Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 40.9 %

Procedure:
4-Chloro-2-fluoro-5-(2-propynyloxy)aniline (1.9 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.52 g) were dissolved in acetic acid (20 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.3 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P. 136.4° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:7]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:19]=4[Cl:28])=[O:17])[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:31]I>CN(C=O)C.O>[Cl:28][C:19]1[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([N:13]1[CH2:14][CH2:15][C:7]2[C:6]([C:5]3[CH:4]=[CH:3][N:2]([CH3:31])[N:1]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:12]1)=[O:17]
Reactant: CI
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccn[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ncnc3c2CCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C3)n1
Yield: 44 %

Procedure:
To a solution of Example 18 (137 mg, 0.33 mmol) in DMF (3 mL) was added NaH, 60% dispersion in mineral oil (16 mg, 0.40 mmol). After 30 minutes MeI (0.03 mL, 0.40 mmol) was then added. After several hours the reaction was diluted with water and then extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afforded the title compound as a white solid (61.2 mg, 43%). MS (ESI) mass calcd. C19H15ClF3N5O, 421.09. m/z found 422.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09-8.92 (m, 1H), 7.82-7.75 (m, 1H), 7.58-7.42 (m, 3H), 7.06-7.01 (m, 1H), 5.19-4.92 (m, 1H), 4.58-4.38 (m, 1H), 4.22-3.94 (m, 4H), 3.57-3.22 (m, 3H).
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[CH3:4][CH:3]([CH3:5])[CH2:2][C:1](=[NH:6])[O:10][CH2:8][CH3:9]
Reactant: CC(C)CC#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)CC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Isovaleronitrile (2.0 g, 24.1 mmol) was dissolved in anhydrous ethanol (48 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 3-methylbutanimidate hydrochloride (4.0 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (br s, 1H), 11.09 (br s, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.48-2.47 (m, 2H), 2.02-2.01 (m, 1H), 1.33 (t, J=7.0 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH:16]([CH3:18])[CH3:17])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=2[CH:16]([CH3:18])[CH3:17])=[O:4])[CH2:24][CH2:23]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of this acetamide (498 mg, 1.57 mmol) in acetonitrile (10 ml) were added 1-(2-hydroxyethyl)piperazine (371 mg, 2.85 mmol) and potassium carbonate (469 mg, 3.39 mmol) successively with ice-cooling, and stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting reside was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; chloroform:methanol=25:1 10:1) and recrystallized from ether-hexane to provide 575 mg (yield 99%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-3-fluorophenyl)acetamide as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]#[CH:10].[C:11]([C:13]1[CH:19]=[C:18](I)[C:16]([NH2:17])=[CH:15][CH:14]=1)#[N:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:17][C:16]2[C:18]([CH:10]=1)=[CH:19][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2
Reactant: N#Cc1ccc(N)c(I)c1
Reactant: C#Cc1cnccc1OC
Product: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1

Procedure:
4-Methoxy-3-ethynyl-pyridine and 4-cyano-6-iodoaniline are processed according to the method described in Example 86 to give 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile. 2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile is purified by HPLC using an Xbridge Shield RP18 with a gradient of acetonitrile in 0.1% NH4OH. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.04 (s, 3H), 7.14 (d, J=1.3 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H), 7.47 (dd, J=8.5, 1.6 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.47 (d, J=5.8 Hz, 1H), 8.91 (s, 1H), 11.91 (br. s., 1H). HRMS (ESI) m/z 250.0968 [(M+H)+ calcd for C16H12N3O: 250.0980].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][C:27]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c6) the title compound is obtained as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12](=[CH:20][CH3:21])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[CH:12]([CH2:20][CH3:21])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC=C1c2c(ccc3c2CCN(C(=O)OCC)CC3)CC1(F)F
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(CC)C(F)(F)C3
Reaction time: 16 h

Procedure:
Into a 100 ml flask, the product from step (a) dissolved in EtOH (20 ml) was added. The flask was purged with Ar and 10% Pd—C (15 mg) was added. The reaction was stirred over hydrogen (atmospheric pressure) for 16 hours. The reaction mixture was filtered through celite and the solvent evaporated in vacuo. The crude residue was purified by silica-gel chromatography (gradient elution: 0 to 20% EtOAc in hexanes) to give the sub-title product as a colorless oil (42 mg). 1H NMR (300 MHz, CDCl3) δ 7.02-6.96 (m, 2H); 4.17 (q, J=7.2 Hz, 2H); 3.65-3.56 (m, 4H); 3.49-3.21 (m, 3H) 2.89-2.83 (m, 4H); 1.76-1.56 (m, 2H); 1.28 (t, J=6.9 Hz, 3H); 0.94 (t, J=7.5 Hz, 3H); MS: ESI (positive): 324 (M+1).
Reaction SMILES: Cl.C([O:6][C:7](=[O:41])[C@@H:8]([NH:10][C:11](=[O:40])[C@H:12]([NH:32]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=[O:31])[NH:16][CH2:17][C@@H:18]([OH:30])[CH2:19][P:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:22])=[O:21])[CH3:9])(C)(C)C>O1CCOCC1.O>[NH2:32][C@H:12]([CH2:13][CH2:14][C:15](=[O:31])[NH:16][CH2:17][C@@H:18]([OH:30])[CH2:19][P:20]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([OH:22])=[O:21])[C:11]([NH:10][C@@H:8]([CH3:9])[C:7]([OH:41])=[O:6])=[O:40]
Reactant: C[C@H](NC(=O)[C@@H](CCC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](N)CCC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
4N HCl in dioxane (5 mL) was added to (S)-2-{(R)-2-tert-butoxycarbonylamino-4-[(R)-3-(cyclohexylmethyl-hydroxy-phosphinoyl)-2-hydroxy-propylcarbamoyl]-butyrylamino}-propionic acid tert-butyl ester (0.351 g, 0.592 mmol) in water (1 mL). The resulting colorless solution was stirred under N2 at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (adjusted with HCl pH=3.5) to 100% CH3CN over 20 min at 45 mL/min. The appropriate fractions were combined and lyophilized to give the title compound (0.096 g, 0.220 mmol) as a white solid. 1H NMR (CD3OD, 300 MHz): δ 4.38 (q, J=7.2 Hz, 1H), 4.04 (m, 1H), 3.90 (t, J=6.3 Hz, 1H), 3.35 (dd, J=5.7, 13.2 Hz, 1H), 3.21 (dd, J=5.7, 13.5 Hz, 1H), 2.41 (m, 2H), 2.11 (m, 2H), 1.92 (br d, 2H), 1.77-1.65 (m, 6H), 1.52 (dd, J=6.3, 13.5 Hz, 2H), 1.43 (d, J=7.2 Hz, 3H), 1.37-1.15 (m, 3H), 1.08-1.00 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 42.95. LCMS m/z: [M+H]+=436.25
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[C:18]([Cl:23])[N:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:19]=[C:18]([Cl:23])[N:17]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Clc1cc(I)cc(Cl)n1
Product: COC(=O)CCc1ccc(C#Cc2cc(Cl)nc(Cl)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (98 mg, 0.52 mmol) and 2,6-dichloro-4-iodopyridine (152 mg, 0.56 mmol) according to the general procedure IF to give 95 mg (55%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:7): Rf=0.11 (EtOAc:PE, 1:7); 1H NMR (CDCl3) δ 7.46 (d, J=8.3 Hz, 2H), 7.34 (s, 1H), 7.22 (s, 2H), 3.68 (s, 3H), 2.99 (t, J=7.7 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.0, 150.7, 142.0, 132.7, 132.3, 128.7, 128.5, 124.4, 119.8, 81.4, 73.8, 51.7, 35.2, 30.9; ESI-MS m/z 356.0 (M+Na+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=[CH:28][C:27]=4[O:35][CH2:36][CH:37]4[CH2:39][CH2:38]4)[C:20]=3[NH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.CC(O)C.[ClH:44].C(OC)(C)(C)C>O1CCOCC1>[ClH:44].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[C:34]5[O:33][CH2:32][O:31][C:30]=5[CH:29]=[CH:28][C:27]=4[O:35][CH2:36][CH:37]4[CH2:38][CH2:39]4)[C:20]=3[NH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Temperature: 80 °C

Procedure:
4-({1-[4-(5-Cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl]-methanoyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester from example A86 (4.02 g; 7.5 mmol) is dissolved in warm (40-70° C.) 2-propanol (37.5 mL). After addition of 4M HCl in dioxane (7.5 mL) the stirred reaction mixture is heated to 80° C. for two hours. Tert-butylmethylether (150 mL) is added to the reaction mixture while still warm (40-70° C.). After cooling in an ice bath the precipitated product is collected, washed with tert-butylmethylether and dried in high vacuo at 50° C. to yield 3.35 g of the title compound as bright yellow solid.
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([O:27][CH3:28])=[O:26])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO>[C:25]([C:21]1[NH:20][CH:24]=[CH:23][N:22]=1)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ncc[nH]1

Procedure:
After a solution of 3.2 g (8.7 mmol.) of 1-trityl-2-carbomethoxyimidazole in 40 mL of a 5% solution of acetic acid in methanol was refluxed for 30 minutes, it was concentrated in vacuo. Recrystallization from ethanol afforded colorless needles, mp 187°-188° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH:32]1([NH:36][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC5CCC5)c4)cc23)CC1
Yield: 34.5 %

Procedure:
Following the general procedure of example 31, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.113 mmol), cyclobutanamine (24.1 mg, 0.339 mmol) and NaBH(OAc)3 (75 mg, 0.545 mmol) were reacted to give the title compound (19.3 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.NC1C(CN)=CC=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Agent: NCc1cccnc1N
Product: NCc1ccnc(N)c1

Procedure:
2-Aminopyridine-4-carbonitrile (L. W. Deady et al, Aust. J. Chem., 35, 2025 (1982)) is reduced catalytically according to the procedure of D. E. Beattie et al for the preparation of 2-amino-3-aminomethyl pyridine (J. Med. Chem, 20, 718, (1977)) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.CN(C)C(=O)C.[H-].[Na+].Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43]>O>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:12][CH2:13]1
Reactant: Fc1ccccc1CCl
Reactant: COc1ccc(CCN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccccc3F)CC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
To a stirred mixture of 3.5 parts of 2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole and 18 parts of N,N-dimethylacetamide were added portionwise 0.5 parts of a sodium hydride suspension 59.4% at room temperature. After stirring for 35 minutes at room temperature and for 10 minutes at 60° C., a solution of 1.7 parts of 1-(chloromethyl)-2-fluorobenzene in 9 parts of N,N-dimethylacetamide was added dropwise at 60° C. After stirring for 10 minutes, the reaction mixture was cooled and poured into 150 parts of water. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 3.0 parts (65.5%) of 1-[(2-fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 109.3° C. (515).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([C:34]1[C:39]([CH3:40])=[C:38]([O:41]C)[C:37]([CH3:43])=[C:36]([CH3:44])[C:35]=1[O:45]C)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH2:28]([C:34]1[C:35](=[O:45])[C:36]([CH3:44])=[C:37]([CH3:43])[C:38](=[O:41])[C:39]=1[CH3:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
CAN Oxidation: A flask was charged with 1-hexyl-2,5-dimethoxy-3,4,6-trimethyl-benzene (203; 1.75 g, 7.5 mmol) and CAN (20 mL) then cooled to 0° C. A solution of CAN (8.4 g, 15.4 mmol) in water (10 mL) was added to the flask. After 1 h the reaction was complete. The reaction mixture was extracted with MTBE (3×20 mL). The combined MTBE layers were dried over MgSO4, filtered and concentrated by rotary evaporation to yield 2-hexyl-3,5,6-trimethyl-[1,4]benzoquinone (205) as a yellow-orange oil which solidified upon standing (1.64 g, 88%). 1H NMR (400 MHz; CDCl3; ppm) 2.49-2.46 (m, 2H), 2.04 (s, 3H), 2.03 (s, 6H), 1.44-1.22 (m, 8H), 0.90 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1F.CO>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[O:4][CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc(Br)ccc1Br
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)ccc1Br
Temperature: 70 °C
Yield: 84 %

Procedure:
Add dropwise potassium tert-butoxide (118.2 ml, 118.2 mmol, 1 M in hexane) to a solution of 1,4-dibromo-2-fluorobenzene (25.0 g, 98.5 mmol) in THF (492 mL) and MeOH (40 mL, 984.7 mmol) at RT. Heat the mixture at 70° C. overnight. Quench the mixture with water (50 mL), dilute with Et2O (400 mL), wash once with saturated NH4Cl (300 mL) and back extract the aqueous with Et2O (200 mL). Dry the combined organic phase over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatograph, eluting with 5-10% ethylacetate/hexane to give 22.0 g (84%) of the title compound. GC m/z (79Br81Br) 266 [M]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH:25][C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OC)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 4-chloro-7.8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile (150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline (160 mg, 0.83 mmol) and pyridine hydrochloride (70 mg, 0.60 mmol) in 15 mL of 2-ethoxyethanol is heated at reflux for 25 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant bright orange solid is collected to provide 86 mg (38%) of 4-(2,4-dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 297° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[C:9]=1[OH:10])[C:5]#[N:6].[F:16][C:17]([F:44])([F:43])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=3)=[O:33])[CH2:26][CH2:25]2)[N:19]=1>>[C:5]([C:4]1[CH:7]=[C:8]([O:11][C:12]([F:13])([F:14])[F:15])[C:9]2[O:10][C:38]([C:37]3[CH:36]=[CH:35][C:34]([C:32]([NH:31][CH2:30][CH:27]4[CH2:28][CH2:29][N:24]([C:20]5[N:19]=[C:18]([C:17]([F:43])([F:44])[F:16])[CH:23]=[CH:22][N:21]=5)[CH2:25][CH2:26]4)=[O:33])=[CH:42][CH:41]=3)=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1cc(N)c(O)c(OC(F)(F)F)c1
Reactant: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Product: N#Cc1cc(OC(F)(F)F)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 3-amino-4-hydroxy-5-(trifluoromethoxy)benzonitrile and 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25) by a procedure analogous to that described in EXAMPLE 109. Mass spectrum (ESI) 591.1 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.47 (d, J=4.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 2H), 8.06 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.59 (s, 1H), 6.72 (d, J=4.6 Hz, 1H), 6.33 (t, J=5.9 Hz, 1H), 4.87 (d, J=13.5 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.93 (m, 2H), 2.00 (m, 1H), 1.90 (br d, J=11.6 Hz, 2H), 1.31 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.B([O-])([O-])O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[C:12]1([N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=4)=[CH:22][C:6]=3[CH:7]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A mixture of methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g), 4-(2-propoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (3 ml), ethanol (3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere overnight, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.26 g) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH:20]=[CH2:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1
Yield: 99 %

Procedure:
A mixture of ethyl 4-hydroxybenzoate (10.0 g, 60.2 mmol) and potassium carbonate (8.32 g, 60.2 mmol) in acetone (50 ml) was added with allyl bromide (7.22 ml, 66.2 mmol) and the mixture was refluxed for 18 h. After that potassium carbonate was filtered off and the solvent was evaporated under reduced pressure, thereby obtaining 12.3 g of a crude containing only the title compound (99% yield).