Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]>CCOCC>[F:4][C:5]([F:15])([F:16])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:3])=[O:10]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: COC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of m-trifluoromethylbenzoic acid (8.0 g, 42.1 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-trifluoromethylbenzoate (8.4 g, 41.2 mmol, yield 97.8%, b.p. 76°-78° C./12 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][F:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:13][CH2:14][F:15])[S:8][C:4]=2[CH:3]=1
Reactant: FCCBr
Reactant: Sc1nc2ccc(Br)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FCCSc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
To 6-bromobenzo[d]thiazole-2-thiol (160 mg, 0.65 mmol) and 1-bromo-2-fluoroethane (165 mg, 1.3 mmol) in 5 mL of NMP was added Cs2CO3 (635 mg, 1.95 mmol). The mixture was stirred at rt for 5 hours. It was added water (20 mL) and precipitate was collected through filtration and washed with water (10 mL) and dried under high vacuum. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford 6-Bromo-2-(2-fluoroethylthio)benzo[d]thiazole as a yellow solid (88 mg, 46%). MS (ESI) m/z 291.9, 293.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]1)=[O:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:23]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrocholoride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (˜100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) δ 1.33-1.50 (m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2H), 2.28 (m, 1H), 3.72 (s, 3H,) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1H). LC-MS (Method J, retention time: 3.01 min), MS m/z 399 (M++1). Step 26ii: Preparation of 1-{[1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)carbonyl]-(1R)-amino}-2(S)-vinylcyclopropanecarboxylic acid ethyl ester
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[CH:31]=[CH:32][C:33](O)=[O:34])(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:34])[CH:36]=[CH:37][CH:38]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(=O)Oc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(OC(C)=O)c1
Yield: 95.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 3-acetoxycinnamic acid (2.0 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (3.1 g, 96%) as an oily product.
Reaction SMILES: Br.Br.C[N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:6][CH2:5]1.[ClH:20]>>[ClH:20].[NH:4]1[CH2:5][CH:6]=[C:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9]1
Reactant: CN1CC=C(c2cnc3ccccc3c2)CC1
Agent: Br
Agent: Cl
Product: C1=C(c2cnc3ccccc3c2)CCNC1

Procedure:
This product was prepared from the compound of Example 7 and using the procedure described in Stages A and B of Example 6. The compound obtained was converted to a salt using an alcoholic solution of hydrogen chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:40]=[CH:39][C:24]2[N:25]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:26](=[O:32])[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:20][C:21]1[CH:40]=[CH:39][C:24]2[N:25]([CH:33]3[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][CH:5]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=4)[CH2:37][CH2:38]3)[C:26](=[O:32])[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:23]=2[CH:22]=1
Reactant: CC(=O)Cn1c(=O)n(C2CCNCC2)c2ccc(Cl)cc21
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(=O)Cn1c(=O)n(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane, 5 parts of 5-chloro-1,3-dihydro-3-(2-oxopropyl)-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is stirred while warming in 2,2'-oxybispropane. The turbid mixture is filtered hot over hyflo and the clear filtrate is allowed to cool to room temperature while stirring. The crystallized product is filtered off and recrystallized from 2-propanol, yielding 5-chloro-1-{1 -[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-3 -(2-oxopropyl)-2H-benzimidazol-2-one; mp. 175.3° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([NH:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[Br:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl.C(N(CC)C(C)C)(C)C>[C:1]([O:5][C:6](=[O:23])[CH:7]([N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[Br:22])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NCc1sccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)N(Cc1sccc1Br)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of 2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tert-butyl ester (91.6 mg, 0.231 mmol) in dichloromethane (3.3 ml) and N,N-diisopropylethylamine (44 μl) was added a solution of 2,4-Dichloro-benzoyl chloride (34 μl, 0.243 mmol) in dichloromethane (1.3 ml). The reaction mixture was stirred at room temperature under nitrogen overnight. Then, the mixture was extracted with sodium bicarbonate/dichloromethane. The extract was dried (sodium sulfate) and evaporated under reduced pressure to yield 2-[(3-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid tert-butyl ester with 92% yield. 1H NMR(Varian 400 MHz, CDCl3) δ(ppm) presence of rotomers 8.08 (d, 0.5H, J=8.7 Hz, ArH), 7.56 (d, 0.5H, J=2.0 Hz, ArH), 7.40 (m, 2H, ArH), 7.23 (m, 2.5H, ArH), 6.99 (d, 0.5H, J=5.4 Hz, ArH), 6.92 (m, 2H, ArH), 6.83 (d, 0.5H, J=5.0 Hz, ArH), 6.54 (d, 1H, J=7.1 Hz, ArH), 5.78 (d, 0.5H, J=8.0 Hz, ArH), 5.20 (m, 1H, NCH2), 4.85 (m, 1H, NCH2), 4.16 (m, 1H, CHCH2), 3.10 (m, 2H, CHCH2), 1.47 (s, 9H, tBu).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc([C@H]3CCCN3)oc2-c2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CN2CCC[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of (2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (400 mg) and 3-bromomethyl-1-ethoxycarbonylmethoxybenzene (0.76 g) in N,N-dimethylformamide (10 ml) was added K2CO3 (1 g) at room temperature. The mixture was stirred for 2 hours at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-2-(4,5-diphenyloxazol-2-yl)-1-(3-ethoxycarbonylmethoxybenzyl)pyrrolidine (0.27 g). MS (m/z): 483 (M+ +1) IR (Neat): 1750 cm-1NMR (CDCl3, δ): 1.25 (3H, t, J=7.0 Hz), 1.8-2.5 (5H, m), 3.14 (1H, m), 3.60 (1H, d, J=14 Hz), 3.84 (1H, m), 3.85 (1H, d, J=14 Hz), 4.23 (2H, q, J=7.0 Hz), 4.48 (2H, s), 6.71 (1H, d, J=8 Hz), 6.8-7.0 (2H, m), 7.16 (1H, t, J=8.0 Hz), 7.3-7.8 (16H, m)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:7]2[CH:15]=[CH:16][C:17]([C:19](F)(F)F)=[CH:18][C:6]=2[N:5]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N>>[S:30]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:19]1[C:17]1[CH:16]=[CH:15][C:7]2[N:8]([CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]=2[CH:18]=1
Reactant: COCc1nc2cc(C(F)(F)F)ccc2n1C1CCOCC1
Reactant: Nc1ccccc1S
Agent: N
Product: COCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 8.2 %

Procedure:
An eggplant flask was charged with 2-methoxymethyl-1-(tetrahydropyran-4-yl)-5-trifluoromethylbenzimidazole (see Working Example 6-1) (0.102 g, 0.32 mmol), 2-aminobenzenethiol (0.041 g, 0.33 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 120° C. and stirred for 48 hours. After being allowed to cool, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. Chloroform extraction, drying over anhydrous magnesium sulfate, and the solvent being distilled off gave a crude product (0.21 g), which was purified by silica gel column chromatography (MeOH/CHCl3=1/20) to yield the title compound (0.010 g, 8.1% yield) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([N:48]([CH2:50][CH3:51])[CH3:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:50]([N:48]([CH3:49])[CH:45]1[CH2:44][CH2:43][CH:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:47][CH2:46]1)[CH3:51]
Reactant: CCN(C)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CCC(N(C)CC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-{4-[ethyl(methyl)amino]cyclohexyl}-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 236A). 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.07 Hz, 6 H) 1.39 (t, J=7.33 Hz, 3 H) 1.70-1.86 (m, 4 H) 2.04 (br. s., 2 H) 2.19 (d, J=7.83 Hz, 2 H) 2.71 (br. s., 1 H) 2.86 (s, 3 H) 3.17-3.19 (m, 3 H) 3.33 (s, 1 H) 3.34-3.37 (m, 2 H) 3.39 (s, 1 H) 3.43-3.52 (m, 1 H) 3.89 (s, 3 H) 4.05-4.14 (m, 4 H) 4.55 (s, 2 H) 7.01 (dt, J=8.02, 2.31 Hz, 1 H) 7.15 (t, J=2.02 Hz, 1 H) 7.42 (d, J=8.34 Hz, 1 H) 7.57 (d, J=8.08 Hz, 1 H) 8.36 (br. s., 1 H). MS (ES+): m/z 719.25/720.29 (100/20) [MH+]. HPLC: tR=1.17 min (UPLC TOF: polar—3 min).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1>>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN1CCC(=O)CC1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C2CCN(C)CC2)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound 60 (72.0 mg, 62.0%) was obtained in the same manner as that in Example 10, by using compound 1 (100 mg, 0.167 mmol) obtained in Example 1, and 1-methylpiperidin-4-one (Aldrich; 0.205 mL, 1.67 mmol).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:5][N:4]([CH2:3][N:9]=[CH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:6]
Reactant: NCC1CCNCC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)CN=CC1CCNCC1

Procedure:
N,N-Dimethylformamide dimethyl acetal (23.3 ml) was added to 4-aminomethylpiperidine (20.0 g) in toluene (20 ml) and the mixture was boiled under reflux for 3 hours removing the water formed using a Dean and Stark apparatus to give a solution of 4-(dimethylaminomethyliminomethyl)piperidine. The mixture was cooled to ambient temperature and 2-bromoethyl phenyl ether (22.1 g) then triethylamine (24.3 ml) were added. The mixture was boiled under reflux for 10 hours and then evaporated to dryness. The residue was dissolved in 2M hydrochloric acid (200 ml) and heated on a steam bath for 24 hours. The mixture was cooled to ambient temperature and washed with dichloromethane. The aqueous layer was basified with 6M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 186°-242° C. at 0.8 mbar. The distillate was dissolved in methanol (50 ml) and treated with concentrated aqueous ammonia solution (20 ml, specific gravity 0.88) and then left at ambient temperature for 18 hours. The solution was concentrated by evaporation and water (200 ml) was added. The mixture was extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride. A solid was collected by filtration and recrystallised from propan-2-ol/IMS to give 4-aminomethyl-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([S:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]1[O:18][C:8]2[CH:9]=[CH:10][C:11]([S:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)Sc1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a mixture of 0.64 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, 6 ml of tetrahydrofuran and 0.53 g of triphenylphosphine, 0.87 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.57 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethylthio)benzoxazole (hereinafter, referred to as “active compound 77”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cccc(F)c2[nH]1
Product: Fc1cccc2ccc(Cl)nc12
Temperature: 25 °C

Procedure:
8-Fluoroquinolin-2(1H)-one (26 g, 159 mmol) was slurried phosphoryl trichloride (163 mL, 1753 mmol, 11 eq) and heated to 125 for 2 h. The reaction was cooled to rt and poured onto 1.2 L of ice water with vigorous stirring. When mixture had cooled to rt, the orange solid was filtered and washed with water and dried under vacuum overnight to afford 27 g of crude material. The crude material was recrystallized from hexanes by dissolving in ˜700 mL of hexanes at reflux and decanting away from residual tar. The hexane solution was cooled to 0° C. and the precipitate 2-chloro-8-fluoroquinoline was filtered. The mother liquor was concentrated in vacuo and recrystallized from hexanes to obtain a second crop of 2-chloro-8-fluoroquinoline. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (dd, J=8.6, 1.2 Hz, 1H), 7.62 (br d, 1H), 7.52 (td, J=7.8, 4.7 Hz, 1H), 7.45 (m, 2H). 1-(2-Chloro-8-fluoroquinolin-3-yl)ethanol
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([F:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].C1COCC1.Cl>CO>[F:3][C:4]1[C:13]([F:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OC)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
Sodium hydroxide (2N, 50 mL) was added into a mixture of methyl 2,3-difluoro-4-methoxybenzoate (10.0 g, 49.5 mmol), THF (100 mL) and MeOH (100 mL). The mixture was stirred at room temperature for 6 h, and acidified with HCl (2N). The precipitated solid was filtered off, washed with water and dried to give a white solid (8.9 g, 96% yield, m.p. 194-196° C.); MS m/e 187 (M−H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[NH4+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26]([NH2:36])=[O:27])[N:25]=1)[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(=O)O)c(-c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
2-((1R)-1-(tert-Butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid (0.17 g; 0.362 mmol) was dissolved in methylene chloride (8 ml). 1-Hydroxybenzotriazole (0.049 g; 0.362 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.083 g; 0.434 mmol) were added. The reaction mixture was stirred 15 min at room temperature. Ammonium hydrogencarbonate (0.057 g; 0.724 mmol) was added and the reaction mixture was stirred 12 h at room temperature. Methylene chloride (20 ml) was added and the reaction mixture was washed with sodium hydrogencarbonate (10%; 10 ml), sodium hydrogensulfate (5%; 2×10 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×15 cm) using ethyl acetate/heptane (1:1) as eluent to afford 0.155 g of 2-((1R)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[O:15])[NH:23][NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: NNc1ccccc1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NNc2ccccc2)CCCCC1

Procedure:
To 6.6 grams (0.0315 moles) of 1-t-butylazo-1-isocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added dropwise 3.42 grams (0.0315 moles) of phenylhydrazine. The reaction was very exothermic and rapid. Pentane was added to slurry the solid product and the slurry was filtered. The white solid filter cake was air dried and weighed 10.0 grams (100% crude yield). The product melted at 140°-142° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1670 cm-1 and NH bands at 3100, 3230 and 3320 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:26][C:25]([F:27])([F:28])[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1)([OH:33])[C:29]([F:30])([F:32])[F:31]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 89.5 %

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (19.30 mmol, 4 g), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (19.30 mmol, 6.51 g) and potassium carbonate (19.30 mmol, 2.67 g) in acetonitrile (10 mL) was refluxed for 20 hours and was then concentrated under reduced pressure. Dichloromethane was added and the insolubles were filtered off. The filtrate was chromatographed on silica eluting with a gradient of dichloromethane to dichloromethane/ethyl acetate (10%) to give the title compound (8 g).