Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH:17]([CH3:19])[CH3:18])=O)N)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC[N:41](CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[CH:17]([CH3:19])[CH3:18])=[N:41][N:6]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(C)N1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCC[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate 58a (346 mg, 1.30 mmol), Ph3P (681 mg, 2.60 mmol) and Et3N (723 μL, 5.20 mmol) in THF (10.0 mL) at 0° C. was added hexachloroethane (616 mg, 2.60 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (220 mg, 68%). LCMS (Method 4): Rt 0.32 min, m/z 249.1 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C:12]([NH:21][CH3:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[C:28](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH3:22][N:21]([CH3:28])[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10][C:9]([N:23]([CH3:25])[CH3:24])([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: CNC1(c2ccccc2)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Reactant: BC#N
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(C2(N(C)C)CCC(c3ccccc3)(N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from Example 68 (96 mg, 0.28 mmol) and formalin (0.39 mL, 37% aqueous solution) in acetonitrile (3 mL) was mixed with sodium cyanoboron hydride (72 mg, 1.15 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaCl (5 mL) and then extracted with ether (3×10 mL). The organic solution was dried over Na2SO4 and concentrated to low volume in a vacuum. The remaining residue was purified by means of flash chromatography with ethyl acetate/methanol (2:1→1:1→1:1+2% NH3).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:16][CH:17]([CH3:41])[CH2:18][NH:19][C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:21]1.C(=O)([O-])[OH:43].[Na+].O>C1COCC1>[F:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[NH:6][C:7]([C:9]([N:19]([CH2:18][CH:17]([CH3:41])[CH3:16])[C@H:20]3[CH2:25][C@@H:24]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH2:23][N:22]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:21]3)=[O:43])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])O
Reactant: Fc1cc2nc(C(Cl)(Cl)Cl)[nH]c2cc1F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nc2cc(F)c(F)cc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 5,6-difluoro-2-(trichloromethyl)-1H-benzimidazole (500 mg) and tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (680 mg) in THF (50 ml) were added sodium hydrogen carbonate (1.3 g) and water (20 ml), and the mixture was stirred at room temperature for 1 hr and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (710 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(C(=O)O)c1N
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-amino-3-methoxy benzoic acid (5.00 g, 29.9 mmol) in THF (50 mL) were added EDCl (6.88 g, 35.9 mmol), HOBt (4.85 g, 35.9 mmol), N-methylmorpholine (3.60 g, 35.9 mmol), and aqueous ammonia (50% v/v, 30 mL). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the product was extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Removal of solvent gave product 2-amino-3-methoxy-benzamide as a light orange solid. Yield: 1.70 g (34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 64 %

Procedure:
Trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 26, Step 1, 92 mg, 0.2 mmol), (4-methoxycarbonylphenyl)boronic acid (42 mg, 0.3 mmol) and 1,1,bis(diphenylphosphino)-ferrocenpalladium(II)dichloromethane (8 mg, 0.01 mmol) in dioxane (0.6 ml) was treated with water (0.44 ml) and 2N—Na2CO3 (0.3 ml, 0.6 mmol) and stirred at 70° C. under argon for 19 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 4:1) to give the title compound as a white solid (62 mg). MS (m/e)=484.1 [M+H+].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 19.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 80 mg, 0.262 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.521 mmol), oxalyl chloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.90 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 8.18 (d, J=6.9 Hz, 2H), 7.85 (m, 2H), 7.75 (s, 3H), 7.41-7.33 (m, 2H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS [M+H]+: 575.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]([O-])=O.[Na+].[Sn].[ClH:15]>O>[ClH:15].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [Sn]
Solvent: O
Product: COc1cccc(NN)c1

Procedure:
A suspension of 3-methoxyaniline (10 g) in concentrated hydrochloric acid (85 ml) was stirred at ca. 0° and a solution of sodium nitrite (5.75 g) in water (25 ml) was slowly added over a period of 30 min keeping the temperature of the mixture at ca. 0°. After 1 h a solution of tin II chloride dihydrate (59 g) in concentrated hydrochloric acid (50 ml) was added over a period of 1.5 h, to the cooled suspension keeping the temperature below 0° C. The suspension was stirred for a further 30 min, filtered and washed with dried ether to give the title compound as a solid (14 g) m.p. 171°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:26][CH3:25])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CN
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and methylamine (2M in THF).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(=O)CC.O>[CH2:6]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: c1c[nH]cn1
Reactant: C#CCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: O
Product: C#CCCCn1ccnc1
Yield: 53.8 %

Procedure:
A mixture of pent-4-ynyl methanesulfonate (1.06 g), imidazole (534 mg) and K2CO3 (3.66 g) in 2-butanone (11 mL) was heated to reflux overnight. Work-up (DCM, H2O), drying (Na2SO4) and concentration gave 1-(pent-4-ynyl)-1H-imidazole (472 mg).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1>ClCC(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[CH:17][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Fc1cccc(F)c1
Agent: ClCC(Cl)(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 75.3 %

Procedure:
To a mixture of phthalic anhydride (64.8 g, 438 mmol), tetrachloroethane (600 mL) and 1,3-difluorobenzene (100 g, 877 mmol) was added anhydrous A1C13 (141 g, 964 mmol) over 20 minutes while maintaining the reaction temperature below 40° C. The temperature was increased to 90° C. for 2 hours, the reaction mixture was cooled and poured into ice/6N HCl. The mixture was extracted with ether (2×1.2 L) and the combined ether extracts were dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized from hot ethyl acetate to afford 86.5 g (75%) of 2-(2,4-difluorobenzoyl)benzoic acid, m.p. 129°-131 ° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[Cl:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[N:2]1
Reactant: C#Cc1cccnc1
Reactant: [N-]=[N+]=Nc1cc(C(=O)O)ccc1Cl
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: O=C(O)c1ccc(Cl)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
4-Chloro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-chloro benzoic acid (U.S. Ser. No. 04/102,492) and 3-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[S:22][S:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:36])[CH3:35])([OH:39])=[O:38]
Reactant: CC(C)CC(NC(=O)c1ccc(F)cc1SSc1cc(F)ccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CC(NC(=O)c1ccc(F)cc1SSc1cc(F)ccc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 62.5 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-fluoro-phenyldisulfanyl]-4-fluorobenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (3.1 g, 4.5 mmol) from Example 27, 30 mL dichloromethane, 30 mL trifluoroacetic acid, and 3.0 mL anisole. The crude product was recrystallized from dimethylformamide/methanol/water to afford 1.6 g of the title compound, mp 261-262° C.
Reaction SMILES: [C:1](=[O:3])=[O:2].C([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=O.[C:14]([O:23][CH3:24])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18]C([O-])=O>>[CH3:6][CH:7]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:1]([O:3][CH3:14])=[O:2].[CH2:17]([CH:16]([C:1]([O-:3])=[O:2])[CH2:15][C:14]([O:23][CH3:24])=[O:22])[CH3:18]
Reactant: O=C=O
Reactant: COC(=O)CCCCC=O
Reactant: COC(=O)CCCCC(=O)[O-]
Product: CCC(CC(=O)OC)C(=O)[O-]
Product: COC(=O)C(C)CCC(=O)[O-]

Procedure:
The cleavage is advantageously carried out in the presence of molecular oxygen or of a gas which contains molecular oxygen as well as an inert gas, such as nitrogen, carbon dioxide, argon or steam. A molar ratio of formylvaleric ester to molecular oxygen of from 1:0.05 to 1:3, in particular from 1:0.2 to 1:1.5, e.g. from 1:0.5 to 1:1.25, is preferably used. This increases the catalyst life and in particular the yield of pentenoic esters. The concomitant use of molecular oxygen was not indicated, since it was known from European Patent 131,860 that methyl 5-formylvalerate is oxidized to monomethyl adipate in a yield of 96% by molecular oxygen at as low as 50° C., and it was therefore to be expected that 4- and 3-formylvaleric esters would be oxidized in a similar manner to give monomethyl 2-methylglutarate and monomethyl 3-ethylsuccinate.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]Cl)=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:22])=[CH:15][CH:14]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C(CCl)Sc1ccc(Cl)cc1
Reaction time: 168 h

Procedure:
A solution of 42 g (0.286 mole) of phenyl vinyl sulfone in 200 ml of carbon tetrachloride and 100 ml of methylene chloride was treated with 45 g (0.252 mole) of p-chlorobenzenesulfenyl chloride. The reaction mixture was allowed to stand seven days at 23° C. Filtration through a thin layer of clay removed a small amount of flocculent solid. Evaporation of the filtrate at reduced pressure gave 51.5 g (60%) of crude product, m.p. 60°. Recrystallization from a mixture of 100 ml of ethyl acetate and 30 ml of pentane gave pure product m.p. 79°-81°.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH2:13][CH2:14][S:15][C:16](=[O:34])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)[NH2:18])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][C@@H:17]([C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])=[O:34])[NH2:18])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1cccc(C(=O)c2ccccc2)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The product of Example 12 was deprotected by reaction with trifluoroacetic acid in anisole. The reaction mixture was incubated at room temperature for one hour, following which trifluoroacetic acid and anisole were removed in vacuo at 32° C. The reaction mixture was then partitioned between saturated NaHCO3 and ethyl acetate in the cold. The bicarbonate phase was washed twice with ethyl acetate and once with ether. Then, in the presence of ethyl acetate, the bicarbonate phase was acidified with HCl, and, after extraction, the ethyl acetate phase was collected and washed with saturated NaCl, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The product was further purified by chromatography on Sephadex G-25, trademark Pharmacia Company, Uppsala, Sweden, using a 1.2 cm×96 cm column eluted with butanol:acetic acid:water, 4:1:5 (volume ratio). 2.20 me fractions were collected. Most of the product was found in fractions 21 through 23 as determined by positive reaction with o-tolidine/chlorine reagent and with phenazine methosulfate at pH 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]([C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:11]([C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.1 %

Procedure:
3-Fluorophenylboronic acid (0.70 g, 5.0 mmol), ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (0.981 g, 5.0 mmol), Cu(OAc)2 (0.908 g, 5.0 mmol), pyridine (2.45 ml, 30 mmol) and 4A MS (1.9 g) were combined in CH2Cl2 (48 ml) and stirred open to air at RT for 4 d. The reaction mixture was diluted with EtOAc (150 mL), washed with 3M HCl (2×50 mL), H2O (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography to afford ethyl 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazole-5-carboxylate (0.786 g, 54% yield) as colorless oil. MS (ESI) m/z: 291 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:12]([NH:14][C:15]2[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:30][NH2:31].Cl>CCN(CC)CC>[CH3:30][NH:31][C:20]([C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CN
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
2-[2-(4-Methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylic acid (EXAMPLE 127, 399 mg, 0.91 mmol) was condensed with MeNH2.HCl in the presence of NEt3, utilising the general procedure described in EXAMPLE 65, to give the title compound: RTA=2.82 min; m/z (ES+)=452.3 [M+H]+.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[C:22]1[CH:23]=[C:24]2[CH:30]=[CH:29][N:28]([CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])[C:25]2=[CH:26][N:27]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[C:22]1[CH:23]=[C:24]2[CH:30]=[CH:29][N:28]([CH:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])[C:25]2=[CH:26][N+:27]=1[O-:9])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)ncc21
Solvent: ClCCl
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)[n+]([O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Chloro-benzenecarboperoxoic acid (c.a. 60%, 198 mg, 0.69 mmol) is added to a solution of 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.057 mmol) in DCM (4 mL), and the mixture is stirred for 30 min at room temperature. The mixture is washed with a saturated aqueous Na2CO3 solution, brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the residue on silica gel (EtOAc) gives 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10](=[O:24])[CH2:9][CH2:8][C:7]=2[C:6]([CH:25]=O)=[CH:5][CH:4]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:25]=[C:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:24])[CH2:9][CH2:8]2
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(CN2C(=O)CCc3c(C=O)ccc(OC)c32)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CN2C(=O)CCc3c(C=C4SC(=O)NC4=O)ccc(OC)c32)cc1
Yield: 89.3 %

Procedure:
7.0 g of 8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 3.25 g of 2,4-thiazolidinedione were suspended in 70 ml of toluene. Ten drops of piperidine and ten drops of acetic acid were added, followed by heating and refluxing for 4 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 8.0 g (90% yield) of 5-[8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene]thiazolidine-2,4-dione as a light yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=[O:4].[Cl:13][C:14]1[N:19]=[N:18][C:17](/[N:20]=[C:21](/N(C)C)\[CH3:22])=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([C:2]2[N:18]3[N:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]3=[N:20][C:21]=2[CH3:22])=[O:4])=[C:6]([F:12])[CH:7]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1F
Reactant: C/C(=N\c1ccc(Cl)nn1)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F

Procedure:
Combine 2-chloro-1-(4-chloro-2-fluorophenyl)ethanone (1.5 kg, 5.44 mol), and (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylacetimidamide (1.19 kg, 5.72 mol) in DMF (10.14 L) and heat at 120° C. for 5 h. After cooling, add water (30 L) and stir to crystallize the product. Collect the product by filtration and rinse the cake with water (2×12 L) and heptanes (2×10 L) then dry under vacuum to obtain title compound. (1.490 kg, 84.44%; mp=160° C., M+=324).