Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#N)=[CH:7][CH:6]=1.[Br:14][C:15]1[CH:20]=C[C:18]([N+:21]([O-])=[O:22])=[CH:17][CH:16]=1.O>CO.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:22][N:21]=[C:18]3[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][C:12]=23)=[CH:9][CH:10]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2onc3ccc(Br)cc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 148 g of potassium hydroxide in 300 ml of anhydrous methanol at 0° C. was added 21.3 g (0.145 mole) of 4-methoxy phenylacetonitrile. The mixture was stirred at 0° C. for 10 min. and then a solution of 25.4 g (0.126 mol) of p-bromo nitrobenzene in 300 ml of tetrahydrofuran and methanol (1:2) was slowly added over a period of 1 h. The deep purple mixture was continuously stirred and maintained at 0°-5° C. during addition. The temperature was then raised to 55° C. using a hot water bath and reaction mixture was stirred for another 3 h. On cooling, the reaction mixture was poured into 1500 ml of water, and the brown precipitate was separated by suction filtration. The product was washed twice with water followed by cold methanol. The yellow solid so obtained was recrystallized twice from methanol to give needle like light yellow crystals. Yield 19.5 g (51%). mp 137.1° C. Anal. calcd. for C14H10NO2Br: c, 55.29; H, 3.31; N, 4.61. Found: C, 54.99; H, 3.14; N, 4.62.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][CH2:31][CH2:32]I>C(#N)C.O>[F:30][CH2:31][CH2:32][N:22]1[CH2:21][CH2:20][C:6]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CCF)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (60 mg, 0.19 mmol) was dissolved in acetonitrile (1 mL). Potassium carbonate (82 mg, 0.9 mmol) and 1-Fluoro-2-iodo-ethane (45 mg, 0.25 mmol) were added and stirred at RT for 1 h. The reaction mixture was heated at 80° C. for 1 h. After 1 h the reaction mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtained 33 mg of desired product. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.62 (d, 2H), 7.80 (d, 2H), 7.42 (s, 1H), 7.36 (s, 1H), 7.10 (m, 2H), 5.05 (m, 1H), 4.92 (m, 1H), 4.65 (s, 2H), 3.82 (m, 3H), 3.78 (m, 1H), 3.20 (m, 2H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.O>ClCCl>[F:30][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][S:23](=[O:39])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCSCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=S1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
0.61 g (1.4 mmol) of 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazine dissolved in dichloromethane (20 ml) was added with m-chloroperbenzoic acid (0.35 g, 2.0 mmol) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.27 g (yield: 42%) of the titled compound as colorless crystals.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C@H:30]([O:39]C3CCCCO3)[C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])=[CH:26][CH:25]=2)=[C:18]([CH2:46][CH2:47][CH3:48])[C:17]=1[OH:49])(=[O:15])[CH3:14]>CO>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C@H:30]([OH:39])[C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])=[CH:28][CH:29]=2)=[C:18]([CH2:46][CH2:47][CH3:48])[C:17]=1[OH:49])(=[O:15])[CH3:14]
Reactant: CCCc1c(SCc2ccc([C@H](OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCc1c(SCc2ccc([C@H](O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
Add p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) to a solution of (S)-3-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (177 mg, 0.34 mmol) in methanol (5 ml) at room temperature. Stir the mixture for 1.5 hours, concentrate, and dissolve the residue in ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (35 ml). Wash the organic layer with saturated aqueous sodium bicarbonate, brine, dry over sodium sulfate and concentrate. Purify the crude product via silica chromatography eluting with 1:2 ethyl acetate:hexanes to give the title compound (122 mg, 84%). MS (m/z) 430 (M−H).
Reaction SMILES: Br[C:2]1([C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([O:10][CH:11]([F:13])[F:12])[CH2:4]1)[NH2:3].[Cu][C:15]#[N:16].C(N)CN.Cl>CN(C=O)C.O>[C:15]([C:2]1([C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([O:10][CH:11]([F:13])[F:12])[CH2:4]1)[NH2:3])#[N:16]
Reactant: N#C[Cu]
Reactant: CC1=CC=C(OC(F)F)CC1(N)Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: O
Product: CC1=CC=C(OC(F)F)CC1(N)C#N
Temperature: 150 °C
Reaction time: 8 h

Procedure:
1-Bromo-3-difluoromethoxy-6-methylaniline (1.70 g, 6.74 mmol) is initially charged in 7 ml of DMF, and copper(I) cyanide (0.79 g, 8.76 mmol) is added. The reaction is stirred at 150° C. overnight. After cooling to room temperature, the DMF is removed under reduced pressure and 15 ml of water and ethylenediamine (3.6 ml, 53.9 mmol) are added to the residue. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is then acidified to pH=5 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate (6 times). The combined organic phases are dried over sodium sulphate and then purified chromatographically on silica gel. (logP: 1.90; MH+: 199, 1H-NMR (400 MHz, DMSO, ppm): 2.12 (s, 3H), 5.91, (s, 2H), 7.10 (t, 1H), 7.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][NH:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:7]([C:6]2[C:5]([O:4][C:3]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=3[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=2)=[O:9])=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: Clc1ccc2c(c1)NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccc(Cl)cc21
Temperature: 110 °C
Yield: 9.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.5 mL) was added 7-chloro-1,2,3,4-tetrahydro-quinoline hydrochloride (33.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 90562-34-8]), triethylamine (30.4 mg, 42 μL, 0.3 mmol, 2.0 equiv; [CAS RN 121-44-8]) and HATU (62.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 110° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 6 mg (10%) of the title compound. MS (ISP): 435.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:31])[O:3]1
Reactant: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitrile (5 g, 16.7 mmol) in anhydrous toluene was added, at room temperature under a blanket of nitrogen, Lawesson's reagent (6 g, 14.8 mmol). The reaction mixture was heated at reflux for 2 hrs, allowed to cool to room temperature, and solvent was removed in vacuo. The residue was purified by a silica gel column chromatography (THF:hexane/1:3) to yield the title compound as a yellowish solid (2.4 g, 46%): mp 211-212° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 7.88 (s, 1H), 7.46-7.52 (m, 2H), 7.16 (d, 1H, J=8.3 Hz), 2.30 (s, 3H), 1.68 (s, 6H); MS (ESI) m/z 313 [M−H]−; Anal. Calcd. For C16H14N2OS2; C, 61.12; H, 4.49; N, 8.91. Found: C, 60.91; H, 4.48; N, 8.66.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([CH3:11])[CH:4]=1)#[N:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:18][CH:19]=1.O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C[Si](OP(=O)=O)(C)C.Cl>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:34])[N:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=3)[C:21](=[S:22])[NH:23]2)=[C:5]([CH3:11])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1C=O
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1C
Temperature: 25 °C

Procedure:
4-Cyano-2-methylbenzaldehyde (200 mg, 1.38 mmol), 3-trifluoromethylphenyl thiourea (276 mg, 1.25 mmol), ethyl 3-oxobutanoate (179 mg, 1.38 mmol) and trimethylsilyl polyphosphate (225 mg) in 5 ml THF are stirred overnight at reflux temperature. The reaction mixture is cooled to room temperature, and after addition of 20 ml 0.5 M hydrochloric acid the aqueous phase is extracted with ethyl acetate (2×20 ml). The combined organic layers are washed with saturated aqueous sodium carbonate solution and dried with sodium sulfate. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: aceto-nitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1>O1CCOCC1>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([NH2:1])[CH:10]=1
Reactant: N
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(N)cc(Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Ammonia, 2.0 M in methyl alcohol (6.0 mL, 12 mmol) was added to a stirred yellow suspension of 4,6-dichloro-2-methylpyrimidine (Aldrich) (0.487 g, 3 mmol) in 1,4-dioxane (10.0 mL) at room temperature. The resulting mixture was sealed and stirred at 70° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 10% MeOH in DCM) to give 6-chloro-2-methylpyrimidin-4-amine (0.25 g, 58%) as a white solid. MS (API-ES) m/z 144 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:14])=[O:15])[CH2:33][C:32]2[CH:35]=[CH:36][C:29]([OH:28])=[CH:30][CH:31]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(NCCN(CC=Cc1ccc(Cl)cc1)Cc1ccc(O)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
0.2 g of the product of Example 172 and 0.13 g of p-hydroxybenzaldehyde were dissolved in 10 ml of methanol, to the solution were added 60 mg of sodium cyanoborohydride and two drops of acetic acid, and the mixture was stirred for 2 days at a room temperature. The reaction mixture was concentrated under a reduced pressure, and after adding a saturated sodium chloride aqueous solution, extracted three times with 20 ml of ethyl acetate. The extracts were combined, washed with sodium chloride, dried over magnesium sulfate, filtered and concentrated under a reduced pressure. The resulting residue was purified on a silica gel column (silica gel 10 g, eluant: 2% methanol in chloroform), to obtain 150 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C#N.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]=[C:10]([C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14]([F:24])([F:23])[F:13])[NH:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CNC(=O)c1cc(Cl)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A 1.8 M lithium diisopropylamide THF solution (45.3 ml, 81.6 mmol) was diluted with THF (68 ml). Thereafter, a solution obtained by dissolving the 5-chloro-2,N-dimethylbenzamide (5.0 g, 27.2 mmol) prepared in step A in THF (28 ml) was added dropwise to the diluted solution at −78° C. Thereafter, a solution obtained by dissolving 2-trifluoromethylbenzonitrile (4.65 g, 27.2 mmol) in THF (28 ml) was further added thereto, and the obtained mixture was then stirred at −78° C. for 2.5 hours. The temperature of the reaction solution was increased to a room temperature, and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, a solid generated as a result of vacuum concentration was filtrated, so as to obtain 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (6.87 g; yield: 78%) in the form of a colorless solid.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].O1CCOCC1.[C:16]1([CH2:22][O:23][CH2:24][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([CH2:22][O:23][CH2:24][CH:25]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Reactant: OCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(COCc1ccccc1)OCCCCCO
Temperature: 80 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
Into another flask, KOH (25.8 g), HO(CH2)5OH (47.9 g) and dioxane (200 ml) were charged and stirred at 90° C. until KOH was dissolved. Then, from a dropping funnel, PhCH2OCH2CH(CH3)OTs (71.2 g) and dioxane (75 ml) were added at 90° C. over a period of 20 minutes. After further stirring at 80° C. for 20 hours, water (350 ml) was added. Extraction with dichloromethane (100 ml) was carried out three times, and the extracted organic phase was washed with water (150 ml), then dried over anhydrous magnesium sulfate, filtered and further concentrated. The concentrated liquid was purified by silica gel column (eluent: hexane/ethyl acetate) to obtain PhCH2OCH2CH(CH3)O(CH2)5OH (20.8 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][OH:6].[H][H].Cl[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=1>CCCCCC.CN(C)C=O>[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][O:6][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)C(F)F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(OCC(F)(F)C(F)F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
After 840 mg (19.3 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 40 ml of dimethylformamide, and 3.00 g (22.7 mmol) of 2,2,3,3-tetrafluoropropanol were gradually added to the suspension at 0° C. under a nitrogen atmosphere. When generation of hydrogen gas stopped, a solution in which 3.40 g (18.3 mmol) of ethyl 6-chloronicotinate was dissolved in 15 ml of dimethylformamide was added dropwise to the resulting mixture at the same temperature for about 30 minutes. After the dropwise addition, the mixture was stirred for 30 minutes and the reaction mixture was poured into ice-water, followed by extraction with benzene. After the extract was dried, the solvent was distilled off and the thus obtained oil was purified over column chromatography [eluted with a mixed solvent of benzene-hexane (1:1)] using silica gel to obtain 4.42 g (yield: 86%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O)[CH3:2].Cl.[OH:17][NH3+:18]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:18][OH:17])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NO)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
22.4 g (0.1 mol) of (4-Methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester and 7.6 g (0.1 mol) of hydroxylammonium hydrochloride are dissolved in 180 ml of pyridine and the mixture is stirred at room temperature for 16 hours. The yellowish solution is diluted with water and ethyl acetate, the organic phase separated and the aqueous phase extracted several times with ethyl acetate. The combined organic extracts are washed with diluted hydrogen chloride and water and the solvent is evaporated. 24 g (100%) of crude hydroxyimino-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester (66:34 mixture of the E and Z-isomers) are thus obtained and used in the next step without further purification. The structure is confirmed by the 1H-NMR spectrum (in CDCl3). δ[ppm]: 7.46 (d,2H), 7.19 (d,2H), 4.44 (E) and 4,32 (Z) (two d,2H) 2.47 (Z) and 2.46 (E) (s,3H) 1.37 (E) and 1.28 (Z) (t,3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[N:12]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.25 h

Procedure:
To a solution of the compound obtained in Example 29 (3) (0.0457 g) in N,N-dimethylformamide (1.4 ml), 60% sodium hydride (0.006 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 15 minutes, followed by addition of 4-fluorobenzyl bromide (0.02 ml), and the mixture was stirred for 1 hour. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.0403 g of the desired product as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)CC)C>C(Cl)Cl.O>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccccc2[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.300 g, 1.04 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.707 g, 1.60 mmol), and 2-aminobenzimidazole (0.213 g, 1.6 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.45 mL, 3.2 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (20 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (0.396 g, 95%) as a white solid: mp 193.4-196.8° C.; EI-HRMS m/e calcd for C21H2,Cl2N3O (M+) 401.1062, found 401.1058.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O>[CH2:21]([S:1][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (1.24 g, 9 mmol) and hexyl bromide (0.63 ml, 4.5 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound.