol) in DCM (25 mL) was cooled in an ice/brine bath. To this solution was added mCPBA (14.61 g, 85 mmol). The reaction mixture was allowed to warm to RT and was stirred overnight. The mixture was subsequently diluted with DCM until all solids were dissolved and was washed with 1N NaOH (2×200 mL) and with brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid (4.03 g, 71%). ESI-MS m/z [M+H]+ 135.1.
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28][O:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:25][CH2:24][CH2:23]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(CO[C@H]2CCC[C@H](COC(Cn3ccnc3)c3ccccc3)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
A solution of 106 mg of 1-phenyl-2-(1-imidazolyl)ethanol in 1 ml of dimethylformamide was stirred with 5 mg of 55% sodium hydride at 50° C. for 30 minutes and the mixture was then left to cool at room temperature. To the resulting mixture were added 3 ml of a dimethylformamide solution containing 300 mg of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, prepared as described in Example 2(a); the mixture was then stirred at 80° C. for 4 hours and then at 90° C. for 1 hour. At the end of this time, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate and then concentrated to evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 30:1 by volume mixture of ethyl acetate and triethylamine, to give 107 mg of the title compound as a liquid.