Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11]N1C(=O)CCC1=O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 10 °C
Yield: 58 %

Procedure:
2-Oxindole (82.9 g) was suspended in 630 mL acetic acid and the misture was mechanically stirred and cooled to 10° C. in an ice water bath. Solid N-iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1 hour at 10° C. The suspended solid which was always present became very thick at this time. The solid was collected by vacuum filtration, washed with 100 mL of 50% acetic acid in water and then with 200 mL of water and sucked dry for 20 minutes in the filtration funnel. The product was dried under vacuum to give 93.5 g (36%) of 5-iodo-2-oxindole containing about 5% 2-oxindole by proton NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Br.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][C:5]=1[F:11]
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1F
Agent: Br
Product: COC(=O)c1ccc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from 2-Fluoro-4-hydroxy-benzoic acid methyl ester and 2-(bromomethyl)pyridine hydrobromide. MS (ES+) 262
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4c(c3)C(=O)c3ccccc3-4)c2cc1OC
Temperature: 160 °C
Reaction time: 7 h
Yield: 33.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-9-fluorenone (269 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (58 mg, yield 34%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][CH:12]=[O:13].[F:14][C:15]([F:21])([F:20])[Si](C)(C)C.Cl>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:13][CH:12]([C:15]([F:21])([F:20])[F:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1]1
Reactant: O=CCC1CCc2ccccc2O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CC1CCc2ccccc2O1)C(F)(F)F
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 7.6 g (43 mmol) of 3,4-dihydro-2H-1-benzopyran-2-acetaldehyde in 110 ml of tetrahydrofuran are added dropwise, at -10° C., 7.1 ml (52 mmol) of trifluorotrimethylsilylmethane and a solution of 90 mg (2 mg/mmol) of tetrabutylammonium fluoride in 5 ml of tetrahydrofuran. The mixture is allowed to react for 2 hours at 0° C., then it is hydrolyzed for 2 hours using a 1M solution of hydrochloric acid and the product is extracted with diethyl ether. The organic phase is then washed with water, dried over sodium sulfate and then concentrated under reduced pressure. By chromatography of the residue on a silica column using a 50/50 mixture of dichloromethane and of cyclohexane, 8.6 g of product are obtained in oil form.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=1[C:22]#[N:23].CCN(C(C)C)C(C)C>CC#N>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:20]([CH2:19][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[C:21]([CH:24]=1)[C:22]#[N:23]
Reactant: COc1ccc(CBr)c(C#N)c1
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(C#N)c1

Procedure:
Using General Procedure A: Reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine, 2-bromomethyl-5-methoxybenzonitrile (Ando, K. et al. Bull. Chem. Soc. Jpn. 1980, 53, 2885-2890), DIPEA and KI in CH3CN gave 5-methoxy-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzonitrile as an orange oil. 1H NMR (CDCl3) δ 1.60 (d, 3H, J=6.9 Hz), 2.08 (s, 3H), 3.73 (d, 1H, J=15.0 Hz), 3.74 (d, 1H, J=12.3 Hz), 3.78 (s, 3H), 3.92 (d 1H, J=12.3 Hz), 3.93 (d, 1H, J=15.0 Hz), 4.03 (q, 1H, J=6.9 Hz), 6.95-7.04 (m, 3H), 7.16 (ddd, 1H, J=7.5, 5.0, 1.0 Hz), 7.29 (t, 2H, J=6.6 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.65 (td, 1H, J=7.7, 1.8 Hz), 8.32 (dd, 1H, J=4.8, 1.2 Hz), 8.58 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14].C(N(CC)CC)C>C1COCC1>[CH3:13][C:9]1[C:8]2[O:14][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc2c1OCC(=O)N2
Reaction time: 24 h
Yield: 78.4 %

Procedure:
A solution of chloroacetyl chloride (0.71 mL, 8.94 mmol) in THF (5 mL) was added dropwise to a solution/suspension of 2-amino-6-methylphenol (1 g, 8.13 mmol) and triethylamine (1.24 mL, 8.94 mmol) in THF (50 mL) which had been pre-cooled in an ice-water bath. After stirring for 5 minutes a further portion of triethylamine (1.24 mL, 8.94 mmol) was added. The mixture was stirred and warmed to r. t. After 24 h the reaction was allowed to stand overnight. The mixture was concentrated in vacuo and the residue was partitioned between water (100 mL) and EtOAc (50 mL). Brine (20 mL) was added to the aqueous phase, and this was further extracted with EtOAc (50 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo, and purified by column chromatography (SiO2, 20-100% EtOAc/heptane) to give an orange-brown solid (1.04 g), which was dissolved in THF (10 mL) and triethylamine (2 mL), and the mixture left to stand for 3 days. The mixture was concentrated in vacuo and purified by column chromatography (SiO2, 10-50% EtOAc/heptane) to give a cream solid (0.6 g). This was dissolved in DCM (40 mL), and the solution was washed with aqueous NaOH (2M, 10 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (0.29 g, 22%) as a beige solid. LCMS (ES+) 164 (M+H)+, RT 2.61 minutes (Method 1).
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:9]=12)[CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([N:6]1[C:17](=[O:18])[C:16]2=[CH:15][NH:14][C:10]3[C:9]2=[C:8]([CH:13]=[CH:12][N:11]=3)[CH2:7]1)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 49.8 %

Procedure:
Into a 8 mL scintillation vial equipped for stirring was added (S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (6 mg, 0.018 mmol). N,N-dimethylformamide (2 mL), HATU (8.29 mg, 0.022 mmol) and 4-methylmorpholine (2.2 mg, 0.022 mmol) were added and the solution was allowed to stir at room temperature for 1 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow solid (2.8 mg, 49.4%). 1H NMR (500 MHz, CD3OD) δ 0.97 (t, J=7.32 Hz, 3 H) 1.74-1.98 (m, 5 H) 1.98-2.14 (m, 1 H) 3.08-3.22 (m, 1 H) 3.37-3.47 (m, 1 H) 3.65-3.77 (m, 1 H) 4.07 (s, 1 H) 5.05 (s, 2 H) 5.62 (dd, J=8.54, 7.08 Hz, 1 H) 7.11 (d, J=4.88 Hz, 1 H) 7.80 (s, 1 H) 8.29 (br. s., 1 H). [M+H] calc'd for C17H20N4O2, 313; found, 313.6.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COc1ccccc1Br)c1ccccc1
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
(1)-(i) A suspension of 6.72 g of 60% sodium hydride in 40 ml of tetrahydrofuran is added dropwise to a solution of 24.17 g of 2-bromophenol in 210 ml of tetrahydrofuran at 4° C. and the mixture is stirred at the same temperature for 15 minutes. A solution of 30.66 g of phenacyl bromide in 60 ml of tetrahydrofuran is added dropwise to the mixture. The mixture is stirred at the same temperature for 30 minutes and further refluxed for 2.5 hours. The reaction mixture is evaporated to remove solvent, and water is added to the residue. The aqueous mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography and recrystallized from a mixture of ethyl acetate and n-hexane to give 21.49 g of (2-bromophenyl)(benzoylmethyl)ether as colorless needles.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)([OH:17])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O.C1CCCCC=1>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]2([OH:17])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: OC1(c2cccnc2)CCNCC1
Yield: 93.5 %

Procedure:
To a solution of 1-carbobenzyloxy-4-(3-pyridyl)piperidin-4-ol (described in example 87d) (3.17 g, 10.2 mmol) in ethanol (100 mL) was added 10% palladium on carbon (2.0 g). This was followed by cyclohexene (50 mL) in large excess. The reaction was heated to reflux under nitrogen for 2 h. The suspension was cooled, filtered and the catalyst rinsed with fresh ethanol The filtrate was reduced in vacuo to yield 1.70 g (94%) of an off-white solid which did not require any additional purification. 1H NMR (D6 -DMSO, 300 MHz) 8.68 (d, J=2.0 Hz, 1H), 8.42 (dd, J=1.5, 4.6 Hz, 1H), 7.83 (ddd, J=1.9, 2.1, 4.0 Hz, 1H), 7.35 (dd, J=4.8, 8.0 Hz, 1H), 2.97 (ddd, J=2.3, 12.2 Hz, 2H), 2.78 (m, 2H), 1.86 (ddd, J=4.5, 12.9 Hz, 2H), 1.56 (m, 2H), 2.50 (m, 1H) MS (CI, CH4) m/z 179 (M+1,100), 207 (M+29,16), 161 (39)
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:21])([CH2:11][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([CH2:7][C:8]([OH:21])([CH2:11][C:12]([CH3:13])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:20])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(CC(O)(CO)CC1CCCCC1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CC(O)(C=O)CC1CCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, 160 mg of 2-cyclohexylmethyl-4-methyl-4-phenyl-1,2-pentanediol is reacted with 342 mg of pyridine-sulfur trioxide complex, 1.95 ml of DMSO and 0.39 ml of triethylamine to form 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanal ('H-NMR (CDCl3); δ=0.90-1.60 (m, 10H), 1.30 (s, 3H), 1.41 (s, 3H), 1.76 (m, 2H), 1.95 (m, 1H), 2.20 (d, 1H), 2.35 (d, 1H), 2.97 (s, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.76 (s, 1H)). The crude product is reacted with 137 mg of 5-aminoquinoline and 524 mg of sodium triacetoxy borohydride to form imine (180 mg; 'H-NMR (CDCl3); δ=0.90-1.90 (m, 18H), 2.25 (m, 1H), 2.80 (d, 1H), 3.00 (d, 1 H), 3.76 (t, 1H), 5.06 (d, 1H), 6.25 (d, 1H), 7.10-7.55 (m, 8H), 8.25 (d, 1H), 8.87 (dd, 1H); MS (ESI), 415). Reductive amination with 49 mg of sodium borohydride yields 130 mg of end product after column chromatography.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:35]#[CH:36])([CH3:34])([CH3:33])[CH3:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:36]#[C:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(C)C
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(C#CC(C)(C)C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3,3-dimethylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (72) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using t-butylacetylene. 1H-NMR: 400 MHz, (CD3OD) δ: 7.70 (d, J=8 Hz, 1H), 7.65 (s, 1H), 7.57 (m, 3H), 7.33 (m, 2H), 7.19 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H), 1.27 (s, 9H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.78.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 025 mmol) and 3-[(cis)-3,5-dimethyl-piperazine-1 carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (103.5 mg, 90%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:40]1[CH:41]=[CH:42][C:37]([CH2:36][NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:38][CH:39]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (15.4 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (30 μL) was added followed by 4-aminomethylpyridine (14 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.8 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 19 h then eluted directly on silica gel column (2-10%MeOH in CH2Cl2) to yield 8.9 mg of the title compound. 1H NMR (500 MHz, CDCl3,partial): δ 8.56 (m, 2H); 8.46 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.96 (s, 1H); 7.81 (d, J=7.9 Hz, 1H); 7.71 (d, J=7.8 Hz, 1H); 7.63 (d, J=7.8 Hz, 1H); 7.47 (t, J=7.7 Hz, 1H); 7.24 (d, J=5.9 Hz, 1H); 6.79 (d, J=5.5 Hz, 1H); 6.64 (br s, 1H); 5.77 (br s, 1H); 5.5.24 (br s, 1H); 4.65 (m, 2H); 1.66 (d, J=7.1 Hz, 3H). Mass Spectrum (ESI): m/e 450.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([NH:30][CH3:31])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:37]OCCl>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:17]([C:18](=[O:19])[N:20]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:31][N:30]4[CH3:37])=[CH:28][CH:29]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Reactant: ClCOCCl
Solvent: ClCCl
Product: CN1CN(Cc2ccccn2)C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Reaction time: 15 h
Yield: 65.2 %

Procedure:
In a solution of 0.06 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylamino-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-332) synthesized similarly to Synthetic Example 18 in 5 ml of dichloromethane, 0.03 g of chloromethylether was added, and stirred at the same temperature for 15 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:1) to obtain 0.04 g of the aimed product as colorless oily substance.
Reaction SMILES: O[C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])([O-])=O.[K+].[K+]>>[CH2:18]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: CC1(O)c2ccccc2C(=O)N1c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Product: C=C1c2ccccc2C(=O)N1c1ccncc1
Temperature: 200 °C
Yield: 66 %

Procedure:
A mixture of 2,3-dihydro-3-hydroxy-3-methyl-2-(4-pyridyl)-1H-isoindol-1-one (10.20 g) and phosphorus pentoxide (6.03 g) was heated under vacuum at 200° C. for 20 minutes. Ice water was then added and the mixture was basified with K2CO3 solution. The resulting solid was filtered, dried and passed through a column of florisil (ethyl acetate) to give 6.23 g of a solid. A 2.0 g portion was recrystallized from methanol to give 1.37 g of platelets, mp: 173°-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31]>C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:7][C:2]=1[N:1]=[C:30]=[S:31]
Reactant: S=C(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C=S)c(Cl)cc2F)c1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
A mixture of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)-2,4 (1H,3H)-pyrimidinedione (1.0 g, 2.96 mmol) in toluene is cooled to 0° C., treated sequentially with triethylamine (0.91 mL, 6.52 mmol) and thiophosgene (0.25 mL, 3.26 mmol), warmed to and stirred at room temperature for 5 hours, and filtered to remove solids. The resultant filtrate is concentrated in vacuo to give the title product as an orange solid (1.1 g, 98% yield) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:26])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:5][C:6]1[C:11]([N:12]([CH2:3][O:2][CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)(=[O:14])=[O:15])=[CH:10][C:9]([Cl:26])=[CH:8][N:7]=1
Reactant: O=S(=O)(Nc1cc(Cl)cnc1Br)c1cccc(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
Methoxymethyl chloride (720 mg, 8.94 mmol) was added dropwise to a mixture of N-(2-bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (2.51 g, 6.04 mmol) and potassium carbonate (5.1 g) in THF (60 mL) at room temperature. After 5 h, the potassium salts removed by vacuum filtration, and the filtrate was concentrated under reduced pressure. The residual light yellow solid was chromatographed on silica gel using ethyl acetate-hexane to provide N-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as white crystals. MS m/z 461.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccccc1/C=C/C(=O)O
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccccc1/C=C/C(=O)Nc1ccn(Cc2ccc(C(C)=O)o2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]3([CH2:42][OH:43])[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37]3)[NH:13]2)=[O:11])[CH2:4][O:3]1>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:44])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]3([CH2:42][OH:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[NH:13]2)=[O:11])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(CC3(CO)CC=CCC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CCNC(=O)C2NC(CC3(CO)CCCCC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (0.28 g, 0.43 mmol) prepared in Example 117d in ethyl acetate (10 mL) was added PtO2 (0.1 g). The suspension was shaken vigorously under H2 atmosphere (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a white solid (0.27 g, 96%)