Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:28])[N:13]([CH2:15][C:16]3[CH:17]=[N:18][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][CH:21]=3)[CH:14]=2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:22]([C:19]1[N:18]=[CH:17][C:16]([CH2:15][N:13]2[CH:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]=[CH:11][C:12]2=[O:28])=[CH:21][CH:20]=1)#[CH:23]
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(C#C[Si](C)(C)C)nc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-1-((6-(2-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)pyridin-2(1H)-one (0.60 mmol, 240 mg), tetrabutylammonium fluoride (1.20 mmol, 1.2 mL) in THF (5 mL) and H2O (1 mL) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was taken up in CH2Cl2, washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 3%. The fractions were collected and evaporated. The residue thus obtained was triturated with diisopropyl ether. The precipitated solid was filtered off and dried. Further purification by circular chromatography-TLC CH2Cl2/MeOH(NH3)sat. 3% yielding 1-((6-ethynylpyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (68 mg, 35%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:13][NH:14]C(=O)C[Cl:17].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[ClH:17].[NH2:14][CH2:13][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[OH:11]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CN)c(O)c1
Product: Cl
Temperature: 25 °C

Procedure:
A finely powdered mixture of 15 g (0.10 mol) of 3-tert-butylphenol and 12.4 g (0.10 mol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 90 mL acetic acid and 10 mL (98%) sulfuric acid at 0° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 20 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 10-30% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[Cl:9][C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1.Br[C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>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>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:18]2[O:22][C:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: Clc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Product: N#Cc1cccc(-c2ccc(-c3ccc(Cl)cn3)o2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.5 %

Procedure:
Pd(PPh3)4 (5 mg, 0.004 mmol) was added to a solution of hexamethylditin (160 mg, 0.49 mmol) and 5-chloro-2-bromopyridine (76 mg, 0.395 mmol) in toulene (1 mL) under argon. The resulting solution was stirred at 80° C. for 16 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (20 mg, 0.019 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (79 mg, 0.32 mmol) were added and the resulting solution was stirred at 110° C. for 14 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 25-50% chloroform in hexane to 2% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with hexanes and purification by preparative TLC (90% dichloromethane in hexane) afforded 15.7 mg (17%) of 3-(5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile (97.5% pure by GC/MS, contaminated with 2.5% dimer). 1H-NMR (CDCl3), δ (ppm): 8.55 (d, 1H), 8.03 (s, 1H), 7.94 (dd, 1H), 7.73 (s, 2H), 7.54 (m, 12), 7.16 (d, 1H), 6.88 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1B(O)O>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=4[CH3:30])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: Cc1ccc(C)c(B(O)O)c1
Product: Cc1ccc(C)c(-c2cccc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)c2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 2,5-dimethylphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (CDCl3) δ 8.3(d, 1H), 7.4-8.05(m, 9H), 7.2(d, 1H), 7.1(d, 2H), 6.8(d, 1H), 4.3(t, 2H), 3.75(m, 4H), 3.0(t, 2H), 2.7(m, 4H), 2.4(s, 3H), 2.3(s, 3H).
Reaction SMILES: [CH3:1][CH:2](O)[CH3:3].[C:5]([O-:8])(=O)[CH3:6].[K+].[C:10]([O-:13])(O)=[O:11].[Na+]>C(O)C>[CH3:3][C:2]([C:10]([O:13][CH2:6][CH2:5][OH:8])=[O:11])=[CH2:1]
Reactant: O=C([O-])O
Reactant: CC(=O)[O-]
Reactant: CC(C)O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)C(=O)OCCO
Temperature: 50 °C
Reaction time: 13.5 h
Yield: 6287.9 %

Procedure:
10.02 g of the intermediate siloxane of formula 5, 15.52 g of ally alcohol (Wako Pure Chemical Industries), 25.04 g of 2-propanol (super dehydrated) (Wako Pure Chemical Industries), 0.20 g of 10% potassium acetate in ethanol, 0.10 g of 1% BHT/IPA, and 0.05 g of 1% MQ/IPA were added into 300 ml eggplant-shaped flask. To this solution 0.40 g of 1% H2PtCl6/6H20/IPA was added and stirred at 50° C. for 13.5 h. After that 0.4128 g of 1% NaHCO3 aq. was added and stirred for over 1 h at room temperature. Then the reaction mixture was evaporated and vacuum dried at 35° C. To this mixture about 5 g of acetone and 15 g of DI water were added with vigorous shaking. The mixture was then centrifuged (7000 rpm, 5° C., 10 min). The upper (aqueous) layer was removed. This operation was repeated three times in total. To this mixture 5 g IPA was added and the reaction mixture was evaporated and vacuum-dried at 40° C. Then 0.06 g of 1% BHT/IPA and 0.03 g of 1% MQ/IPA were added and then evaporated and vacuum-dried at 45° C. The reaction yielded 16.6762 g of a polysiloxane, designated H30AA-5K, having the structure of Formula 3 (above) wherein R2 is a methyl group, m is 0, n is ˜30, and p is 0. The siloxane had an HLB value of about 3 and a hydroxyl content of about 13 wt. %.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(Cl)Cl.B(F)(F)F.[CH3:17]COCC.C(=O)(O)[O-].[Na+].[CH2:27]1[CH2:32][CH2:31]CCC1>CCCCCC.C(OCC)(=O)C>[C:32]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:31])([CH3:27])[CH3:17]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOCC
Reactant: C1CCCCC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cccc(C=O)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
EX-654A) 3-Hydroxybenzaldehyde (4.08 g, 33.4 mmol) was slurried in 50 mL of anhydrous CH2C2 and added to t-butyl-2,2,2-trichloroacetiridate (25.0 g, 114 mmol) in 200 mL of anhydrous cyclohexane with an additional 50 mL of CH2Cl2 used in transfer. The mixture was stirred under nitrogen until uniform, then boron trifluoride diethyl etherate (0.50 mL, 4 mmol) was added via syringe and stirring was continued for 1 h. Powdered sodium bicarbonate (50 g, 0.6 mol) was added, and the solution was filtered through a silica gel plug, washing the plug with hexane. The solvent was evaporated to give crude product 3.54 g (59%) as an amber oil (85% pure by GC analysis). Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 1.88 g (32%) of pure 3-t-butoxybenzaldehyde product as a colorless oil. 1H NMR (C6D6) δ9.59 (s, 1H), 7.44 (br s, 1H), 7.20 (d t, 1H), 6.92 (m, 2H), 1.07 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:21]([C:20]1[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18])=[O:22]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.2 %

Procedure:
To a solution of 4-nitro-L-phenylalanine methyl ester hydrochloride salt (7.44 mmol, 1.94 g), 2chloro-6-methylbenzoic acid (8.2 mmol, 1.4 g) and HBTU (8.2 mmol, 3.11 g) in DMF (27 mL) was added diisopropylethylamine (18.6 mmol, 3.24 mL) at room temperature. The clear solution was stirred for 48 h at room temperature and was diluted with 100 mL of ethyl acetate. The solution was washed in turn with 0.5N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL) then was dried (MgSO4) and filtered. Concentration of the solution to dryness gave 2.67 g (95%) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester as a colorless solid, mp 120-123° C. HRMS: Obs. mass, 376.4274. Calcd. mass, 376.4238 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[Cl:39]>C(O)C.O.Cl>[Cl:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1
Yield: 16 %

Procedure:
A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.1 g (0.38 mmole) of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide in 10 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, and then heated in a pressure tube at 130 degrees for 3 hours. After removal of the solvents under reduced pressure, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.028 g of 3-chloro-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-179) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:15](=[O:16])[CH:14]2[CH:9]1[CH:10]1[CH2:17][CH:13]2[CH:12]=[CH:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1CCCC1.[OH-].[Li+].Cl>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:10]2[CH2:17][CH:13]([CH:12]=[CH:11]2)[CH:14]1[C:15]([OH:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C21
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1C2C=CC(C2)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 4-Oxo-3-aza-tricyclo[4.2.1.0(2,5)]non-7-ene-3-carboxylic acid tert-butyl ester (60.94 g, 0.2590 mol;) and Tetrahydrofuran (800 mL, 10 mol;) in 2 L Ehrlenmeyer flask. Addition of 1.00 M of Lithium hydroxide in Water (780 mL) gave a slight exotherm and the flask was cooled during addition of LiOH solution with an ice water bath. The mixture was then warmed to rt following addition and stirred at room temperature overnight. Cooled 0° C. in ice/water bath. Added conc HCl to pH 2. A milky white liquid ensued. The THF was mostly removed by rotovap to give a precipitated solid in the water. This aqueous/solid mixture was diluted with 700 mL of CH2Cl2 and stirred for two hours during which the solid completely dissolved in the organic layer. The aqueous was further extracted with 400 mL of CH2Cl2 and the combined organics were dried (MgSO4), filtered and concentrated to give 3-tert-Butoxycarbonylamino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid as an off-white solid, put on high vac at 40° C. to remove excess dichloromethane present in the solid sample. (60.40 g, 92%). 1H-NMR(CDCL3, 400 MHz): δ 12.0 (broad absorption, 1H) 6.97 (d, J=10.6 Hz, 1H), 6.20 (s, 1H); 3.96 (t, J=9.6 Hz, 1H), 2.99 (s, 1H), 2.74 (s, 1H), 2.60 (d, J=8.4 Hz, 1H), 2.09 (d, J=9.3 Hz, 1H), 1.66 (d, J=9.4 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:41])[NH:15][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[C:16](=[O:41])[NH:15][N:14]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)n[nH]c(=O)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
1-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (40 mg, 0.066 mmol) was dissolved in DCM (664 μl) and then TFA (25.6 μl, 0.332 mmol) was added at RT. After stirring for 30 min, the reaction was quenched with saturated aqueous NaHCO3 (1 mL). A white solid precipitated out of the solution and was filtered off with the aid of water. The solid was washed with 3 mL of water and dried to afford the product 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (16 mg, 50% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 6.83 (d, J=4.38 Hz, 1H), 7.24 (d, J=4.49 Hz, 1H), 7.41-7.53 (m, 3H), 7.60 (d, J=7.80 Hz, 1H), 8.15 (dd, J=8.49, 1.87 Hz, 1H), 8.63 (d, J=1.82 Hz, 1H), 13.10 (s, 1H). m/z (ESI) 483.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:36]([O:38][C:39](=[O:61])[C@@H:40]([NH2:60])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][C:54]=3[CH3:58])[C:49]2=[O:59])=[CH:44][CH:43]=1)[CH3:37]>ClCCl.C(N(CC)CC)C>[CH2:36]([O:38][C:39](=[O:61])[C@@H:40]([NH:60][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][C:54]=3[CH3:58])[C:49]2=[O:59])=[CH:46][CH:47]=1)[CH3:37]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(N2C(=O)c3cccc(C)c3C2=O)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 45 °C
Reaction time: 8 h

Procedure:
The mixture of 88.2 mg of 2-chloro-6-methyl benzoic acid, 99.1 mg of 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride, 79.1 mg of 1-hydroxybenzotriazol hydrate, 107 μl of triethylamine, 100 mg of (2S)-2-amino-3-[4-(4-methyl-1,3-dioxo-1,3-dihydroisoindole-2-yl)phenyl] propionic acid ethylester hydrochloride and 1 ml of dichloromethane was stirred at 45° C. overnight. The mixture was purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].C[O:12][C:13](=O)[C:14]1[C:19]([I:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:15]2[C:14](=[C:19]([I:20])[CH:18]=1)[C:13](=[O:12])[N:2]([CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH2:22]2
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN2Cc3cc(F)cc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A mixture of 4-cyano-benzyl amine (0.218 g, 1.3 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.374 g, 1.0 mmol), and K2CO3 (0.277 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.160 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.83 (s, 2H), 7.13 (d, 1H), 7.42 (d, 2H), 7.64 (m, 3H). GC-MS: m/z 392 (M)4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH:31]([F:33])[F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH:31]([F:33])[F:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCC(F)F)nc1Cl
Yield: 69.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoroethoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (122a) (0.24 g, 0.48 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (8 mL) to obtain 0.16 g of the title compound as a colorless solid (71%).
Reaction SMILES: [NH2:1][C:2]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40].ClCCl.CO>CN(C)C=O>[NH2:1][C:2]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([S:39]([C:32]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=2[O:30][CH3:29])(=[O:41])=[O:40])[C:3]1=[O:13]
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 0 °C
Yield: 78.5 %

Procedure:
3.54 g (12.03 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were dissolved in 80 ml of anhydrous dimethylformamide (dried over molecular sieve). Under an atmosphere of nitrogen and with cooling using an ice-bath, 1.49 g (13.23 mmol) of potassium tert-butoxide were added a little at a time. The colour of the reaction mixture changed, and the brown solution was stirred at 0° C. for another hour to ensure that the deprotonation proceeded to completion. At low temperature, 3.16 g (13.23 mmol) 2,4-dimethoxybenzenesulphonyl chloride were added, and the mixture was stirred at 0° C. for another two hours. The course of the reaction was monitored by TLC (silica gel, dichloromethane/methanol in a ratio of 9:1). The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was evaporated. The residue was suspended in diethyl ether and stirred until the product precipitated as a solid and could be removed by filtration. After removal of the solvent, the mother liquor was once more treated with diethyl ether (2×) until finally, after drying, 4.67 g (9.44 mmol, 79%) of the desired 3-amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile were obtained as a solid substance.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[CH2:36]>C(O)C(O)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37](/[CH:35]=[CH:36]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:12])[C:5](=[O:11])[NH:6]3)=[CH:38][CH:39]=1
Reactant: O=C1Nc2cccc(I)c2C1=O
Reactant: C=Cc1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(O)CO
Solvent: CC#N
Product: O=C1Nc2cccc(/C=C/c3ccc(O)cc3)c2C1=O
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3-dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 3734-44), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of tri-o-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): δ6.6-7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCI−MS m/z 264 (M−1)−. Condensation of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): δ6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), ), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz, 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCI−MS m/z433 (M−1)−.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Reaction time: 3 h

Procedure:
2 g of cis-4-hydroxycyclohexanecarboxylic acid (13.87 mmol, 1 eq.) are placed in 50 mL of a 4/1 mixture of toluene/methanol at room temperature. Trimethylsilyl-diazomethane (111 mL, 221.96 mmol, 16 eq.) is poured into the reaction medium with stirring. After 3 hours at room temperature, the reaction medium is evaporated to give 2.6 g of methyl cis-4-hydroxycyclohexanecarboxylate.