Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C[O:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:20]([F:23])([F:22])[CH2:19][NH:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:29])=[O:27])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Temperature: 25 °C

Procedure:
A mixture of N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoro ethyl)urea (250.0 mg, 0.6050 mmol), [3-(methoxycarbonyl)phenyl]boronic acid (160 mg, 0.91 mmol Aldrich, Cat. No. 591130), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol Aldrich, Cat. No. 216666) and sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (10 mL) and a few drops of water was heated at 120° C. overnight under nitrogen. After the reaction was cooled to r.t., 1.0 M sodium hydroxide in water (2.4 mL,) was added to the above mixture. The reaction mixture was heated at 100° C. 2 h., and then cooled to r.t. The reaction mixture was diluted with ethyl acetate, and extracted with 1N NaOH aqueous solution twice. The combined aqueous phases were acidified to pH˜2 with 6 M HCl aqueous solution, and then extracted with ethyl acetate twice. The combined organic phases (only the extracted portion with acidic aqueous solution) were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product. LCMS (M+H)+: m/z=455.1.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].CC(C)([O-])C.[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(81 mg, 0.204 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (23 mg, 0.205 mmol). The reaction was stirred for 15 min before adding methyl bromoacetate (0.020 ml, 0.211 mmol, Aldrich). The reaction was heated to 60° C. and stirred overnight, under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a brown gum (38.5 mg); LCMS: (System 4) MH+=470, tRET=2.90 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([CH2:15][CH:16]=C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:20].[Na+].CCOCC>[Os](=O)(=O)(=O)=O.O>[C:10]([CH:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:18])[CH2:15][CH:16]=[O:20])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C(=O)OCC)C(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(CC=O)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Ethyl 3-(4-methylphenyl)-3-oxo-2-(allyl)-propanoate (74.21 g, 301 mmol, 1.0 eq), osmium tetroxide (100 mg, cat.), sodium metaperiodate (141.8 g, 663 mmol, 2.2 eq), ether (500 mL) and water (1 L) were mixed and stirred at room temperature. After 24 hours, an additional 110 mg of OsO4 was added and after another 24 hours, 200 mg more of OsO4 was added together with sodium metaperiodate (190 g, 888 mmol, 3.0 eq). After 4 days, the layers were separated and the ether layer washed with aqueous sodium bisulfite (1×500 mL) followed by brine (1×300 mL). The ether layer was dried (MgSO4) and the solvent removed in vacuo to yield 64.99 g of a dark brown oil. This oil was flash chromatographed over silica gel in 4:1 hexane/ethyl acetate to yield 37.5 g of an amber oil. NMR (200 MHz, CDCl3 ) δ9.79 (s, 1H); 7.93 (d, 2H, J=9 Hz); 7.27 (d, 2H, J=9 Hz); 4.87 (t, 1H, J=7 Hz); 4.13 (q, 2H, J=7 Hz); 3.37-3.08 (AB multiplet, 2H); 2.40 (s, 3H); 1.14 (t, 3H, J=7 Hz). Anal. Calcd. for C14H16O4 : C, 67.73; H, 6.50. Found: C, 67.53; H, 6.54.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]([C:12](Cl)=[O:13])([CH2:9][CH:10]=[CH2:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:20]>CC(C)=O>[C:12]([C:3]([CH:2]([F:15])[F:1])([CH2:9][CH:10]=[CH2:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:13])[NH2:20]
Reactant: C=CCC(C(=O)Cl)(C(=O)OCC)C(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: C=CCC(C(N)=O)(C(=O)OCC)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-difluoromethyl-2-chlorocarbonyl-4-pentenoate prepared as in Step A above (3.16 g) in acetone (25 mL) is added ammonium acetate (3.16 g). The mixture is stirred at room temperature for 3 hours. The insoluble material is filtered and the filtrate concentrated at reduced pressure. The residue is dissolved in ether (50 mL). The organic phase is washed with water, brine and dried over magnesium sulfate to give ethyl 2-carbamoyl-2-difluoromethyl-4-pentenoate (2.65 g) as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:36][CH3:37])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl[C:39]([O:41][CH3:42])=[O:40].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:36][CH3:37])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=2)[C:39](=[O:40])[O:41][CH3:42])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]amine (428 mg, 0.81 mmol) and methyl chloroformate (126 μL, 1.39 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropylethylamine (566 μL, 3.25 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (25 mL). The mixture was extracted with EtOAc (70 mL), and the organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 20% EtOAc/hexanes afforded methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]carbamate. Rf=0.37 (25% EtOAc/hexanes). LCMS=585.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.03 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.04-7.06 (m, 2H), 6.83 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.37 (bs, 2H), 3.93 (bs, 2H), 3.36 (s, 3H), 3.26 (s, 3H), 2.73 (m, 1H), 1.15 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=CC([Cl:31])=C(Cl)C=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([Cl:31])=[C:14]([Cl:18])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1Cl
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)c(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 1-bromo-3,4-dichlorobenzene.
Reaction SMILES: F[C@H]1CN(C2C=CC(CC3C=CC=CC=3C)=CC=2)[C@H]([CH2:21][C:22]([O:24][CH3:25])=[O:23])C1.[C:26]([Cl:29])(=O)C.[ClH:30].C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl>[ClH:29].[CH3:22][OH:23].[CH2:26]([Cl:29])[Cl:30].[CH3:25][O:24][C:22]([CH3:21])=[O:23]
Reactant: CC(=O)Cl
Reactant: COC(=O)C[C@@H]1C[C@@H](F)CN1c1ccc(Cc2ccccc2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
methyl 2-((2R,4R)-4-fluoro-1-(4-(2-methylbenzyl)phenyl)pyrrolidin-2-yl)acetate: A ˜3 M solution of HCl/MeOH/CH2Cl2/MeOAc was prepared by addition of acetyl chloride (0.64 mL) to a 1:1 solution of MeOH/CH2Cl2 (2.4 mL) at 0° C. The resulting solution of HCl was added to 37C (0.0051 g, 0.017 mmol). After stirring at rt for 2 h, the reaction was basified with sat. Na2CO3 (aq) and the desired product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography to provide 37D (yellow oil, 0.0021 g, 6.2 mmol, 37% yield). LC-MS Anal. Calc'd for C21H24FNO2 341.42. found [M+H] 342.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.14 (3 H, q, J=4.77 Hz), 7.07-7.11 (1 H, m), 7.01 (2 H, d, J=8.25 Hz), 6.56 (2 H, d, J=8.25 Hz), 5.30 (1 H, d, J=53.34 Hz), 4.29-4.38 (1 H, m), 3.89 (2 H, s), 3.67-3.69 (1 H, m), 3.63-3.75 (3 H, m), 3.50-3.61 (1 H, m), 2.99 (1 H, dd, J=15.40, 2.75 Hz), 2.54-2.68 (1 H, m), 2.25 (3 H, s), 2.17 (2 H, dd, J=15.40, 9.90 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:12])[NH2:11])[CH:3]=1.Cl[CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=O>C(O)(=O)C>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:10]2[S:12][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:14][N:11]=2)[N:5]=1
Reactant: O=C(CCl)C(F)(F)F
Reactant: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc(-c2cc(Cl)c(Cl)c(Cl)n2)s1
Yield: 17.8 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carbothioamide (2.85 g, 11.8 mmol) and 1-chloro-3,3,3-trifluoroacetone (2.59 g, 17.7 mmol) in glacial acetic acid (25 mL) was heated at reflux for 4 hours. Upon cooling, the solids formed were filtered and washed with water (3×100 mL) and sodium bicarbonate (3×50 mL). The solids were then dissolved in dichloromethane and the organic phase was washed with brine (150 mL), and dried (MgSO4). The solvent was removed and the residue purified by preparative liquid chromatography (90% acetonitrile in water) to give 2,3,4-trichloro-6-[5-(trifluoromethyl)-1,3-thiazol-2-yl]pyridine (0.70 g, 2.1 mmol); 1H NMR (CDCl3) δ 7.91 (s, 1H); 8.29 (s, 1H) and give 2,3,4-trichloro-6-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridine (0.20 g, 0.6 mmol); 1H NMR (CDCl3) δ 8.24 (1H, s), 8.39 (1H, s).
Reaction SMILES: [CH3:1]N(C)C=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:29])=[CH:22][CH:21]=1>O.C1(C)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:29])[C:30]3[C:31](=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[N:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:1]=2)=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.7 %

Procedure:
A solution of N,N-dimethylformamide (268 mg, 286 μL, 3.67 mmol) and tetrahydrofuran (2.94 mL) cooled to 0° C. was treated with oxalyl chloride (373 mg, 256 μL, 2.94 mmol). During the addition process, vigorous gas evolution occurred, the reaction became cloudy and a thick white precipitate formed. At this time, the ice bath was removed. The reaction mixture was stirred at 25° C. for 45 min and then was concentrated in vacuo. The resulting white paste was treated with toluene (11.8 mL) and 4-{3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propyl}-benzoic acid methyl ester (290 mg, 734 μmol). This mixture was then heated to 115° C. for 5 h and then was stirred at 25° C. overnight. At this time, the reaction was diluted with water (30 mL) and extracted into methylene chloride (3×30 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (40 g column; 1-10% methanol/methylene chloride) afforded 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28.7 mg, 9.65%) as a brown solid. ES+-HRMS m/e calcd for C23H17ClN2O3 [M+H+] 405.1000. Found 405.0995; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.73 (d, J=4.7 Hz, 1H) 8.29 (s, 1H) 8.14-8.24 (m, 2H) 7.85 (d, J=8.2 Hz, 2H) 7.79 (d, J=7.9 Hz, 1H) 7.63-7.72 (m, 1H) 7.47 (d, J=8.2 Hz, 2H) 7.43 (m, 1H) 7.21 (d, J=1.7 Hz, 1H) 3.89 (s, 2H) 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([Cl:18])=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(=O)c1ncc(OC)c([N+](=O)[O-])c1Cl
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(OC)c([N+](=O)[O-])c1Cl

Procedure:
To methyl 3-chloro-5-methoxy-4-nitro-pyridine-2-carboxylate, N-oxide (0.300 g, 1.12 mmol) in 5 mL of chloroform was added PCl3 (0.664 mL, 7.62 mmol). The reaction mixture was heated to reflux for 8 hr and then concentrated to dryness in vacuo to give 300 mg of a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])=[O:20]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])=[O:20]
Reactant: CN(CCCNC(=O)CBr)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)COc1nc2ccccc2s1)Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 59.3 %

Procedure:
0.0756 g (0.5 mmol) 1,3-benzothiazol-2-ol is dissolved in 5 ml dimethylformamide, 0.15 g (1.1 mmol) dry potassium carbonate is added and under stirring at room temperature 0.18 g (0.5 mmol) 2-bromo-N-{3-[(3,4-dichlorobenzyl)(methyl)amino]propyl}acetamide in 2 ml dimethylformamide is added dropwise. Stirring is continued for 24 hours. The reaction mixture is poured onto ice-water mixture, the precipitated crystals are filtered off, washed with water to obtain 0.13 g title compound. Mp: 113-115° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1c[nH]c2ccc(O)cc12
Product: N#CCc1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from benzyl bromide and 5-hydroxyindole-3-acetonitrile. MS ES (MH−)=263.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)CCN6CCCCC6)CC5)cc34)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into the suspension of (3-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydro pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (122 mg, 0.190 mmol), 1-piperidinepropanoic acid (48.4 mg, 0.305 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl) (76.7 mg, 0.400 mmol) and 1-hydroxy benzotriazole (HOBt-H2O) (30.6 mg, 0.200 mmol) in DMF (4.5 mL) was added N,N-diisopropylethylamine (167 μL, 0.952 mmol) under N2 at rt. The reaction mixture, which became a clear wine-red solution, was stirred at rt for 18 h. After that time, the reaction mixture was treated with water/saturated NaHCO3 (5 mL/5 mL) and extracted with EtOAc (4×20 mL). The combined extracts were washed with water (2×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain a light-brown oil that was purified using the mass-directed purification system to yield the title compound as yellow oil. 1H NMR (CD3OD, 400 MHz): δ=1.69 (brs, 2H), 1.88 (brs, 4H), 2.57 (s, 3H), 2.66 (brs, 2 H), 2.95-3.03 (m, 2H), 3.32 (brs, 4H), 3.41 (t, 2H, J=6.0 Hz), 3.76 (t, 1H, J=5.4 Hz), 3.85 (t, 1H, J=5.6 Hz), 4.28 (brs, 2H), 6.30 (d, 1H, J=2.8 Hz), 6.51-6.55 (m, 1H), 7.49 (d, 1H, J=8.4 Hz), 7.55-7.59 (m, 1H), 7.98-8.00 (m, 1H), 8.19 (s, 1H), 8.42 (s I H). MS (ES+): m/z 485.00 (70) [MH+]. HPLC: tR=1.70 min (ZQ2000, polar—5 min).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[CH3:40][O:41][C:42]1[C:47]([C:48](=[O:50])[CH3:49])=[CH:46][CH:45]=[C:44]([O:51][CH3:52])[N:43]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2([CH2:49][C:48]([C:47]1[C:42]([O:41][CH3:40])=[N:43][C:44]([O:51][CH3:52])=[CH:45][CH:46]=1)=[O:50])[OH:39]
Reactant: COc1ccc(C(C)=O)c(OC)n1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2ccc(OC)nc2OC)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and 1-(2,6-dimethoxypyridin-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.12 (d, 1H), 7.39 (s, 1H), 7.27 (d, 1H), 6.80 (d, 1H), 6.35 (d, 1H) 4.63 (bs, OH), 4.00 (s, 3H), 3.83 (s, 3H), 3.71 (d, 1H), 3.68 (m, 2H), 3.47 (d, 1H), 1.73 (m, 2H), 0.99 (t, 3H). Calculated mass for C20H21ClN2O5, 404.11. Observed 427.1 (M+Na)
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12](CC)([O-])=[O:13].C=CCCCC>C(N(CC)CC)C>[CH3:1][C:2]1[CH2:10][CH:9]([CH2:8][CH2:7][CH2:3][CH3:4])[O:13][N:12]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC[N+](=O)[O-]
Solvent: C=CCCCC
Solvent: CCN(CC)CC
Product: CCCCC1CC(C)=NO1

Procedure:
A reactor was charged with 20.0 parts phthalic anhydride, 20.9 parts nitroethane, 34.0 parts 1-hexene and heated to reflux. Then, 13.8 parts of triethylamine was slowly added over a one hour period. The mixture was refluxed for 20 hours. The product mixture was vacuum fractionally distilled to provide 3-methyl-5-butylisoxazoline in good yields.
Reaction SMILES: [C-:1]#[N:2].[Na+].O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1>CS(C)=O>[OH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(CCO)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1ccc(CCO)cc1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
Sodium cyanide (1.8 g, 37 mmol) was added to a stirred solution of the intermediate from Step B (10 g, 31 mmol) in DMSO (100 mL). The mixture was heated to 60° C. overnight (˜16 hours) and then the DMSO was removed under reduced pressure. DCM (100 mL) was added to the residue and the resulting mixture was washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 5.4 g of the title intermediate (99% yield), which was used without further purification.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][O:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:18]1[N:17]([CH2:16][O:15][CH3:14])[CH:21]=[CH:20][N:19]=1)[OH:39])([CH3:25])([CH3:23])[CH3:24]
Reactant: COCn1ccnc1
Reactant: CC(C)(C)c1ccccc1C(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccccc1)c1ccccc1C(C)(C)C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere and at -60° C., 38 ml. (0.08 mol) of a butyllithium solution (20% in n-hexane) were added drop-wise over the course of 45 minutes to a mixture of 9.6 g. (0.08 mol) of N,N,N',N'-tetramethylethylenediamine and 7 g. (0.06 mol) of 1-(methoxymethyl)imidazole in 100 ml. of anhydrous tetrahydrofuran. The mixture was stirred for another two hours under the same conditions and then 16 g (0.0675 mol) of o-tert.-butylbenzophenone in 100 ml. of anhydrous tetrahydrofuran were added dropwise. After the addition was completed, the mixture was stirred for 2 hours at -60° C., and one hour at room temperature. The mixture was decomposed with 5 ml. of water, the precipitate was filtered off and the filtrate was dried over sodium sulphate and concentrated. The solid residue was crystallised from isopropyl alcohol. α-(o-tert.-Butylphenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol was obtained. Melting point 149°-150° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:24])=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 134.5 %

Procedure:
4-{[4-(Trifluoromethyl)phenyl]carbonyl}benzoic acid (200 mg, 0.68 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.496 mL, 6.8 mmol) added. The reaction mixture was heated at reflux for 1 h. Further thionyl chloride (0.496 mL, 6.8 mmol) was added and heating continued for 3 h. On cooling, the reaction mixture was concentrated in vacuo to give 4-{[4-(trifluoromethyl)phenyl]carbonyl}benzoyl chloride as an oily white liquid (0.286 g) which was used directly in step 2.