Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH:7]=[CH:8][N:9]=1.CO.[ClH:21].[CH:22](=O)[CH2:23][CH3:24].C([BH3-])#N.[Na+].Cl>CO>[ClH:21].[ClH:21].[CH2:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)[CH:7]=[CH:8][N:9]=1)[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: NCCSc1nccn1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCCSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2-aminoethylthio)-1-(3,5-diflorobenzyl)imidazole (2.69 g, 0.010 mole) in absolute methanol (25 ml) is added 5 N hydrochloric acid methanol (1 ml, 0.005 mole) followed by propionaldehyde (4.25 g, 0.10 mole) and sodium cyanoborohydride (0.38 g, 0.006 mole). The reaction mixture is stirred at 25° C. for 72 hours and then concentrated hydrochloric acid is added until the pH is at least 2. The volatiles are removed in vacuo and then the residue is partitioned between water and ether. The layers are shaken together and separated, the pH of the aqueous extract is adjusted to greater than 10 with solid potassium hydroxide and then the product is extracted into ether. The ether extract is dried with anhydrous magnesium sulfate and then hydrogen chloride in ether is added slowly until a slight excess is present. The precipitated solid is filtered and recrystallized from ethanol-ether to give 2-(2-propylaminoethylthio)-1-(3,5-difluorobenzyl)imidazole dihydrochloride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].C(O)(=O)C.[C:40](=[O:45])([O:43]C)[O:41][CH3:42]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][C@H:13]3[O:45][C:40]([O:41][CH3:42])=[O:43])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)OC
Reactant: COCO[C@H]1C[C@H](OC(C)=O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Solvent: CC(=O)O
Product: COCO[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregn-6-en-5α-ol, following by addition of 0.2 ml of acetic acid. The mixture was stirred in an atmosphere of argon gas at a temperature of 100° C. for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 130 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.[H][H]>C(OCC)(=O)C.O.[Pt](=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)nc1Br
Yield: 98.7 %

Procedure:
2-Bromo-3-methoxy-6-nitropyridine (Desc. 5; 9.0 g, 38.6 mmol) and platinum (IV) oxide hydrate (250 mg) in ethyl acetate (250 ml) was hydrogenated at 20 psi hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate concentrated to give the product as a yellow solid (7.73 g, 38.1 mmol, 99% yield).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:14]1([CH2:20][C:21](Cl)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=P(Cl)(Cl)Cl>>[CH2:20]([C:21]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(Cc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), phenylacetylchloride (170 mg, 0.145 ml, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.026 mg (9.4%); MS m/z: 277.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 4.34 (s, 2H); 7.25-7.28 (m, 1H); 7.29-7.38 (m, 4H); 7.83 (d, 1H, 3J=8.7 Hz); 7.91 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.19-8.20 (m, 1H); 8.85 (s, 1H); HPLC (METHOD [A]): rt 11.17 min (100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Li+].Br[CH2:31][CH2:32][CH2:33][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44]>CN(C=O)C>[O:44]=[C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42](=[O:43])[N:34]1[CH2:33][CH2:32][CH2:31][N:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN4C(=O)c5ccccc5C4=O)c3=O)nc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a DMF (5 mL) suspension of (R)-ethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.20 g, 0.54 mmol) was added LiH (6.8 mg, 0.81 mmol) at 0° C., followed first by 20-minute stirring, then addition of a DMF (1 mL) solution of 2-(3-bromopropyl)isoindoline-1,3-dione (0.29 g, 1.1 mmol). The reaction was warmed to ambient temperature and stirred for 17 hours. After cooling to 0° C. the reaction was quenched with ice-water (30 mL) and the aqueous was extracted with EtOAc (3×50 mL). The combined organic layers were backwashed with water and brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH/DCM to yield the desired product (0.2 g, 66% yield). MS (apci) m/z=559.0 (M+H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])C.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([NH:23][C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CCOc1c(Nc2c(C)cccc2O)c(=O)c1=O
Solvent: ClCCl
Product: Cc1cccc(O)c1Nc1c(NC(C)(C)C)c(=O)c1=O
Reaction time: 168 h

Procedure:
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione (0.4 g, 1.62mmol) in t-butylamine (4.8mL) and dichloromethane (4.8mL) was allowed to stand at room temperature for 7 days. The slurry was filtered, rinsed with ethyl acetate, and dried. Chromatography with 10% methanol in dichloromethane, followed by trituration with 5% ethyl acetate in hexane gave 3-tert-butylamino-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione, 0.18 g (0.66 mmol, 41%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:14]=[CH:15][CH:16]=1>C(Cl)Cl.O>[CH3:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:2][OH:3])=[O:26])[CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: Cc1cccc(CCCCCCCCC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(CCCCCCCCC(=O)NO)c1

Procedure:
To a cold, stirring suspension of 1.3 gm hydroxylamine hydrochloride and 1.8 gm sodium carbonate in 25 ml CH2Cl2 was added dropwise 4 gms 9(3-methylphenyl)nonanoyl chloride. The reaction mixture was stirred at 5°-10° for 45 min, then 2.1 ml H2O was added and the mixture stirred overnight at room temperature. The suspension was then diluted with CH2Cl2 and water, shaken, and the organic layer was separated. It was washed three times with water and once with NaCl solution, dried over MgSO4, and filtered. The solvent was removed in vacuo to give an oil which solidified but which could not be crystallized. The solid was disolved in ether, shaken with 5% KOH, and the ether discarded. The aqueous layer was acidified and the precipitated solid extracted into CHCl3. The chloroform was washed twice with water and once with NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting oil was purified by silica gel column chromatography, using gradually increasing cocentrations of ethyl acetate in chloroform (0, 10%, 15%, 25%). Fractions containing the major component (detected by thin layer chromatography--Rf=0.4 in 1:1 ETOAc:CHCl3) were collected and evaporated down to give an off-white solid which was crystallized from CH2Cl2 :hexanes. Yield 1.3 gms (33%) product of m.p. 49°-50°. Elemental analysis: calculated C 72.98, H 9.57, N 5.32% found C 72.80, H 9.56, N 5.32%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.Cl.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][C@@H:29]([C:27]3[O:26][N:25]=[C:24]([CH3:23])[N:28]=3)[CH3:30])=[O:13])=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1ccc(-n2nc(Br)c3ccc(C(=O)O)cc32)cc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-n2nc(Br)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3-Bromo-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (233.7 mg, 0.389 mmol, with 4 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (94.2 mg, 0.471 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (156.1 mg, 0.814 mmol), 1-hydroxy-7-azabenzotriazole (28.9 mg, 0.212 mmol), and N-methylmorpholine (0.171 mL, 1.554 mmol) were dissolved in N,N-dimethylformamide (3.800 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 0.5 mL) and trifluoroacetic acid (ca 0.5 mL). The reaction mixture purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid. The product fractions were concentrated under reduced pressure. The residue was taken up in ethyl acetate (15 mL), washed with sodium bicarbonate (2×20 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give the title compound (153.9 mg, 0.350 mmol, 90% yield) as a tan solid. HRMS: [M+1]=440.0730.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:33]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of EXAMPLE 74 (90.0 mg, 0.20 mmol) in methanol (1.0 ml) was added sodium borohydride (15.4 mg, 0.407 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel cartridge (a gradient of 0-10% methanol in dichloromethane) to give racemic 2-{4-[3-(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}-1-phenylethanol as a light yellow solid. LC-MS (m/z): 445.10 [M+H]+. 1H NMR (CDCl3, 500 MHz): δ 8.90 (d, J=4.8 Hz, 2H), 8.23-8.29 (m, 2H), 7.35-7.37 (m, 4H), 7.29-7.34 (m, 1H), 7.13-7.17 (m, 3H), 4.80 (dd, J=10.4 Hz, 3.4 Hz, 1H), 4.28-4.34 (br, 1H), 3.81-3.87 (br. 1H), 3.34 (d, J=11.4 Hz, 1H), 3.01 (d, J=1.4 Hz, 1H), 2.50-2.63 (m, 3H), 2.02-2.29 (m, 4H). The racemic 2-{4-[3-(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]piperidin-1-yl}-1-phenylethanol was resolved using ChiralPak™ AD column using 60% IPA in heptane to give a faster eluting enantiomer and a slower eluting enantiomer.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([N:16]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH2:15][CH2:14]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: NC1CC1
Solvent: CCO
Product: O=C(O)C1CCN(C2CC2)C1=O
Yield: 70.1 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and cyclopropanamine (0.309 mL; 4.36 mmol) in ethanol (3 mL). 1-cyclopropyl-2-oxopyrrolidine-3-carboxylic acid 0.172 g (70%) was obtained as a white solid.
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:17]([NH:20][NH2:21])(=O)[CH3:18]>CCO>[CH3:18][C:17]1[NH:20][N:21]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: CC(=O)NN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a suspension of ethyl benzimidate hydrochloride (2.0 g, 10.8 mmol) in EtOH (10 mL) was added sodium ethoxide (3.49 g, 4 mL, 10.8 mmol) at RT. The precipitated NaCl was filtrated off and washed with EtOH (14 mL). The filtrate was charged with acetohydrazide (880 mg, 11.9 mmol) and stirred at RT for 6 d. The crude reaction mixture was concentrated in vacuo. The crude product was suspended in NaOH (1M aqueous solution, 50 mL) and extracted with tert-butyl methyl ether (100 mL). The organic layer was washed with water (50 mL) and the aqueous layers were back-extracted with tert-butyl methyl ether (50 mL). After addition of dry ice to adjust the pH to 7, the organic layer appeared to contain almost no product and was discarded. The aqueous layer was adjusted to pH=7 by addition of HCl (25% aqueous solution) and extracted with dichloromethane (6×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/hexane gradient) as white solid (154 mg, 9%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: CI
Reactant: N#Cc1cc(Nc2cccnc2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cccnc1)c1ccnc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
NaH (185 mg, 7.71 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (17.5 mL) was added. The slurry was cooled to 0° C. and compound 10 (1.374 g, 7.003 mmol, 1.000 eq) was added as a solution in THF (17.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (481 μL, 7.71 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 473 mg (32%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.5 Hz, 1H), 8.56 (dd, J=1.2, 4.7 Hz, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.81 (dq, J=1.4, 8.2 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J=2.6 Hz, 1H), 6.80 (dd, J=2.7, 6.0 Hz, 1H), 3.36 (s, 3H); ES-MS [M+1]+:211.1.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[C:40](=[O:41])[NH:39][N:38]=[CH:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[F:23][CH:22]([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:39]2[C:40](=[O:41])[N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[CH:37]=[N:38]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)nc1C
Yield: 79 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-(difluoromethoxy)benzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 79% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.44-7.36 (m, 2H), 7.14-7.06 (m, 2H), 6.47 (t, JH-F=73.8 Hz, 1H), 4.99 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.35 (t, J=7.0 Hz, 3H); MS (ES+) m/z 411.2 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][N:17]([CH3:31])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)(c2ccc(I)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a flask containing sodium hydride (0.07 g, 2.9 mmol, 5 eq.) under Ar at 0° C. was added a solution of 4-(4-iodo-phenyl)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 0.58 mmol) in DMF (5 mL). The resulting mixture was warmed to room temperature and stirred for 2 h, heated to 35° C. for 0.5 h and CH3I (0.36 mL, 5.8 mmol, 10 eq.) was added. The mixture heated at 35° C. for a further 2 h. The reaction was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (25 mL) and saturated brine (25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash column chromatography by eluting with 30% EtOAc/hexanes to give 4-(4-iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.022 g, 0.42 mmol, 72%). 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.20 (d, 2H), 3.93 (m, 2H), 3.78 (m, 1H), 3.53 (m, 1H), 3.07 (m, 2H), 2.60 (m, 3H), 2.24 (m, 2H), 1.93 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C=O)C>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(NC(=O)Nc3ccccc3)ccc21
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A solution of 6-amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 48 mg, 200 μmol) in anhydrous DMF (2 mL) was treated with PhNCO (33 μL, 300 μmol) & pyridine (16 μL, 20 μmol). The mixture was stirred for 16 h & then partitioned between EtOAc (30 mL) & H2O (20 mL). The organic layer was washed with H2O (20 mL) & brine (20 mL), before being dried (MgSO4). After filtration, the solution was concentrated & a precipitate formed. This precipitate was collected by filtration & washed with cold EtOAc to give the title compound (58 mg, 80%): δH ((CD3)2SO)=3.60 (s, 3H), 7.00 (t, 1H), 7.10 (s, 1H), 7.30 (t, 2H), 7.45 (d, 2H), 7.65 (d, 1H), 7.75 (dd, 1H), 8.15 (d, 1H), 8.70 (s, 1H), 9.00 (s, 1H); m/z (ES+)=362.2
Reaction SMILES: [CH3:1]N1C2C(=CC=C(N)C=2)CC1.[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].CI.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=2)[CH2:19][CH2:20]1
Reactant: CN1CCc2ccc(N)cc21
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
1-Methyl-2,3-dihydro-1H-indol-6-ylamine. 6-Nitroindoline (2 mmol) was combined with methyl iodide (2.2 mmol), n-Bu4I (7.4 mg, 0.020 mmol), and K2CO3 (350 mg, 2.5 mmol) in acetone (10 mL). The mixture was stirred at 25° C. for 16 h. The mixture was partitioned between CH2Cl2 and satd. aq. NaHCO3 (20 mL), and the organic layer was dried and concentrated. Purification by silica gel chromatography provided 1-methyl-6-nitroindoline (300 mg, 84%). To a solution of 1-methyl-6-nitroindoline (194 mg, 1.15 mmol) in MeOH (2 mL) was added FeCl3.6H2O (3 mg), Me2NNH2 (0.80 mL, 11 mmol), and charcoal (25 mg). The mixture was heated at reflux for 4 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to provide the desired compound in quantitative yield. Step B. (1-Benzyl-piperidin-4-yl)-(1-methyl-2,3-dihydro-1H-indol-6-yl)-amine. The product from Step A (161 mg, 1.1 mmol) was converted to the desired compound as in Example 2, Step B. Step C. The title compound (80 mg, 35%) was prepared as in Example 2, Step C. 1H NMR (500 MHz, CDCl3): 7.63 (d, J=15.5 Hz, 1H), 7.30-7.25 (m, 10H), 7.02 (d, J=7.4 Hz, 1H), 6.38-6.36 (d, J=8.8 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H), 6.14 (s, 1H), 4.73-4.68 (m, 1H), 3.46-3.34 (m, 4H), 3.02-2.86 (m, 4H), 2.73 (s, 3H), 2.17-2.12 (m, 2H), 1.86-1.77 (m, 2H), 1.61-1.51 (m, 2H). MS: exact mass calculated for C30H33N3O, 451.26; m/z found, 452.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 45.4 %

Procedure:
A mixture containing methyl 4-hydroxybenzoate (45.6 g), octadecylbromide (100 g), and potassium carbonate (41.4 g) in 2-butanone (200 ml) was heated at reflux for 16 hours. The solvent was then removed until 125 ml of 2-butanone had been collected. While it was still warm, the remaining material was poured into methanol (400 ml). The product was filtered and recrystallized from 2000 ml of methanol to give methyl 4-octadecyloxybenzoate (55 g).