Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2SC(C(N)=O)=C(OCC3C=CC=CC=3C(F)(F)F)N=2)C2C=CC=CC=2N=C1.Cl[C:31]1[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:47])([F:46])[F:45])[N:35]=1.[CH3:51][O:52][C:53]1[C:61]([O:62][CH3:63])=[CH:60][C:56]2[N:57]=[CH:58][NH:59][C:55]=2[CH:54]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:63][O:62][C:61]1[C:53]([O:52][CH3:51])=[CH:54][C:55]2[N:59]([C:31]3[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]([F:47])([F:46])[F:45])[N:35]=3)[CH:58]=[N:57][C:56]=2[CH:60]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(-c3nc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cc1OC
Yield: 54.9 %

Procedure:
The title compound was prepared in a manner analogous to the procedure described above for the preparation of 2-(1H-benzimidazol-1-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide, using the following materials: 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.146 g, 0.434 mmol), 5,6-dimethoxybenzimidazole (0.0851 g, 0.478 mmol), K2CO3 (0.0720 g, 0.521 mmol) and DMF (4 mL). Flash chromatography afforded 0.114 g (55%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.87-7.73 (m, 4H), 7.61 (m, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 6.94 (br s, 1H), 5.85 (s, 2H), 3.83 (s, 3H), 3.72 (s, 3H). MS m/z 479 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 574.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:37](F)[CH:36]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]>CS(C)=O.O>[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:36]=[CH:37][C:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[C:46]([NH:7][CH:8]5[CH2:13][CH2:12][O:11][CH2:10][CH2:9]5)[CH:47]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NC1CCOCC1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
0.95 g of potassium carbonate and 4.62 g of 4-aminotetrahydropyran are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 3 hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.5 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Br:13])[C:3]=1[NH2:4].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[NH2:4][C:3]1[C:5]([Br:13])=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[CH:22]=[O:23]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1c(Br)cc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
2,6-Dibromo-4-(trifluoromethyl)aniline (3.19 g, 10.0 mmol, 1.00 eq) was dissolved in THF (50 mL) and cooled to −78° C. A 2.5 M solution of n-butyllithium in hexanes (8.40 mL, 21.0 mmol, 2.10 eq) was added dropwise over 15 min. The mixture was stirred at −78° C. for 1 h. A solution of DMF (1.03 mL, 14.0 mmol, 1.40 eq) in THF (5 mL) was added, and the mixture was stirred an additional 1 h at −78° C. The reaction was allowed to come to −15° C. over 30 min and then quenched with brine. The mixture was diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 1.74 g of the desired product as a pale yellow, crystalline solid. ES/MS m/z 268, 270 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.OO.C([O-])([O-])=[O:37].[K+].[K+].FC(F)(F)C(O)=O>CS(C)=O.C(Cl)Cl>[CH2:26]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH2:24])=[O:37])=[C:19]([Cl:25])[CH:18]=2)=[CH:12][CH:11]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 149.7 %

Procedure:
Combine the compound of step 1 (95 mg, 0.21 mmol), H2O2 (25 μl) and K2CO3 (15 mg, 0.10 mmol) in DMSO (0.8 mL), and stir the mixture at room temperature overnight. Add water and extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Purify by flash chromatography (EtOAc/hexane 50/50) to give a yellow oil. Dissolve the oil in CH2Cl2 (3 mL) and add trifluoroacetic acid (240 μL), and stir the mixture at room temperature for 4 hour. Eliminate the solvent. Purify by an SCX column to give the title compound (57 mg, 76%). Electrospray MS M+1 ion=381. 1H-NMR (CDCl3, 400 MHz): 7.82 (d, 1H, J=8.5 Hz), 7.35-7.20 (m, 7H), 6.99-6.95 (m, 3H), 6.90 (dd, 11, J=2.5 and 8.5 Hz), 6.53 (m, 2H), 3.83 (s, 2H), 2.95-2.89 (m, 2H), 2.86-2.81 (m, 2H).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([CH:42]=O)=[CH:36]2>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](/[CH:42]=[CH:20]/[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[CH:36]2
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2[nH]c(/C=C/C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Benzyl (triphenylphosphoranylidene)acetate (49.2 g, 0.120 mol) was added to a stirred solution of 5-methoxy-1H-indole-2-carbaldehyde (1) (20.0 g, 0.114 mol) in CH2Cl2 (500 mL) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue slurried with methanol (200 mL), whereupon crystallisation of the product occurred. The mixture was filtered, washed with several portions of cold methanol, and dried to give benzyl (2E)-3-(5-methoxy-1H-indol-2-yl)-2-propenoate (2) in a 30.46 g, 87% yield as pale yellow plates; mp 155–157° C. 1H NMR δ (CDCl3) 8.28 (s, 1H), 7.69 (d, J=16.1 Hz, 1H), 7.43–7.32 (m, 5H), 7.23 (d, J=9.1 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.92 (dd, J=9.1, 2.3 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 6.24 (d, J=16.1 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H).Found: C, 74.45; H, 5.62; N, 4.58. C19H17NO3 requires C, 74.25; H, 5.57; N, 4.56.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(OC1C=C(C(C2C(Cl)=NC=CN=2)[NH:49]C(=O)C(C)(C)C)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:49])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Reactant: CC(C)(C)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 55 °C

Procedure:
1-(3-Benzyloxyphenyl)-3-tert-butyl-8-chloroimidazo[1,5-a]pyrazine: A mixture of POCl3 (3 mL, 5 g, 33 mmol) and N-[(3-benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2,2-dimethylpropionamide (109 mg, 0.266 mmol) is heated to 55° C. for 6 d. POCl3 is evaporated, a cold solution of NH3 in iPrOH (2 M, 5 mL) is added, the suspension is filtered, and the solid is washed with iPrOH. The crude material contained in the combined filtrate and washings is adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with hexanes:EtOAc 10:1 (1-22)→5:1 (23-40)], yielding the title compound as yellow oil that slowly solidifies; 1H NMR (CDCl3, 400 MHz) δ 1.59 (s, 9H), 5.13 (s, 2H), 7.03 (d, J=8.0 Hz, 1H), 7.27-7.42 (m, 7H), 7.46 (d, J=7.2 Hz, 2H), 7.87 (d, J=4.8 Hz, 1H). MS (ES+): m/z 392.1/394.0 (12/4) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:20][C@H:21]([C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: N#Cc1cccc(Oc2ncc(Cl)cc2C(=O)O)c1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(C#N)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-cyanophenoxy)nicotinic acid (step 1) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 44): 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=2.7 Hz), 7.98–7.95 (2H, m), 7.89–7.86 (1H, m), 7.64–7.38 (6H, m), 5.42–5.31 (1H, m), 1.61–1.58 (12H, m); MS (ESI) m/z 476 (M−H)−.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[CH3:14])[C:8]([O:10]CC)=[O:9])[CH3:4]>CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:19][CH:20]=1)[CH3:14])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Yield: 65.2 %

Procedure:
A solution of KOH (113.6 mg, 2.04 mmol) in EtOH (2 mL) was added dropwise to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid diethyl ester (0.7 g, 1.84 mmol) in methylene chloride (4 mL) and EtOH (10 mL) at 0° C. under argon and the reaction mixture was stirred over night. 1M KOH (100 mL) was added and the mixture was washed with methylene chloride. The aqueous phase was acidified to pH 2 using 2 M HCl and extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure to give the crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid monoethyl ester (423 mg, 65%).
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7]12[C:25](=[O:26])[CH2:24][CH2:23][CH:8]1[CH:9]1[C:14]([CH2:15][CH2:16]2)=[C:13]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:12](=O)[CH2:11][O:10]1>C1(C)C=CC=CC=1>[CH3:6][C:7]12[CH2:16][CH2:15][C:14]3[CH:9]([O:10][CH2:11][C:12]4[C:13]=3[CH2:17][CH2:18][C:19](=[O:21])[CH:20]=4)[CH:8]1[CH2:23][CH2:24][C:25]2=[O:26]
Reactant: CC(=O)CCC1=C2CCC3(C)C(=O)CCC3C2OCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC12CCC3=C4CCC(=O)C=C4COC3C1CCC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 25% (w/w) solution of sodium methoxide in methanol (2.71 mL, 12.8 mmol, 1 eq) was added to a stirred solution of the crude 3a-Methyl-6-(3-oxo-butyl)-1,2,4,5,9a,9b-hexahydro-3aH-9-oxa-cyclopenta[a]naphthalene-3,7-dione in toluene (200 mL) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. The reaction was then quenched with a 10:1 (v/v) of ammonium chloride/potassium bisulfate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried with magnesium sulfate. The resulting solution was filtered, evaporated and the residue purified by flash chromatography using 30-50% ethyl acetate in hexane to yield the title compound as a white solid.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>C(Cl)Cl.CO>[N:52]1([CH2:51][CH2:50][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1cc(OCCN2CCCC2)ccc1Nc1ncc(-c2ccsc2)s1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using 1-(2-chloroethyl)-pyrrolidine hydrochloride. The title compound: ES-MS: 439.9 [M+H]+; single peak at tR=3.36 min (System 2); Rf=0.22 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11]O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:20]>>[Cl:20][CH2:11][C:3]1[C:2]([F:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: OCc1cc2c(cc1F)OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc2c(cc1CCl)OCO2
Temperature: 25 °C
Yield: 90 %

Procedure:
(6-Fluoro-benzo[1,3]dioxol-5-yl)-methanol (650 mg, 3.8 mmol) was added to SOCl2 (20 mL) in portions at 0° C. The mixture was warmed to room temperature for 1 h and then heated at reflux for 1 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with sat. NaHCO3 solution to pH ˜7. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 5-chloromethyl-6-fluoro-benzo[1,3]dioxole (640 mg, 90%), which was directly used in the next step.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
(S)-tert-Butyl 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound III-16) 18.4 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 10.3 g, (yield 83%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1OCCCC)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:18]>O1CCCC1.CO>[NH2:18][C:7]1[C:8](=[O:11])[C:9](=[O:10])[C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1c(N)c(=O)c1=O
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Preparation A: A solution of 1,2-dibutoxy-1-cyclobutene-3,4-dione (6.09, 0.027 mole) in 40 mL of tetrahydrofuran was cooled to 5° C. in an ice-water bath and treated dropwise over a period of 9 minutes with a solution of 1.8 mL of concentrated ammonium hydroxide in a mixture of 8 mL of tetrahydrofuran and 1 mL of methanol. After stirring at 5° C. for 30 minutes and at ambient temperature for 90 minutes the mixture was concentrated under reduced pressure to a slurry. A small amount of Skellysolve B was added and the product was collected by filtration after 16 hours of standing at 0° C. to give 3.26 g of the title compound. A sample (8.54 g) was partly dissolved in acetone, filtered and cooled to give 4.51 g of purified title compound; mp=165.5°-168° C. (clear melt).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)([CH3:29])[CH3:28]
Reactant: CC(C)O
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C/C(=C\c1ccc(C(=O)OC(C)C)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and isopropanol there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid isopropyl ester of melting point 119°-120° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:68]([N:70](C)[C@@H:71]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[CH2:72]C)=O)N=2)CC1)=O>C(#N)C>[CH3:68][N:70]([C@@H:71]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH3:72])[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)=[O:3]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(1,1-Dimethylethyl) 4-(5-carboxy-2-thiazolyl)-1-piperazinecarboxylate (i.e. the product of Example 4, Step B) (1.0 g, 3.2 mmol) was suspended in 10 mL of dry acetonitrile and treated with triethylanaine (892 μL, 6.4 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.33 g, 3.5 mmol) followed by (α,R)—N,α-dimethylbenzenemethanamine (i.e. the product of Example 1, Step C) (200 μL, 1.38 mmol). The reaction mixture was stirred at ambient temperature for 3 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.38 g of an orange foam. Purification by silica gel chromatography using an ethyl acetate/hexanes gradient from 1:9 to 100:0 gave 0.78 g of the title compound as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: CNC
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.45 ml) was added to a stirred suspension of (R)-N-[2-chloro-4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (1.81 g) in DCM (100 ml) containing DMF (10 drops). The mixture was stirred for 5 hours and then a solution of dimethylamine (4.2 ml, 2M solution in methanol) was added, and the solution was stirred overnight. The reaction mixture was washed with dilute hydrochloric acid solution (2×25 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM to yield the title compound (0.68 g) as a solid. M.p. 120.5° C. (Mettler FP62 apparatus); NMR: (CDCl3): 1.70 (s, 3H), 2.90 (s, 3H), 3.10 (s, 3H), 5.20 (s, 1H), 7.5 (d, 2H), 7.85 (d, 1H), 7.90-8.00 (m, 3H), 8.60 (d, 1H), 9.40 (s, 1H); MS (ESP−): 477.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([NH:40][CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN=C=O
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 88 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of methyl isocyanate. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).