Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][C@H:16]4[C:28]#N)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[K+].[OH2:32]>C(O)CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][C@@H:16]4[C:28]([OH:32])=[O:30])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)C[C@@H]2O
Agent: [K+]
Solvent: OCCO
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@@H](C(=O)O)C[C@@H]2O
Temperature: 160 °C

Procedure:
A solution of 571 mg (1.47 mmol) of 46 crude, 2.54 g (45.3 mmol) KOH in H2O (6 mL) and ethylene glycol (34 mL) was stirred and heated at 160° C. for 112 h without a reflux condenser to allow H2O to evaporate. The reaction mixture was poured into H2O (700 mL) and washed with Et2O (2×, 100 mL). The aqueous phase was adjusted to pH 2 with concentrated HCl and extracted with Et2O (3×, 100 mL). Combined organic extracts were washed with 10% sodium metabisulfite (50 mL), H2O (50 mL), dried over Na2SO4 and concentrated in vacuo giving 535 mg (89%, two steps) of 47 as a tan solid. Data for 47: TLC, T-3, Rf 0.575; 1H NMR (400 MHz, DMSO-d6) 60.69 (s, 3H, H-18), 3.61 (ddd, 1H, J=8.7, 8.7, 5.0 Hz, H-17α), 4.73 (d, 1H, J=5.0 Hz, 17-OH), 5.04 (s, 2H, benzylic-H), 6.67 (d, 1H, J=2.6 Hz, H-4), 6.74 (dd, 1H, J=8.7, 2.6 Hz, H-2), 7.17 (d, 1H, J=8.7 Hz, H-1), 7.31–7.42 (m, 5H, Ar—H), 12.07 (s, 1H, OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:7][CH2:6]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:19])=[O:15])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(CC(=O)N1CCC[C@H]1C(=O)O)C2
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COc1ccc2c(c1)CCC(CC(=O)N1CCC[C@H]1C(=O)N1CCCC1)C2
Yield: 24 %

Procedure:
A colorless oil of 1-[1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline prepared in Reference Example 21 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 24%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][CH2:7][C:8]1[C:15]([F:16])=[C:14](F)[C:11]([CH2:12][OH:13])=[C:10]([F:18])[C:9]=1[F:19])[CH3:5].O.Cl>CO.COCCOCCOC>[F:18][C:10]1[C:9]([F:19])=[C:8]([CH2:7][O:6][CH2:4][CH3:5])[C:15]([F:16])=[C:14]([O:2][CH3:1])[C:11]=1[CH2:12][OH:13]
Reactant: CCOCc1c(F)c(F)c(CO)c(F)c1F
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Solvent: O
Product: CCOCc1c(F)c(F)c(CO)c(OC)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of sodium methoxide (generated from 0.13 g sodium) in dry methanol (20 cm3) was added to a solution of 4-(ethoxymethyl)-2,3,5,6-tetrafluorobenzyl alcohol (1.2 g) in dry diglyme. The stirred reaction mixture was heated at 90° C. for a period of 4 hours, under an atmosphere of dry nitrogen, after which time a further portion of sodium methoxide (0.1 g) was added, and heating continued for a further 8 hours. After cooling to the ambient temperature the reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The brown residue was subjected to column chromatography on silica gel using hexane containing increasing amounts of diethyl ether (from 0% to 100%) by volume as eluent. The crude product thus obtained was again subjected to chromatography on silica gel in a similar manner to give 2,3,5-trifluoro-4-(ethoxymethyl)-6-methoxybenzyl alcohol as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N+:15]([O-:27])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(COc2ccc3ccncc3c2)cc1
Solvent: ClCCl
Product: [O-][n+]1ccc2ccc(OCc3ccccc3)cc2c1
Yield: 98.1 %

Procedure:
A solution of 7-benzyloxyisoquinoline (International Patent Application publication no. WO 94/20459) (0.50 g, 2.13 mmol) in CH2Cl2 (20 mL) was stirred with 3-chloroperbenzoic acid (mCPBA) (1.1 g, 3.19 mmol) at room temperature for 2.5 h. The mixture was diluted with CH2Cl2, and then washed with sodium dithionite (1 M), potassium carbonate (1 M) and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to leave 7-benzyloxyisoquinoline N-oxide (0.521 g, 2.09 mmol) as a cream-coloured powder.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]=O.[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][CH:27](N)[CH2:26][CH:25]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1>CO>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][CH:27]([N:2]([CH3:1])[CH3:5])[CH2:26][CH:25]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: COc1cc(Nc2nc3c(s2)CC(N)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(s2)CC(N(C)C)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.8 %

Procedure:
Sodium cyanoborohydride (14.53 mg, 0.231 mmol) and formaldehyde (16.15 μL, 0.217 mmol) were added to a solution of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (18 mg, 0.038 mmol, from example 78) in MeOH (0.4 mL). The mixture was stirred at rt for 20 hours. The crude reaction mixture was purified using preparatory HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN. Flow rate: 40 ml/min, 30-95% B, 20 min to afford 10 mg (47% yield) of the titled compound as a white solid. LC-MS (M+H)+ 498.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])=[C:6]2[O:25][CH2:26][O:27][C:5]2=[C:4](I)[CH:3]=1.[CH2:29]([O:32][CH3:33])[C:30]#[CH:31].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:23]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:31]#[C:30][CH2:29][O:32][CH3:33])=[C:5]3[O:27][CH2:26][O:25][C:6]=13)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)#[N:24]
Reactant: COc1cc2ncc(C#N)c(Nc3c(Cl)cc(I)c4c3OCO4)c2cc1OC
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Temperature: 25 °C

Procedure:
A mixture of 4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline (0.25 g), methyl 2-propynyl ether (0.09 ml), N,N-diisopropylamine (0.154 ml), bis(triphenylphosphine)palladium(II) dichloride (0.069 g), cuprous iodide (0.028 g) and ethyl acetate (10 ml) was stirred and heated to reflux for 12 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained the title compound as an oil (0.138 g); NMR Spectrum: (DMSOd6) 3.42 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.38 (s, 2H), 6.17 (s, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 7.92 (s, 1H), 8.39 (s, 1H), 9.42 (br s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:13][C@@H:12]1[CH3:42])(=[O:10])[CH3:9]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:13][C@@H:12]1[CH3:42])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(-c3cn(CCC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cn(CCC(=O)O)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 78 %

Procedure:
Trifluoracetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-{(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoate (for a preparation see Example 91) (1.06 g, 2.19 mmol) in DCM (5 mL). The reaction mixture was allowed to stand at room temperature for 16 h then most of the solvent were removed in vacuo. The residue was co-evaporated twice with toluene then triturated with Et2O to give 3-{(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoic acid trifluoroacetate (920 mg, 1.696 mmol, 78%) as an off-white solid.
Reaction SMILES: CI.[C:3](=O)([O-])O.[K+].[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2>CN(C=O)C>[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([O:27][CH3:3])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2
Reactant: O=C(O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Methyl iodide (6.5 mL, 104 mmol) and potassium hydrogencarbonate (17.0 g, 170 mmol) were added to a DMF (200 mL) solution of the compound obtained in Example 21 (26.1 g, 85 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 24.0 g (88%) of the captioned compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:28])[N:12]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:13]([CH3:19])=[N:14]2)(C)(C)C.[ClH:30]>CO.C(Cl)Cl.CCOCC>[ClH:30].[NH2:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:28])[N:12]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:13]([CH3:19])=[N:14]2
Reactant: Cc1nc2cccc(CNC(=O)OC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 8 h

Procedure:
To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-carbamic acid tert-butyl ester (10.4 g, 25.9 mmol) in methanol (108 mL) and methylene chloride (108 mL), was added 2 M HCl in ether (304 mL), and the mixture was stirred overnight. Solvent was evaporated, and the residue was stirred in ether (200 mL) for 2 hours. The suspension was filtered to give 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride as a light yellow solid (8.9 g, 102% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22]([OH:24])=O)([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([CH3:21])([CH3:20])[C:22]([NH:31][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[O:24])=[CH:16][CH:17]=2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(Cc3ccccc3)C(=O)O)cc2)c1

Procedure:
Using RSR13 acid (1.6 g, 4.7 mmol), phenylalanine methyl ester hydrochloride (1.08 mg, 4.7 mmol) and 1-hydroxybenzotriazole hydrate (697 mg, 5.2 mmol), N-methylmorpholine (711 mg, 7.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.08 g, 5.3 mmol) in dimethylformamide (40 mL), the two isomers were prepared in 2.2 g yield (96%).
Reaction SMILES: [Cl:1][C:2]1([Cl:21])[C:5](=[O:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=1.O[O:23][S:24]([O-:26])=O.[K+].[CH2:28](Cl)Cl>CO.O.CCOCC>[Cl:1][C:2]1([Cl:21])[C:5](=[O:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:24]([CH3:28])(=[O:26])=[O:23])=[CH:17][CH:18]=1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C2(Cl)Cl)cc1
Reactant: ClCCl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C2(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1 (790mg) in CH2Cl2 (10 mL) and MeOH (10 mL) was added a solution of Oxone® (3.6 g) in H2O (10 mL). The mixture was stirred at r.t. for 2 hr and diluted with Et2O. The organic phase was washed with H2O, brine, dried (MgSO4) and the solvents evaporated. The resulting solid residue was stirred vigorously in hexane/Et2O for 1 hr and then filtered to afford the title compound as a yellow solid, m.p. 124°-125° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([S:7]([O-:10])(=[O:9])=O)=[CH:4][CH:3]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CCOCC>[C:18]([NH:22][S:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)[O-])o1
Reactant: CC(C)(C)N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
At a temperature of 30° to 50° C., 248 gm (1.35 mol) of sodium 5-methyl-furan-2-sulfonate were admixed in portions with 281 gm (1.35 mol) of phosphorus pentachloride and the mixture was stirred for 15 minutes at 50° C. The reaction mixture was then poured over ice and extracted with ether. The ether phase was washed until neutral, dried and evaporated. The residue (200 gm of 5-methyl-furan-2-sulfonic acid chloride) was dissolved in 500 ml of ether, and the solution was added dropwise to a solution of 280 ml (2.7 mol) of tert.-butylamine in 500 ml of ether at a temperature of 5° to 10° C. After stirring at room temperature and at reflux temperature, each for 2 hours, the reaction mixture was washed with ice water, dilute hydrochloric acid and water and then evaporated. The residue was recrystallized from cyclohexane, yielding 180.5 gm (61.5% of theory) of N-tert. butyl-5 -methyl-furan-2-sulfonamide. M.p. 113°-114° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:19].[Na+]>ClCCl>[CH3:1][O:8][C:9]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:19].[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCC(COCc2ccccc2)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CCC(CO)CC1
Product: O=CC1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (4-benzyloxymethyl-cyclohexyl)-methanol (1.40 g, 6 mmol) in dichloromethane (28 mL) is added Dess-Marin reagent (2.53 g, 6 mmol) at 0° C., and the mixture is stirred for 0.5 hour while warming to room temperature. After addition of saturated aqueous NaHCO3, the aqueous layer is extracted with EtOAc. The combined organic layer (dried with MgSO4) is concentrated. The desired product, 4-benzyloxymethyl-cyclohexanecarbaldehyde, is obtained (1.07 g, 79%) after purification using silica gel column chromatography (eluent: EtOAc/hexane).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:9][C:8](=[O:10])[O:7][C:5](=[O:6])[CH2:4]1.[CH3:13][O:14][C:15]([C:17]1([S:21][C:22]2[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])[CH2:20][CH2:19][CH2:18]1)=[O:16]>C1C=CC=CC=1>[Cl:30][C:23]1[C:22]([S:21][C:17]2([C:15]([O:14][CH3:13])=[O:16])[CH2:18][CH2:19][CH2:20]2)=[CH:27][C:26]([NH:28][C:8](=[O:10])[CH2:9][CH:3]([C:2]([F:1])([F:12])[F:11])[CH2:4][C:5]([OH:7])=[O:6])=[C:25]([F:29])[CH:24]=1
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CCC1
Solvent: c1ccccc1
Product: COC(=O)C1(Sc2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc2Cl)CCC1
Yield: 84.7 %

Procedure:
A mixture of 3.6 g of 3-trifluoromethylglutaric anhydride and 5.8 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclobutanecarboxylic acid methyl ester in 65 ml of benzene is heated under reflux for 3 hours while stirring. The resulting precipitate is then separated off, washed with diisopropyl ether and dried, yielding 7.9 g of N-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclobutylthio)-phenyl]-3-trifluoromethylglutaric acid monoamide having a melting point of from +165° to +167° C.
Reaction SMILES: N1C=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[F:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].ClC1C(C(F)(F)F)=CC=CC=1C(O)=O.C(Cl)Cl.[CH3:47][N:48](C=O)C>>[F:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:47]=[N:48][CH:5]=[CH:4][N:3]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: CN(C)C=O
Reactant: c1cnc(-n2nnc3c2CCNC3)nc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCc2c(nnn2-c2cnccn2)C1

Procedure:
The title compound was prepared in a manner analogous to Example 65 substituting the product of Example 69, Step A for 1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine, 2-fluoro-3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)-benzoic acid and DCM for DMF. MS (ESI): mass calcd. for C17H12F4N6O, 392.1. m/z found, 393.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.52 (dd, J=15.7, 1.4 Hz, 1H), 8.66 (dd, J=7.3, 2.5 Hz, 1H), 8.52-8.45 (m, 1H), 7.80-7.71 (m, 1H), 7.72-7.58 (m, 1H), 7.38 (dt, J=14.9, 7.7 Hz, 1H), 5.09 (s, 1H), 4.67 (s, 1H), 3.67 (s, 1H), 3.43 (t, J=5.8 Hz, 1H), 3.33 (s, 1H), 1.88-1.71 (s, 1H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[C:5]=1[C:25]([O:27][CH3:28])=[O:26].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:3]([C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[C:5]=1[C:25]([O:27][CH3:28])=[O:26])=[O:2]
Reactant: CCCOC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Reaction time: 5.5 h
Yield: 28.5 %

Procedure:
To a solution (132 ml) of n-propyl 6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (13.28 g) in acetone was added dropwise 6 N hydrochloric acid (13.2 ml) at 12° C. with stirring, and the stirring was continued for 5.5 hours. The resultant mixture was adjusted to about pH 7 with an aqueous sodium bicarbonate solution. The acetone was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with an aqueous sodium chloride solution, water and petroleum ether, successively, and then recrystallized from a mixture of benzene and n-hexane. The crystals were collected by filtration and washed with diethyl ether to give n-propyl 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (3.37 g), mp 137.5°-141.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)N=C2C=CC(c3cccc(Cl)c3)=CN21
Yield: 63.1 %

Procedure:
To a round-bottom flask was added 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69 mg, 0.25 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), dioxane (5 mL) and water (1 mL). The mixture was heated at reflux until the starting material was consumed monitored by HPLC-MS. The solution was cooled and water was added. The reaction mixture was extracted twice with ethyl acetate and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to provide the desired product as an off-white solid (43 mg, 63%). 1H NMR (CDCl3) δ 7.84 (dd, J=1.8 and 9.1 Hz, 1H), 7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH+); HRMS: calc'd MH+ for C15H13ClN2O 273.0794; found 273.0800.