Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>[Cu]>[C:24]1([N:21]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:2]4[CH:7]=[CH:6][C:5]([C:8]5[CH:9]=[CH:10][C:11]([N:21]([C:2]6[CH:7]=[CH:6][C:5]([C:8]7[CH:9]=[CH:10][C:11]([N:21]([C:2]8[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=8)[C:24]8[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=8)=[CH:12][CH:13]=7)=[CH:4][CH:3]=6)[C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)=[CH:12][CH:13]=5)=[CH:4][CH:3]=4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(-c5ccc(N(c6ccccc6)c6ccc(-c7ccc(N(c8ccccc8)c8ccccc8)cc7)cc6)cc5)cc4)cc3)cc2)cc1
Yield: 48.5 %

Procedure:
8.66 g (0.021 mol) of N,N,N'-triphenylbenzidine thus obtained, 4.06 g (0.01 mol) of 4,4'-diiodobiphenyl, 2.90 g (0.021 mol) of anhydrous potassium carbonate, 0.32 g (0.005 mol) of copper powder, and 10 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 195° C. to 210° C. for 20 hours. The reaction product was then extracted with 140 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated. To the concentrate was then added 120 ml of n-hexane to recover a crude crystal. The crude crystal thus recovered was then purified by column chromatography (carrier: silica gel; elute: 1/2 mixture of toluene and n-hexane) to obtain 4.73 g (yield: 48.5%) of N,N'-bis(4'-diphenylamino-4-biphenylyl)-N,N'-diphenylbenzidine. The melting point of the product was from 242.5° C. to 243.5° C.
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[H-].[Na+].[C:19]([N:29]1[CH2:37][C@H:36](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][C@H:30]1[C:31]([O:33][CH3:34])=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1C=CC=CC=1>[C:19]([N:29]1[CH2:37][C@@H:36]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH2:35][C@H:30]1[C:31]([O:33][CH3:34])=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1C[C@H](C23CC4CC(CC(C4)C2)C3)CN1C(=O)OCc1ccccc1

Procedure:
A solution of 5.3 g. (0.035 mole) of 1-adamantanol in 40 ml. of dimethylformamide and 80 ml. of benzene is treated with 1.6 g. of sodium hydride (50% dispersion in mineral oil). The mixture is refluxed for 15 minutes, cooled, and treated with 7.5 g. (0.017 mole) of N-carbobenzyloxy-trans-4-tosyloxy-L-proline, methyl ester. The resulting reaction mixture is stirred and refluxed for four hours, cooled, and the solvent removed under reduced pressure. The residue is dissolved in 100 ml. of chloroform and then washed with 25 ml. of water (3 times). The organic phase is dried (MgSO4), filtered, and the solvent evaporated to give N-carbobenzyloxy-cis-4-(1-adamantyl)-L-proline, methyl ester.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:14][C:15](=O)[C:16]1[C:21]([I:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]2[C:16](=[C:21]([I:22])[CH:20]=1)[C:15](=[O:14])[N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:12])[F:1])=[CH:11][CH:10]=1)[CH2:24]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: NCc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A mixture of 4-difluoromethoxy-benzyl amine (0.173 g, 1.0 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.270 g, 0.73 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-difluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.84 (s, 2H), 6.52 (t, 1H), 7.10 (m, 3H), 7.28 (d, 2H), 7.64 (d, 1H). GC-MS: m/z 433 (M)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li][CH2:12][CH2:13]CC.C(=O)C>C1COCC1.CCCCCC>[CH3:12][CH:13]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:6]1
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccccc1Br
Agent: CC=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 35 %

Procedure:
To a solution of 2-bromobenzoic acid (0.50 g, 2.49 mmol) in THF (12.0 ml) cooled at −78° C. was added 2.5M n-BuLi in hexane (2.0 ml). After stirring for 25 minutes, a solution of acetaldehyde (0.142 g, 3.23 mmol) in THF (0.3 ml) was added. The reaction was allowed to warm to room temperature after 8 minutes at −78° C., and then quenched into 10% HCl aqueous solution (30 ml). The acidic solution was rapidly stirred for 1.5 hours, and then extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 aqueous solution, brine, dried with anhydrous Na2SO4, and rotary evaporated to an oily residue. Gradient chromatography of the oil residue through a silica gel column with 20% to 30% EtOAc in hexane afforded 3-methyl-2-benzofuran-1(3 H)-one as a clear oil (130 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][NH:62][CH2:61]1>C(#N)C>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][N:62]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:61]1
Reactant: Clc1ccccc1C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccccc2Cl)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (38 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (9 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16ClF3N2O2: 420.0852, found 420.0854.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1.[H-].[Na+]>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[N:16]=[C:15]([C:20]([F:22])([F:23])[F:21])[N:14]=1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Temperature: 0 °C
Reaction time: 60 h
Yield: 68.7 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (3.64 g, 23.0 mmol, Acros Organics) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (5.00 g, 23.0 mmol SynChem, Inc.) were dissolved in tetrahydrofuran (41 mL) in a vial and cooled to 0° C. A 60% mixture of sodium hydride in oil (1.10 g, 27.5 mmol, Aldrich) was added. The reaction was stirred for 30 minutes at 0° C. and at 25° C. for 60 hours at which time TLC analysis showed that most of the starting material had been consumed. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was purified by silica gel chromatography using 10-20% ethyl acetate (EtOAc)/hexanes to give the product 4-113 chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine as a white solid (5.35 g). 1H NMR (400 MHz, CDCl3) δ: 6.90 (s, 1H), 5.35 (m, 1H), 3.95 (s, 4H), 1.60-2.05 (m, 8H).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10](C#N)=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:6])[CH3:2].[C:15](=[O:18])([O-])[O-:16].[Na+].[Na+]>C(O)C.Cl>[CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10]([C:15]([OH:16])=[O:18])=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:6])[CH3:2]
Reactant: CCN(CCCl)c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCN(CCCl)c1ccc(C(=O)O)cc1
Yield: 40 %

Procedure:
To a solution of 2.5 g (12.0 mmol) of 4-[N-ethyl,N-(2-chloroethyl)amino]benzonitrile in 25 ml of ethanol, 25 ml of concentrated hydrochloric acid were added, followed by reflux under heat for 12 hours. The reaction mixture was allowed to cool down. Sodium carbonate was then added to basify the solution, followed by washing with chloroform. The water layer was acidified with concentrated hydrochloric acid and then extracted with chloroform. The solvent was distilled out under reduced pressure, followed by washing with IPA, whereby 1.1 g of white powder were obtained (yield: 40%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.S(Cl)(Cl)=O.[C-:17]#[N:18].[K+].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:17]#[N:18])[CH:2]=1
Reactant: [C-]#N
Reactant: OCc1cnc2ccccc2c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: N#CCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A solution of quinolin-3-yl-methanol (227, 3.1 g, 19.5 mmol) and thionyl chloride (Aldrich, 16.5 mL, 195 mmol) in 50 mL of benzene was refluxed for 3 h. After cooled to room temperature, the solvent was removed under reduced pressure to dryness. This crude product was used directly in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.82 (s, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.97 (t, J=7.4 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 5.09 (s, 2H). MS (EI): m/z 178 (M+H). Quinolin-3-yl-acetonitrile was synthesized from the above crude product, KCN, NaHCO3 and KI in similar manner as described in Example 221. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=2.0 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 4.31 (s, 2H). MS (EI): m/z 169 (M+H).
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C:12]2[C@:7]1([CH3:24])[CH2:8][CH2:9][C@H:10](OC(N1C=CN=C1)=S)[CH:11]=2)([CH3:4])([CH3:3])[CH3:2].C([SnH](CCCC)CCCC)CCC.C(B(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([O:5][C@@H:6]1[C@:7]2([CH3:24])[C:12](=[CH:11][CH2:10][CH2:9][CH2:8]2)[CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCCC2=C[C@@H](OC(=S)n3ccnc3)CC[C@@]21C
Agent: CCB(CC)CC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)O[C@H]1CCCC2=CCCC[C@@]21C
Temperature: 120 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
To a stirred solution of 9.95 g (28.5 mMol) imidazole-1-carbothioic acid(2S,4aS,5S)-O-(5-tert-butoxy-4a-methyl-2,3,4,4a,5,6,7,8-octahydro-naphtalen-2-yl)ester in 285 ml toluene kept under argon atmosphere were added 75.7 ml (285 mMol) of tributyltinhydride and 75.7 ml of a one molar solution of triethylborane in tetrahydrofurane. The reaction mixture was heated to 120° C. for 4 hours and additional 20 ml of tributyltinhydride as well as 20 ml of triethylborane solution (one molar in tetrahydrofurane) were added. The reaction mixture was kept at 120° C. for 3 days, cooled to room temperature and evaporated in vacuo. The residue was chromatographed twice over 900 g silicagel with toluene/hexane 1/1 to yield 4.3 g of pure (4S,4aS)-4-tert-Butoxy-4a-methyl-1,2,3,4,4a,5,6,7-octahydro-naphtalene (liquid).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 85.2 %

Procedure:
To a dried flask containing 3-(trifluoromethyl)benzaldehyde oxime (1.89 g, 10 mol) in methylene chloride (100 mL) was added N-chlorosuccinimide (1.40 g, 10.5 mmol) slowly at 0° C. The reaction mixture was warmed to 45° C. for 2 h, poured over ice, diluted with H2O (20 mL), and extracted with EtOAc (100 mL). The organic phase was washed with H2O (2×25 mL) and saline solution (25 mL), dried over sodium sulfate, concentrated in vacuo to give N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2 g, 90%). LCMS: 224.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:17]#[N:18])=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: Oc1ccc(NCCCCCCCBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCCCCNc1ccc(O)cc1
Yield: 80 %

Procedure:
8-[(4-Hydroxyphenyl)amino]octanenitrile was prepared in 80% yield from 33.2 g [0.11 mol] of 4-[(7-bromoheptyl)amino]phenol and 26.5 g (0.52 mol) of sodium cyanide by the first procedure of Example 2, part d, except that DMSO was used in place of DMF as the solvent.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[O:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>O1CCCC1>[O:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:20]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1ccon1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1ccon1

Procedure:
The named compound is prepared by substituting isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.09 mL isoxazol-3-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([OH:18])[C:16]#[CH:17].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:17]#[C:16][CH2:15][OH:18])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Reactant: C#CCO
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCC#Cc1cnc(Cl)nc1NC1CCCC1
Temperature: 67 °C

Procedure:
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 200 g (0.723 mol, 1.0 eq.) of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (A1f) and 2303 g, (2600 mL) of tetrahydrofuran. The mixture is stirred, heated to reflux (67° C.) and 200 mL of distillate is collected. The sample is cooled to 25° C. and 52.7 g (0.940 mol, 55.6 mL, 1.3 eq.) of propargyl alcohol (A1e), 570.3 g (1.808 mol, 2.5 eq.) of tetrabutylammonium fluoride trihydrate and 25.4 g (0.036 mol, 0.05 eq.) of bis(triphenylphosphine)palladium (II) dichloride are added. The sample is stirred, heated to reflux (67° C.) and maintained at this temperature for 2 h or until 5-7% of the starting material A1f remains as determined by HPLC analysis. The sample is cooled to 25° C. and concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove tetrahydrofuran. 541 g, (600 mL) of ethyl acetate is charged. The sample is again concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove residual tetrahydrofuran. 2706 g (3000 mL) of ethyl acetate and a solution of 63 g of sodium bicarbonate dissolved in 1500 g (1500 mL) of water are added. The sample is stirred at 25° C. for 10 min and the phases are separated. The organic (top) phase is washed once with 1500 g (1500 mL) of water. The sample is stirred for 10 min and the phases are separated. The organic (top) phase is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 625 mL to remove ethyl acetate. 1582 g (2000 mL) of acetone is added to the concentrate. The sample is stirred, heated to reflux (58° C.) and maintained at this temperature for 30 min. It is then cooled to 40° C. and clarified by filtering through a pad of filter cel. The flask and filter cake are washed twice with 158 g (200 mL, 2×100 mL per wash) of acetone. The sample is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 460 mL. It is then cooled to 4° C. and is hold at this temperature for 1 h. The solids are filtered and the filter cake is washed twice with 158 g (2×100 mL) of cold (4° C.) acetone. The solids are dried at 50° C. for 16 h, to afford 85.6 g (47.4%, corrected) of Compound A1d as a tan, crystalline solid, mp=162-163° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:26]1([CH2:29][OH:30])[CH2:28][CH2:27]1>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:7]2[C:2]([O:30][CH2:29][CH:26]3[CH2:28][CH2:27]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCC1CC1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Product: Fc1cc2nc(-c3cccnc3OCC3CC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Example 1, intermediate a) and cyclopropyl-methanol (CAS Reg. No. 2516-33-8). Colorless semi-solid (16%). MS (Turbo Spray): m/z=398.3 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:11][S:12]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc(CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(COS(C)(=O)=O)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
In a sulfonating flask, 50 g (0.32 mol) of 4-methylthiobenzyl alcohol and 46.3 g (0.32 mol) of methylsulfonyl chloride are dissolved in 250 ml of toluene and, with cooling at 10° C., 32.5 g (0.32 mol) of triethylamine are added dropwise. The reaction mixture is then heated to room temperature and stirred overnight. 400 ml of 2N hydrochloric acid are then added to the reaction solution slowly and with cooling. The phases are separated and the organic phase is washed with water, dried over MgSO4 and concentrated in a rotary evaporator. 60 g (80%) of 4-methylthiobenzyl alcohol methanesulfonate are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24]Br)[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[CH2:24][N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2ccc(C(F)(F)F)n2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (632 mg, 4.65 mmol) and 2-benzyloxy-4-bromomethyl-1-nitrobenzene (1.0 g, 3.1 mmol) in DMF (8 mL) is added K2CO3 (642 mg, 4.65 mmol) and the mixture is stirred at RT for 48 h. The mixture is partitioned between EtOAc and water and the organic phase is washed with brine and dried over MgSO4. The solvent is removed under reduced pressure to give the title compound: (M+1)+=378.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH2:19])[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[C:22]=[S:23].O>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH:19][C:22](=[S:23])[NH:21][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=4)[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=NN)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Reactant: O=C(O)c1ccc(N=C=S)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Yield: 79.3 %

Procedure:
5-(2,3-Dihydro-1H-inden-5-yl)-3-(1-hydrazonoethyl)-1-methyl-1H-pyrazol-4-ol (47 mg, 0.174 mmol) in N,N-dimethylformamide (0.94 mL) was stirred with 4-isothiocyanatobenzoic acid (33 mg, 0.184 mmol) at room temperature for 4 hours and 40 minutes. After the reaction, 0.94 mL of water was added, and the resulting pale yellow solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (62 mg, 79% yield).
Reaction SMILES: S1C=CC(CC(O)=[O:8])=C1.C(S)CCS.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CC(C)=O>[CH:24]1([NH:23][C:22]([NH:21][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccsc1
Agent: CN(C)c1ccncc1
Agent: SCCCS
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C

Procedure:
As shown in Reaction 1, 2-(thiophene-3-yl)acetic acid) (1 g, 7.03 mmol), propane-1,3-dithiol (0.753 g, 7.03 mmol), and 4-dimethylaminopyridine (4-DMAP) (2.014 g, 1.75 mol) were dissolved in 80 ml of methylene chloride in a three-neck round bottom flask, after which stirring was performed at 60° C. in a nitrogen atmosphere. The stirred mixture solution was slowly added with N,N′-dicyclohexylcarbodiimide (DCC) (2.89 g, 14.06 mol) dissolved in 20 ml of methylene chloride, and was then allowed to react for 9 hours. The reaction solution was washed using saturated aqueous Na2CO3, dried over MgSO4, and filtered. The remaining solvent was removed by rotary evaporation to obtain a yellowish solution. This solution was diluted with acetone, and cooled to 0° C., to obtain residual 1,3-dicyclohexylurea (“DCU”) as a precipitate. This precipitate was removed by filtration through a paper filter, and addition of acetone and removal of the DCU precipitate were repeated until DCU precipitate was no longer evident in the solution. Finally, the remaining solvent was removed by rotary evaporation, and the crude purified using a silica column eluted with a solution of methylene chloride and methanol (60:1 v/v), thereby producing after collection of the fractions and removal of the solvent, S-3-mercaptopropyl-2-(thiophene-3-yl)ethanethioate (“MTE”) (the monomer) as a pure yellow compound. The characteristic H1-NMR spectrum (in acetone-d6) of the product is shown in FIG. 1.