Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH2:21]=[O:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][OH:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: C=O
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-bromo-2-(imidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 5-bromo-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: C[O:2][C:3]1[C:8]2=[C:9]([CH3:33])[N:10]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]2[CH:6]=[C:5]([CH2:34][O:35][CH3:36])[N:4]=1.[I-].[Li+]>N1C=CC=CC=1>[CH3:36][O:35][CH2:34][C:5]1[NH:4][C:3](=[O:2])[C:8]2=[C:9]([CH3:33])[N:10]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:7]2[CH:6]=1
Reactant: COCc1cc2c(-c3ccccc3Oc3ccccc3)n(COCC[Si](C)(C)C)c(C)c2c(OC)n1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COCc1cc2c(-c3ccccc3Oc3ccccc3)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Yield: 42.8 %

Procedure:
A mixture of Example 44c (0.0816 g, 0.162 mmol) and lithium iodide (0.65 g, 4.85 mmol) in pyridine (1 mL) was heated at 160° C. for 1 hour in a Biotage microwave reactor. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20-80% ethyl acetate in heptanes) to provide 0.034 g (43%) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2].O1C=CN=C1[Cl:25]>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:25])=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC(C)=O
Reactant: Clc1ncco1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)Cl)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture o 4-acetoxy-3,5-dimethoxycinnamic acid (638 mg), dimethylformamide (2 drops) and tetrahydrofuran (8 ml) was added oxazolyl chloride (0.25 ml). The mixture was stirred at room temperature for one hour and then the solvent was distilled off to obtain 4-acetoxy-3,5-dimethoxycinnamic acid chloride as crystals. To a solution of the crystals in dichloromethane (15 ml) were added 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (576 mg) and N,N-dimethylaniline (0.25 ml) with ice cooling. After warming to room temperature, the mixture was stirred for 5 hours, washed in turn with water, aqueous saturated NaHCO3 solution and water, and then dried over MgSO4. The solvent was distilled off and the residue was crystallized from ethanol (729 mg, 67.4%). 5-(4-Acetoxy-3,5-dimethoxycinnamoylamino)-4-(2-chloropheny ethylthieno[2,3-b]pyridine was obtained as colorless prisms by recrystallization from acetone, mp: 133°-135° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CCCCCC>O1CCOCC1.C(OCC)(=O)C>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1
Yield: 69.3 %

Procedure:
4-Chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto, followed by reaction at 80° to 90° C. for 2 hours. Then, the solvent was removed by distillation under reduced pressure, and 10 ml of hexane was added to the residue to wash it. The solvent was removed by decantation. The residue was further similarly treated with 10 ml of ether. The residue was purified by silica gel column chromatography [eluent: hexane:ethyl acetate=2:1 (v/v)]to obtain 1.41 g of a yellow solid (yield: 68.8%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:19]([S:28][CH3:29])[NH:18][N:17]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:19]([S:28][CH3:29])[NH:18][N:17]=2)=[CH:14][CH:15]=1
Reactant: CSN1NN=C(C2=CC=C(CO[Si](C)(C)C(C)(C)C)SS2)N1c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSN1NN=C(C2=CC=C(CO)SS2)N1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[methylthio-[1-(4-hydroxyphenyl)-tetrazol-5-yl]]-1,2-dithiin obtained above (440 mg, 0.94 mmol) in 4 mL of THF was added a solution of 7 mL of 1M tetrabutylammonium fluoride in THF and 4 mL of acetic acid. The reaction mixture was stirred for 1 h at 0° C. until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 60 mL of water and 90 mL ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then concentrated to a small volume. The residue was purified by flash chromatography (ethyl acetate-hexane, 1:3) to yield 265 mg (79.8%) of the title compound as yellow crystals, mp 130°-131° C.; 1H-NMR (CD3OD) δ7.36 (d, J=9.2, 2 H), 6.97 (d, J=9.2, 2 H), 6.47 (d, J=6.0, 1 H), 6.34 (d, J=6.4, 1 H) 4.24 (s 2 H), 4.15 (s, 2 H); 1H-NMR (DMSO-d6):10.26 (s, 1 H, phenol OH), 7.41 (d, 2 H, J=8.8), 6.97 (d, 2 H, J=8.8), 6.52 (d, 1 H, J=6.0), 6.35 (d, 1 H, J=6.0), 5.39 (t, 1 H, J=5.2), 4.30 (s, 2 H), 4.06 (d, 2 H, J=5.2); 13C--NMR (CD3OD) δ160.99, 154.90, 138.09, 130.34, 129.49 127.42, 126.05, 125.77, 117.29, 64.67, 40.01; 1H-NMR NOESY showed an interaction between aromatic and dithiin rings protons. MS (+FAB) 353.5 (MH+); IR (KBr) 3378.7 (OH); 3135 (OH)cm-1. HMBC (DMSO-d6) shows a long range correlation between the protons at 4.30 ppm and the carbon at 154.90 ppm. Anal. calcd for C13H12N4O2S3 :C, 44.30; H, 3.43; N, 15.90; S, 27.29. Found:C, 44.68; H, 3.37; N, 16.24; S, 27.23.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]3[C:26]([O:36][CH3:37])=[C:27]([CH:30]([OH:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:28]=[CH:29][C:19]=3[S:18][C:17]=2[C:16]([O:38][CH3:39])=[CH:15][C:14]=1[CH3:40]>ClCCl>[Br:12][C:13]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]3[C:26]([O:36][CH3:37])=[C:27]([C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:28]=[CH:29][C:19]=3[S:18][C:17]=2[C:16]([O:38][CH3:39])=[CH:15][C:14]=1[CH3:40]
Reactant: COc1cc(C)c(Br)c2c1Sc1ccc(C(O)CC(C)C)c(OC)c1C(=O)OC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C)c(Br)c2c1Sc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
31 mg (0.15 mmol) of pyridinium chlorochromate are added to a solution of 35 mg (0.07 mmol) of the compound from Example XV in 4 ml of dichlormethane and the mixture is stirred at room temperature for 2 hours. The reaction solution is applied to silica gel, eluted with dichloromethane and chromatographed on silica gel using petroleum ether/ethyl acetate 1:3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][NH:28]1>>[O:32]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)nc1C
Yield: 84.5 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (383 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[O:11]1[CH2:15][CH2:14][CH:13]=[C:12]1[Sn](C)(C)C.[Cl-].[NH4+].[OH-].[NH4+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:12]2[O:11][CH2:15][CH2:14][CH:13]=2)[C:3]=1[C:4]#[N:5]
Reactant: C[Sn](C)(C)C1=CCCO1
Reactant: N#Cc1c(N)cccc1Br
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)cccc1C1=CCCO1
Yield: 68 %

Procedure:
2-Amino-6-bromobenzonitrile (0.75 g, 3.81 mmol), (4,5-dihydrofuran-2-yl)trimethylstannane (Menez, P.; Fargeas, V.; Poisson, J.; Ardisson, J.; Lallemand, J.-Y.; Pancrazi, A. Tetrahedron Letters 1994, 35(42), 7767) (1.02 g, 4.38 mmol), and palladium tetrakis(triphenylphosphine) (0.33 g, 0.28 mmol) were refluxed in toluene (10.0 mL) under nitrogen for 1.5 h. Saturated ammonium chloride (12 mL) and ammonium hydroxide (4 mL) were added, and the mixture was extracted with EtOAc. The organic layer was concentrated under vacuum and the residue was purified by chromatography on silica using 35% EtOAc/hexanes to give 0.48 g (68%) of the title compound as yellow oil. 1H NMR (400 MHz, Acetone-d6) δ 2.78-2.83 (m, 2H), 4.40 (t, J=9.2 Hz, 2H), 5.76 (t, J=3.2 Hz, 1H), 6.04 (s, 2H), 6.77-6.80 (m, 2H), 7.28 (t, J=8.0 Hz, 1H). MS 187 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N[S:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[O:30])(=[O:19])=[O:18])CC>>[O:29]=[C:24]1[C:23](=[O:30])[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([S:17]([NH:1][C@@H:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([NH2:12])=[O:11])(=[O:19])=[O:18])[CH:21]=2)[NH:25]1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Product: NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Phe-NH2 following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(C)(=O)=O)c1

Procedure:
To a mixture of methyl 3-bromo-5-(methylsulfonyl)benzoate (0.65 g, 2.2 mmol), p-tolylboronic acid (0.332 g, 2.44 mmol), toluene (10 mL), cesium carbonate (0.795 g, 2.44 mmol), and water (1 mL) under argon was added tetrakis(triphenylphosphine)-palladium(0) (128 mg, 0.111 mmol). The mixture was heated under reflux for 15 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-100% EtOAc/hexane) to yield a white solid. LC-MS: 3.26 min, 305.3 [M+1]+ (weak).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH2:8]([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2[S:13][C:12]=1[C:20]([Cl:22])=[O:21])[CH2:9][CH3:10].[CH3:23][NH:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.CN(C1C=CC=CN=1)C>O.CN(C)C=O>[ClH:22].[Cl:31][C:29]1[CH:30]=[C:25]([N:24]([CH3:23])[C:20]([C:12]2[S:13][C:14]3=[N:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[CH2:8][CH2:9][CH3:10])=[O:21])[CH:26]=[C:27]([Cl:32])[CH:28]=1
Reactant: CNc1cc(Cl)cc(Cl)c1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1=C(C(=O)N(C)c2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Temperature: 70 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
In the mixture of 30 ml of pyridine and 3 ml of dimethylformamide was suspended 938 mg of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 587 mg of N-methyl-3,5-dichloroaniline, and 40 mg of dimethylaminopyridine, followed by stirring at 70° C. for 18 hours. The reaction mixture was cocentrated and to the mixture was added water. The organic layer was extracted with chloroform. The extact was washed with 5% sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the solution was added saturated hydrogenchloride diethylether solution. The mixture was stirred at room temperature, followed by removing the solvent under reduced pressure. The residue was purified by column chromatography (silica gel: 45 g) using a mixed solvent of chloroform and methanol (20:1 by volume) as an eluent. The resulting substance was treated with saturated hydrogenchloride diethylether solution and recrystallized from a mixed solvent of ethanol and diethylether to obtain 461 mg of the titled compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@H:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:28])([CH3:27])[CH3:26]>COCCO>[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@H:32]([NH:40][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@@H](N)Cc1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: COCCO
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 76.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg, 0.125 mmol) and (S)-3-amino-4-phenyl-butyric acid tert-butyl ester (88 mg, 0.375 mmol) (Acros Organics, Thermo Fisher Scientific, Morris Plains N.J.) in 2-methoxyethanol (10 mL) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, and the residue was purified by column chromatography (0-40% EtOAc/hexanes) to give 50 mg of the title compound. MS: (−) m/z 522.25 (M−1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:47])([F:46])[C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=1)[O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([O:34][C:33]4[CH:43]=[CH:44][CH:45]=[C:31]([C:30]([F:29])([F:46])[F:47])[CH:32]=4)[CH:36]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Product: FC(F)(F)c1cccc(Oc2cccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-(3-trifluoromethyl phenoxy)-benzaldehyde. MS (ESI) m/z 629.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (5.0 g, 25.5 mmol) in anhydrous THF (70 mL) was cooled to 0° C. and sodium hydride (60 wt %, 1.5 g, 38.3 mmol) added portion wise. The mixture was stirred at room temperature for 1 h. After which methyl iodide (1.$ mL, 28.1 mmol) was added and the mixture stirred for 14 h. The reaction mixture was carefully quenched with water at 0° C. and diluted with ethyl acetate (200 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (3.8 g, 72%) as a yellow oil: ESI MS m/z 210 [C9H8BrN+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)nc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
In a manner similar to the method described in Example 380, chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (24.9 mg, 0.0405 mmol) in THF (3 ml) was treated with lithium hydroxide hydrate (12.0 mg, 0.286 mmol) in water (1.5 mL). It was stirred at room temperature to give chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid as a white lyophilized solid (25.4 mg, 100). RMS (ES+) m/z Calcd C30H28Cl2F2N4O3+H [(M+H):601.1580. Found: 601.1579.
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(=O)OC(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)=[O:3]>CCOC(C)=O>[NH2:16][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:2]=[O:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccc(C=O)cc2)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccc(C=O)cc2)ccn1
Reaction time: 18 h

Procedure:
A stream of HCl gas was bubbled into a suspension of tert-butyl 4-(4-formylphenyl)pyridin-2-ylcarbamate (2-1, 486 mg, 1.63 mmol) in EtOAc (50 mL) at 0° C. for 2 min. The acidified solution was allowed to reach 23° C. and was then stirred for 18 h. The reaction mixture was concentrated to give 4-(2-aminopyridin-4-yl)benzaldehyde (2-2) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 10.07 (s, 1H), 8.18 (d, 1H, J=5.5 Hz), 7.97 (d, 2H, J=8.6 Hz), 7.74 (d, 2H, J=8.1 Hz), 6.91 (dd, 1H, J=5.5, 1.5 Hz), 6.73 (s, 1H), 4.61 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:36][C@H:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([NH:43][C:44]([C:46]3[N:47]=[CH:48][N:49]([CH3:51])[CH:50]=3)=[O:45])[CH2:38]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[N:6][CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([NH:36][C@H:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([NH:43][C:44]([C:46]3[N:47]=[CH:48][N:49]([CH3:51])[CH:50]=3)=[O:45])[CH2:38]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(-c4nn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c5ncccc45)ncc3F)C2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(-c4n[nH]c5ncccc45)ncc3F)C2)c1
Reaction time: 1 h

Procedure:
To a solution of N-[(1R,3S)-3-[[5-fluoro-2-(1-tritylpyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-1-methyl-imidazole-4-carboxamide, 25, (0.235 g, 0.347 mmol) in dichloromethane (6.90 mL) at room temperature was added Et3SiH (1.661 mL, 10.40 mmol) followed by TFA (0.401 mL, 5.200 mmol). The reaction mixture was stirred for 1 hour. The mixture was diluted with dichloromethane and quenched with aqueous saturated Na2CO3 solution. The organic phase was extracted with ethyl acetate, washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica chromatography (0-7% MeOH [2N NH3] in ethyl acetate) to give the desired product: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=1.46 min (M+H)=436.62.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(Cl)=[O:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:27](=[O:28])[O:20][C:18](=[O:19])[C:17]3=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Product: COc1ccc2c(c1)c(=O)oc(=O)n2-c1ccc(OCc2ccccc2)cc1
Yield: 79 %

Procedure:
N-(4-Benzyloxyphenyl)-5-methoxyisatoic anhydride [VIII; R=5--CH3O, R"=H, OR°=4--OCH2C6H5 ] was prepared from 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid and phosgene according to the procedure of Example 1, part (b), and was obtained in 79% yield as a colorless solid used directly in the next reaction.