Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[S:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[S:11])[CH3:8]
Reactant: CCN=C=S
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=S)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
Potassium carbonate (0.22 g, 1.6 mmol) and ethyl isothiocyanate (0.13 g, 1.8 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.44 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carbothioamide (0.05 g, yield: 9.4%). mp: 114-115° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (t, J=7.3 Hz, 3H), 2.81 (d, J=0.6 Hz, 3H), 3.67 (dq, J=5.7 and 7.3 Hz, 2H), 5.84 (q, J=0.6 Hz, 1H), 7.41 (dd, JHF=2.1 and 9.4 Hz, 1H), 7.62 (s, 1H), 8.54 (br s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(I)cc1
Reaction time: 17 h
Yield: 83.4 %

Procedure:
To a solution of 4-iodobenzoic acid (9.92 g, 40 mmol) in DMF (80 mL) is added potassium carbonate (5.8 g, 42 mmol) and iodomethane (2.6 mL, 42 mmol). The resulting mixture is stirred for 17 hours, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The crude solid is recrystallized in ethyl acetate/hexane to give 8.74 g of title compound. 1H NMR (CDCl3) δ 3.91 (s, 3H), 7.74 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H). MS (EI) m/z 262 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[N:22]([CH2:27][CH3:28])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]4[N:22]([CH2:27][CH3:28])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])=[CH:16][CH:17]=3)[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 46.8 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-amide (0.140 g, 0.374 mmol) and ethyl formate (0.060 mL, 0.816 mmol) were dissolved in anhydrous ethanol (0.250 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.42 mL, 1.12 mmol). This reaction mixture was heated at 78° C. for 0.5-1 h, producing a viscous, dark reddish colored oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 3 with dropwise addition of 1M HCl(aq) causing the formation of a grey precipitate. The suspension was filtered yielding a grey solid as the pure product (0.070 g, 0.175 mmol, 47%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].[ClH:16].[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:30]=O>C(O)C>[ClH:16].[CH3:9][C:8]1[N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=O
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)CCN2CCN(Cc3ccccc3)CC2)cnn1-c1ncccn1
Yield: 34.8 %

Procedure:
1.01 g of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 80 ml of anhydrous ethanol. After adding 1.25 g of 1-benzylpiperazine hydrochloride and 0.45 g of paraformaldehyde, the mixture was heated under reflux for 18 hours. Further, 0.60 g of 1-benzylpiperazine hydrochloride and 0.20 g of paraformaldehyde were added and the resulting mixture was heated under reflux for additional 8 hours. After cooling, the crystals were collected by filtration and extracted with chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue thus obtained was purified by silica gel column chromatography (50 g, chloroform:methanol=50:1), converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and then recrystallized from ethanol. Thus 742 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 104.4 %

Procedure:
Beginning with 1.00 gm (6.6 mmol) 6-chloro-1H-indole and 1.6 mL (13.0 mMol) 1-methyl-4-piperidone, 1.7 gm (100%) of the title compound were recovered as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17][N:18](C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O.[NH2:25]N>CO>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[NH:25][N:18]=[CH:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: NN
Solvent: CO
Solvent: O
Product: Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1cn[nH]c1-2

Procedure:
The mixture of 1 g of 8-chloro-4-dimethylaminomethylidene-1-phenyl-3,4-dihydro-2-benzazepin-5-one, 0.33 g of hydrazine hydrate and 45 ml of methanol is refluxed for 4 hours and evaporated under reduced pressure. The residue is taken up in the minimum amount of acetone-ethanol, the solution acidified with ethereal hydrogen chloride and the precipitate formed filtered off, to yield the 8-chloro-6-phenyl-1H,4H-pyrazolo[4,3-d](2)benzazepine dihydrochloride of the formula ##SPC3##
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8](=[O:11])[CH2:9]Cl)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[S:21])[S-:20].C([NH+](CC)CC)C>O>[OH:11][C:8]1([CH2:7][OH:6])[CH2:9][S:21][C:19](=[S:20])[N:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: S=C([S-])Nc1ccccn1
Reactant: CC(=O)OCC(=O)CCl
Agent: CC[NH+](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1(O)CSC(=S)N1c1ccccn1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
A 5.5 N aqueous solution of sodium hydroxide (36 cc) is added in the course of 5 minutes, at 22°-23° C., to a suspension of 3-chloro-2-oxopropyl acetate (29.9 g) in distilled water (500 cc). The hydrolysis reaction is allowed to proceed for 15 minutes at 22° C. and triethylammonium pyrid-2-yldithiocarbamate (53.6 g) is then added in the course of 5 minutes at a maximum of 23° C. The reaction is allowed to proceed for 2 hours at 20°-23° C. The crystals which have appeared are filtered off, washed with distilled water (50 cc) and then with ethyl ether (50 cc) and dried under reduced pressure (0.1 mm Hg) at 45° C. 4-Hydroxy-4-hydroxymethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (12.0 g), which melts at 134°-135° C., is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[C:4]([CH3:9])[N:3]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Reactant: Cc1nc(N)ccc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: Cc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methylpyridine and 4-(N-morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.09 (1 H, d, J 10 Hz, A-ring CH ortho to SO2NH), 7.68, 7.35 & 7.12 (3×1 H, 3×d, 3×J 10 Hz, pyridyl CH's & A-ring CH ortho to Cl), 7.58 & 7.08 (2×2 H, 2×d, 2×J 10 Hz, C-ring CH's), 7.46 (1 H, s, A ring CH ortho to 2×Cl), 3.71-3.62 (4H, m, CH2OCH2), 2.94-2.85 (4H, m, CH2NCH2), 2.49 (3H, s, CH1). Hplc (Luna 2, Gradient 5): rt=5.81 minutes. LC/MS rt=6.58 minutes, 574/576 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(SC)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 3.85 g. of ethyl 3-mercapto-4-cyclohexylphenylglyoxylate in 40 ml. of water containing 0.65 g. of sodium hydroxide is added 2 ml. of dimethyl sulfate with stirring. The reaction mixture is gradually warmed to 40° C. and stirred for 2 hours. The mixture is cooled and extracted with ether which is washed with water, dried and evaporated in vacuo. The residue is distilled to obtain ethyl 3-methylthio-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC#N
Product: N#CCC(O)c1ccc(F)c(Br)c1

Procedure:
Alkylation of 3-bromo-4-fluorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (4.2 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J=6.8, 2.0 Hz, 1H), 7.44 (ddd, J=8.4, 5.2, 2.4 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 6.08 (bs, 1H), 4.90 (s, 1H), 2.90 (ABd, J=16.8, 5.2 Hz, 1H), 2.83 (ABd, J=16.8, 6.4 Hz, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:32]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[C:13]([C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[C:27](=[O:31])[CH2:26][CH2:25]5)[CH:12]=3)=[CH:7][N:6]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Reactant: C1CNCCN1
Product: O=C1CCc2cc(-c3cc(-c4cnc(N5CCNCC5)nc4)oc3-c3ccncc3)ccc21
Yield: 65 %

Procedure:
The title compound (0.10 g, 65%) was prepared from the product of Example 7 Step 6 and piperazine using the method of Example 7 Step 7; MS(ES+) m/e 438 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18](O)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46].O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18]([NH:45][OH:46])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (1.1 g, 2.6 mmol) in tetrahydrofurane was added carbonyldiimidazole (0.73 g, 4.5 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 2.3 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-propionamide as a white solid (700 mg, 61%): mp 129–131° C.; 1HNMR (DMSO-d6): δ 0.33–0.35 (m, 2H), 0.54–0.57 (m, 2H), 1.15–1.30 (m, 1H), 3.11 (d, J=5 Hz, 2H), 3.87 (d, J=7.5 Hz, 2H), 5.71 (t, J=7.5 Hz, 1H), 6.95–6.98 (m, 1H), 7.03 (t, JH-F=75 Hz, 1H), 7.11–7.17 (m, 2H), 7.85 (s, 4H), 8.80 (s, 1H), 10.60 (s, 1H). 13C NMR (CDCl3): δ 0.7, 3.9, 3.9, 10.8, 35.7, 52.0, 74.6, 112.6, 114.9, 116.7, 120.8, 120.9, 123.6, 124.2, 132.3, 135.00, 137.7, 140.9, 151.3, 169.0; Anal. Calcd. for C22H20F2N2O6: C, 59.19; H, 4.52; N, 6.28. Found: C, 58.98; H, 4.41; N, 6.16.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:11][CH2:10][C@H:9]([OH:12])[C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol (6.4 g, 31 mmol) and pyridine (20 mL) in CH2Cl2 (200 mL) at 0° C. was added p-toluenesulfonyl chloride (7.0 g, 37 mmol) in small portions. The mixture was slowly warmed to rt and stirred for 40 hours, and then diluted with CH2Cl2 (100 mL). The organic phase was washed with aq. NaHCO3, brine, and dried (Na2SO4), and concentrated to yield the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22]O)=[CH:7]2.O=S(Cl)[Cl:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][Cl:26])=[CH:7]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2cc1CCl

Procedure:
Prepared according to Procedure C using (8-chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)methanol (1.10 g, 3.26 mmol) and SOCl2 (1.19 mL, 16.3 mmol, 5 eq) in dichloromethane (5 mL). 8-chloro-3-(chloromethyl)-2-(2-trifluoromethylphenyl)quinoline was obtained as a yellow syrup. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1 H, s), 8.10 (1 H, d, J=8.2 Hz), 8.02 (1 H, d, J=6.3 Hz), 7.95 (1H, d, J=7.4 Hz), 7.72-7.87 (2 H, m), 7.58-7.71 (2 H, m), 4.71 (2 H, dd, J=82.2, 12.1 Hz) Mass Spectrum (ESI) m/e=356.0 and 358.0 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[S:14][C:13]=1[NH:21][C:22]([NH2:24])=[NH:23].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:17]1[CH2:18][CH2:19][C:20]2[N:12]=[C:13]([NH:21][C:22]([NH2:24])=[NH:23])[S:14][C:15]=2[CH2:16]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl chloroformate is added to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine (0.1 mmol) and diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) and the mixture is stirred for another 3 hours at room temperature. After the addition of saturated aqueous sodium carbonate solution extraction is carried out with ethyl acetate; the combined organic phases produce the pure title compound after drying over sodium sulphate and complete evaporation of the solvent.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2nc[nH]c2c1

Procedure:
Benzimidazole-5-carboxylic acid I (12.9 g, 0.08 mmol) was dissolved in 100 mL of EtOH and mL of conc. H2SO4 (0.088 mmol) were added. The solution was refluxed for 24 h. After that the mixture was poured on ice and brought to neutral pH. The resulting mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over Na2SO4. After that the solvent was removed under reduced pressure. Yield: 12.6 g, 83%
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:1][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:8][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0° C., acetic acid (0.02 mL, 0.4 mmol) was added, followed, by N-methylpiperazine (0.3 g, 3 mmol) and sodium triacetoxyborohydride (0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0° C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 0.98 g (80%) of the desired product as a brown oil used in the following step without further purification.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20]([CH3:22])=[O:21])[CH3:11])=[O:9])[C:4](=[O:23])O1.[CH2:25]=O.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:25][N:27]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:4](=[O:23])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20]([CH3:22])=[O:21])[CH:15]=1
Reactant: NCCCC(=O)O
Reactant: C=O
Reactant: CN(Cc1ccc(F)cc1S(C)=O)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(F)cc1S(C)=O)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 18 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a colorless oil (0.015 g, 18% yield). 1HNMR (300 MHz, CDCl3) δ: 7.76 (1H, dd, J=8.05, 2.20 Hz), 7.34 (1H, dd, J=8.41, 5.12 Hz), 7.19 (1H, td, J=8.05, 2.56 Hz), 4.85 (2H, d, J=15.01 Hz), 4.18 (2H, s), 3.58 (2H, t, J=5.86), 3.01 (3H, s), 2.76 (3H, s), 2.39 (2H, t, J=5.86 Hz), 1.95 (2H, t, J=6.22 Hz).