Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(2-methoxyethyl)piperazine (1.2 equiv) to give 185 (21.8 mg, M+1 440.1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][CH2:12][OH:13]>CCOC(C)=O.[Pd]>[NH3:7].[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]([C@H:11]1[CH2:4][CH2:5][CH2:6][NH:7]1)=[O:13]
Reactant: CCO
Reactant: Cc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3)c2c1
Product: N
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of (R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl)]-5-methyl-1H-indole (Example 5b) in EtOAc (10 mL) was added EtOH (10 mL) and Pd/C (1.3 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere until the starting material was consumed. At this time, the reaction mixture was filtered through celite and the solvent was evaporated. The crude product was purified by column chromatography (4:1 CHCl3 : NH3 (2M in MeOH) to yield the title compound (121.5 mg, 15%) as a white solid (mp 194-196° C.).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:11]([CH3:18])[N:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:6][C:7]([OH:9])=O)[CH:2]=[CH2:3].[C:19](Cl)(=O)[C:20](Cl)=O.CN(C=O)C.C([Sn](CCCC)(CCCC)CCCC)=C>C(Cl)Cl>[CH2:1]([O:4][CH:5]([C:10]1[N:11]([CH3:18])[N:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:6][C:7](=[O:9])[CH:19]=[CH2:20])[CH:2]=[CH2:3]
Reactant: C=CCOC(CC(=O)O)c1c([N+](=O)[O-])cnn1C
Reactant: O=C(Cl)C(=O)Cl
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOC(CC(=O)C=C)c1c([N+](=O)[O-])cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-allyloxy-3-(2-methyl-4-nitro-pyrazol-3-yl)propanoic acid (4.33 g, 17 mmol) in DCM (48 mL) at 0° C. under nitrogen was added oxalyl chloride (4.37 mL, 51 mmol) followed by the cautious addition of DMF (0.05 mL) to initiate the acylation. The reaction mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. The residue was dissolved in DME (28 mL), vinyltributyltin (2.48 mL, 8.50 mmol) added and the mixture degassed with nitrogen for 30 min. trans-Benzyl(chloro)-bis(triphenylphosphine)palladium(II) (129 mg, 0.17 mmol) was added and degassing continued for 10 min. The reaction mixture was heated to 65° C. for 1 hr and cooled to room temperature. Concentration under reduced pressure and purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(allyloxy)-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pent-1-en-3-one as a yellow syrup (2.76 g, 61%). A solution of this syrup (250 mg, 0.94 mmol) in toluene (90 mL) was degassed with nitrogen for 30 min at 35° C. Zhan 1B catalyst (26 mg, 0.04 mmol) dissolved in toluene (2 mL) was added to the reaction mixture and degassing continued for 15 min. After stirring at 35° C. for 1 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(2-methyl-4-nitro-pyrazol-3-yl)-3,7-dihydro-2H-oxepin-4-one as a colourless solid (107 mg, 30% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.44 (ddd, J=12.8, 3.4, 2.3 Hz, 1H), 6.15 (m, 1H), 6.01 (dd, J=11.1, 3.4 Hz, 1H), 4.72 (ddd, J=19.8, 3.4, 1.7 Hz, 1H), 4.61 (ddd, J=19.6, 2.4 Hz, 1H), 4.08 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:21]=[C:20]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH:39]([F:41])[F:40])[N:19]=1.O>CN(C)C=O.C(Cl)(Cl)Cl>[F:41][CH:39]([F:40])[C:31]1[N:30]([C:20]2[N:21]=[C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:23]=[C:18]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=3)[N:19]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)ethanone (5.4 mg) in N,N-dimethylformamide (200 μL) were added potassium carbonate (6.9 mg) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction solution were added water and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC to obtain 1-[4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}oxy)phenyl]ethanone (1.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.[ClH:19].[NH2:20][OH:21].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=[N:20]\[OH:21]
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(/C(=N/O)c1ccccc1F)C2

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanone (29.5 g), hydroxylamine hydrochloride (16.5 g) and ammonium acetate (27.5 g) were heated in 80 ml of refluxing ethanol-water (3:1 mixture) for 19 hours. The mixture was cooled and the precipitated product was collected (25.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.[NH2:10][NH2:11]>C(O)(C)C>[F:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)n1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNc1cccc(F)n1
Yield: 76.8 %

Procedure:
2,6-Difluoropyridine (25 g), isopropyl alcohol (100 ml) and hydrazine hydrate (40 ml) were mixed and refluxed with heating for 3 hours. The isopropyl alcohol was evaporated under reduced pressure, and the residue was added with water. The deposited crystals were collected by filtration, washed with water and dried to obtain 6-fluoro-2-hydrazinopyridine (21.2 g, yield: 76.8%). Coloration was observed during drying, and accordingly, the product was used for the next reaction immediately after the drying.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: N#Cc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cccnc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
To a stirred suspension of 2-chloro-nicotinonitrile (Aldrich, 3.30 g, 23.82 mmol) in 2-propanol (30 ml) was added 4-fluoro-benzylamine (3.00 ml, 26.25 mmol) and N,N-diisopropylethylamine (8.30 ml, 47.65 mmol). The reaction mixture was heated to 80° C. for 24 hours. More 4-fluoro-benzylamine (0.55 ml, 4.81 mmol) was added and stirring was continued at 80° C. for another 24 hours. The reaction mixture was cooled to room temperature and the precipitated material was isolated by filtration and washed with 2-propanol. Residual 2-propanol was removed in vacuo affording the title compound (3.04 g) as a white crystalline material. 1H-NMR (DMSO-d6) δ 8.23-8.25 (m, 1H), 7.91 (dd, 1H), 7.73 (t, 1H), 7.34-7.38 (m, 2H), 7.08-7.14 (m, 2H), 6.63-6.67 (m, 1H), 4.57 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[S:8])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([C:28](=O)[CH2:29]Br)[N:22]=1)=[O:20])[CH3:17]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[S:8][CH:29]=[C:28]([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[N:22]=3)[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)c1nc(C(=O)CBr)ccc1O
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Solvent: CCO
Product: CCOC(=O)c1nc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Yield: 56 %

Procedure:
0.7 g of 3,4-diethoxythiobenzamide and 20 ml of ethanol were added to 0.77 g of 2-ethoxycarbonyl-3-hydroxy-6-(2-bromoacetyl)pyridine. The mixture was refluxed for 3 hours. Ethanol was removed by distillation. To the residue was added ethyl acetate-dichloromethane to give rise to crystallization to obtain 0.62 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-ethoxycarbonyl-2-pyridyl)thiazole.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccccc1
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Benzaldehyde (0.40 mmol) then was added thereto. After reacting for 51 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture -was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy-phenylmethylphosphonate as final product in a yield of 90%. The chemical reaction in this Example is shown in chemical formula 27. ##STR21##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O1CCCC1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc(Br)cc2)c1
Reaction time: 72 h
Yield: 80.5 %

Procedure:
A mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)urea (21 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][C:27]1[N:32]=[C:31]([C@H:33](OS(C)(=O)=O)[CH3:34])[CH:30]=[CH:29][CH:28]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:33]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]=1)[CH3:34]
Reactant: Cc1cccc([C@@H](C)OS(C)(=O)=O)n1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cc1cccc(C(C)Sc2c(Cl)ccc3c2CCNCC3)n1
Product: Cl

Procedure:
Use a method similar to the Preparation 177, except that the alkylation is conducted at 0° C., to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with (R)-methanesulfonic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 333 (M+H)+; ee >97%, tR=6.53 min. (Chiral HPLC: Chiralpak OJ 120 Å 4.6×250 mm, 45° C.; eluent: 20% isopropanol with 0.05% triethylamine in SFC, flow rate 2 mL/min, LTV detector at 234 nm).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=2[O:46][CH3:47])=[CH:34][C:33]=1[CH:48]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[N:30]=[C:48]([C:33]5[CH:34]=[C:35]([C:38]6[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=6[O:46][CH3:47])[CH:36]=[CH:37][C:32]=5[OH:31])[NH:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COc1ccc(OC)c(-c2ccc(O)c(C=O)c2)c1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COc1ccc(OC)c(-c2ccc(O)c(-c3nc4ccc(C(=O)Nc5ccc(CCN6CCN(C)CC6)cc5)cc4[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of silica gel (0.8 g) in dichloromethane (3 mL) was added SOCl2 (0.6 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (178.2 mg, 0.5 mmol), 4-hydroxy-2′,5′-dimethoxy-biphenyl-3-carbaldehyde (129.1 mg, 0.5 mmol) and 2 mL dichloromethane were added, and the resulting reaction mixture was stirred at the room temperature for 4 h. After methanol (5 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (217 mg, 84%). 1H NMR (MeOH-d4) δ 2.26 (s, 3H), 2.37-2.72 (12H), 3.73 (s, 3H), 3.77 (s, 3H), 6.80 (m, 1H), 6.94 (s, 1H), 6.95 (m, 1H), 7.03 (d, J=9 Hz, 1H), 7.13 (d, J=9 Hz, 2H), 7.49-7.64 (4H), 7.80 (d, J=9 Hz, 1H), 8.10 (s, 1H), 8.17 (s, 1H). ESI-MS m/z 592 (MH+).
Reaction SMILES: BrC1C=CC([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=CC=1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:11]2[N:12]=[C:13]([CH2:24][CH3:25])[N:14]=[C:9]([NH2:8])[N:10]=2)[CH:21]=1
Reactant: CC[Mg]Br
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2cc(Cl)ccc2C)n1
Yield: 36.1 %

Procedure:
The reaction of the title compound of Example 20 (200 mg, 0.49 mmol) with ethyl magnesium bromide (1 M in diethyl ether, 7.5 ml, 7.5 mmol) in tetrahydrofuran (2 ml) using the method described in Example 22 provided the title compound (44 mg, 22% yield). 1H NMR (CDCl3) 7.80 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.09-7.12 (m, 2H), 2.79 (q, J=7.4 Hz, 4H), 1.13 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4,6-bis(trifluoromethyl)benzoic acid D52 alternative method (400 mg, approximately 1.47 mmol) in DCM (5 ml), containing DMF (1 drop), was treated with oxalyl chloride (166 ul, 1.91 mmol) and stirred under argon for 1 hour. The solvent was carefully removed under reduced pressure and the residue re-evaporated from further DCM. The mixture of acid chlorides was then treated with methanol (3 ml) and kept at room temperature for 2 hours after which time the solvent was again carefully removed under reduced pressure. NMR data indicated this to be a mixture of the title product 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate. The mixture was used without further purification.
Reaction SMILES: [BrH:1].[F:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[CH2:9](O)[CH3:10]>>[CH2:9]([O:6][C:4](=[O:5])[CH:3]([F:2])[CH2:8][CH2:7][Br:1])[CH3:10]
Reactant: CCO
Reactant: O=C1OCCC1F
Reactant: Br
Product: CCOC(=O)C(F)CCBr
Reaction time: 72 h
Yield: 34 %

Procedure:
Hydrogen bromide gas was added over a period of about 30 minutes to a solution of 2-fluorobutyrolactone (1.8 g) in ethanol (15 ml) at 0° C. The reaction mixture was left at room temperature for 3 days, after which it was evaporated in vacuo. The residue was dissolved in icewater, the solution was neutralized with sodiumcarbonate and extracted with ether. The ether solution was washed with an aqueous saturated Na2SO4 solution, dried over Na2SO4 and evaporated to give 4-bromo-2-fluorobutyric acid ethyl ester (1.26 g, 34%). nD20 =1.4698. 1H-NMR (CDCl3, MeSi)δ: 1.3 (t, J=7 Hz, CH3); 2.1-2.8 (m, CH2); 3.55 (t, J=7 Hz, CH2Br); 4.3 (q, J=7 Hz, CH2); 4.75 and 5.55 (two triplets, J=6 Hz, CHF, JCHF =50 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10]O.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[ClH:14].[Cl:14][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]cnc1CSCCO
Solvent: ClC(Cl)Cl
Product: Cc1[nH]cnc1CSCCCl
Product: Cl

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethanol (0.34 g, 2 mmol) and thionyl chloride (0.238 g, 2 mmol) were heated together, with stirring, at reflux temperature in chloroform (10 ml) for one hour, giving a grey solution and a green oil. A second equivalent of thionyl chloride (0.238 g) was added at reflux temperature and immediately the oil went into solution and a solid started to crystallise. After a further 15 minutes at reflux temperature the mixture was cooled and the solid collected (0.395 g). Recrystallisation from acetonitrile gave 1-chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride, m.p. 163°-165°, (0.29 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O>[CH3:23][S:24][CH2:25][C:26](=[O:27])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CSCC(=O)Cl
Reactant: CCOCC(O)COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCC(O)COc1ccc(NC(=O)CSC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
Dissolved in 4 ml of dimethylformamide were 2.00 g of triethylamine and 2.11 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. To the solution was added 1.25 g of methylmercaptoacetyl chloride with ice-cooling and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water and concentrated. The resulting residue was purified by silica gel column chromatography using a 1:5 ethanol-chloroform mixture, giving 2.85 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyl methyl sulfide in 95.3% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH:21]([Mg]Br)([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)([OH:14])[CH:21]([CH3:23])[CH3:22])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone (0.1 g, 0.352 mmol) in THF (10 mL) was added isopropyl magnesium bromide (0.1 g, 0.704 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was quenched with ammonium chloride (5 mL) at 0° C., extracted with ethyl acetate (2×20 mL), washed with water followed by brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude was purifying by the preparative TLC (Mobile phase: 10% MeOH in DCM) to obtain pure 1-(2-(4-fluorophenyl)thiazol-5-yl)-2-methyl-1-(pyridin-4-yl)propan-1-ol (0.023 g, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, 2H), 7.92 (t, 3H), 7.56 (d, 2H), 7.27 (t, 2H), 6.22 (s, 1H), 2.79 (t, 1H), 0.98 (d, 3H), 0.71 (d, 3H); LC-MS m/z calculated for [M+H]+ 329.10. found 329.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](=O)[CH2:29]Br>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:29]=[C:28]([C:27]3[CH:32]=[CH:33][CH:34]=[C:25]([C:24]([F:23])([F:35])[F:36])[CH:26]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3cccc(C(F)(F)F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 18 %

Procedure:
2′-Nitro-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (53 mg, 18%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-(trifluoromethyl)phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H), 8.53-8.58 (m, 2H), 8.38 (s, 2H), 8.27-8.31 (m, 1H), 8.13-8.18 (m, 1H), 7.63-7.82 (m, 4H), 7.41-7.49 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[ClH:22]>>[Cl-:22].[CH:1]([NH2+:4][CH2:5][CH:6]([OH:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NCC(O)CCc1ccccc1-c1ccccc1
Reactant: Cl
Product: CC(C)[NH2+]CC(O)CCc1ccccc1-c1ccccc1
Product: [Cl-]

Procedure:
Following a precedure similar to that of Example 32, 1,2-epoxy-4-(1,1'-biphenyl-2-yl)butane was reacted with isopropylamine to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylamine. The amine base so formed was reacted with hydrogen chloride to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylaminium chloride. M.P. 153°-154° C.