Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][S:4][C:3]=1[C:13]([O:15]C)=O.C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:13](=[O:15])[C:3]3[S:4][CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[NH:1][C:32]2=[O:33])=[CH:27][CH:26]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
Methyl 3-amino-4-phenylthiophene-2-carboxylate (400 mg, 1.71 mmol), triethylamine (0.04 ml, 0.43 mmol), and 4-chlorophenyl isocyanate (0.39 ml, 3.16 mmol) were dissolved in 1,4-dioxane (10 ml) in a reaction vessel. The mixture was heated with stirring at 90° C. for 3 days. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and filtered. The filtered solid was dissolved in a 10% sodium hydroxide/methanol (3 ml/12 ml) solution and refluxed with stirring at 100° C. overnight. After completion of the reaction, the reaction solution was cooled to room temperature, acidified with 3 N hydrochloric acid, and filtered to give 548 mg (1.54 mmol, 90% yield) of the title compound as a solid.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)=[O:2].CC(=CC)C.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].Cl>O.C(O)(C)(C)C>[C:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)([OH:22])=[O:2]
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1cccc2[nH]c(C=O)nc12
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc2[nH]c(C(=O)O)nc12
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a suspension of methyl 2-formyl-1H-benzimidazole-4-carboxylate (460 mg) in a mixture of water (3.2 ml) and t-butyl alcohol (12 ml) were added 2-methyl-2-butene (700 mg) and sodium dihydrogenphosphate (387 mg) in water bath. To the mixture was added portionwise sodium chlorite (901 mg) and stirred for 1 day at same temperature. The reaction mixture was cooled in an ice bath, adjusted to pH 4 with 1N hydrochloric acid and the precipitate was collected by vacuum filtration. The precipitate was washed with ethyl acetate and methanol to give methyl 2-carboxy-1H-benzimidazole-4-carboxylate (400 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[C:8](=[O:12])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c(=O)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 25 °C

Procedure:
The title compound of example 18.1 (32 g, 191 mmol) and potassium carbonate (132 g, 957 mmol) were stirred in dimethylformamide (350 mL) at room temperature. Diisopropylethylamine (10 mL, 57 mmol) was added via a syringe, followed by 2-(trimethylsilyl)ethoxymethyl chloride (44.0 mL, 249 mmol). The reaction was stirred at room temperature and diisopropylethylamine (56.6 mL, 325 mmol) was added over 5 hours via a pressure equalized addition funnel. The reaction was then stirred overnight at room temperature. When TLC analysis showed that the reaction was complete the reaction mixture was diluted with ethyl acetate and washed four times with water and once with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel in 5-40% ethyl acetate in hexanes to purify the desired product (80%, trace amount of o-alkylated product observed).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>CO>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:17]([CH2:16][CH2:14][OH:15])[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Reactant: NCCO
Solvent: CO
Product: O=C1c2ccc(Cl)nc2CN1CCO
Reaction time: 8 h

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (0.1 g, 0.45 mmol) and ethanolamine (0.11 mL, 1.82 mmol) were stirred in MeOH (10 mL) at room temperature overnight. Additional ethanolamine (0.11 mL, 1.82 mmol) was added and stirring continued for 8 hours. Additional ethanolamine (0.22 mL, 3.64 mmol) was then added and stirring continued for 3 days. The solvent was removed in vacuo and the residue purified by silica gel chromatography (0-5% MeOH/EtOAc) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([C:12](OC)=[O:13])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (13.9 g, 0.040 mol) in THF (100 mL) was added LiAlH4 (3.1 g, 0.080 mol) in portions at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was cooled to 0° C. and treated with water (3.1 g) and NaOH (10%, 3.1 mL) successively. The slurry was filtered off and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzo[d][1,3]dioxol-5-yl)methanol (7.2 g, 52%). 1H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2H), 4.57 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 21A (1.0 g, 4.21 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.3 mL, 6.3 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.47 mL, 4.21 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 324.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:37]([CH2:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:30][CH:31]=1)([OH:41])[CH:38]([CH3:39])[CH3:40])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (44.8 mL, 320 mmol) in THF (125 mL) was cooled to -15° C. n-Butyllithium (1.6M, 200 mL, 320 mmol) was added over 20 minutes. The solution was cooled to -40° C. and stirred for 20 minutes. Tert-butyl acetate (43 mL, 320 mmol) in THF (90 mL) was added over 30 minutes and the reaction stirred for 30 minutes at -40° C. 1-(4-Benzyloxy-phenyl)-4-methyl-pentan-3-one (21.0 g, 100 mmol) from Example F in THF (125 mL) was added over 10 minutes and the reaction was stirred at -40° C. for 5 minutes. Acetic acid (40 mL, 700 mmol) was added and the reaction warmed to room temperature. The reaction was stripped to dryness and the product was partitioned between ethyl acetate and saturated NH4Cl. The organic layer was washed with water, 5% NaHCO3 and brine. It was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)[C:22]([CH2:34][CH3:35])=[C:21]([O:36]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1>CO.[Pd]>[CH2:34]([C:22]1[C:21]([OH:36])=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[O:8])[NH:24][C:23]=1[C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1)[CH3:35]
Reactant: CCc1c(-c2ccc3cc[nH]c3c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCc1c(-c2ccc3cc[nH]c3c2)[nH]c(=O)c(C(=O)O)c1O
Reaction time: 2 h
Yield: 48.4 %

Procedure:
The product from Step 1 (104 mg, 0.18 mmol) was combined with 10% Pd/C (20 mg) in MeOH (3 mL). The mixture stirred under H2 (1 atm) for 2 h. The mixture was filtered over a 5 μm frit. The filtrate was concentrated, suspended in CH3CN. The solid was collected and dried to provide the title compound as a tan powder (26 mg, 56%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][NH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]1)[CH3:25]
Reactant: CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C)CC3)nc21

Procedure:
To a mixture containing 1.0 g of 5,8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.0 g of 65% sodium hydride, and 40 ml of dimethylformamide held at 60°C, was added 1.0 ml of ethyl iodide. The resulting mixture was heated in a steam bath for 2.5 hours. Dimethylformamide was distilled off in vacuo, the residue dissolved in 10 ml of water, and the resulting solution neutralized with acetic acid. The precipitate was collected and recrystallized from ethanol to yield 0.72 g of the product, m.p. 232° - 233°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]=[C:34](OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH:33]=[C:34]([C:3]2[CH:4]=[C:5]([O:11][CH:12]([CH3:13])[CH3:14])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1B1OC(C)(C)C(C)(C)O1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-methyl-4-nitro-5-isopropoxy-phenylboronic acid pinacol ester (2.04 g, 6.4 mmol) and 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g, 9.6 mmol) in 110 mL of DME/H2O (10:1 V/V) is added Pd(PPh3)4 (365 mg, 0.32 mmol) and Cs2CO3 (4.2 g, 12.8 mmol). The reaction mixture is heated under N2 at 80° C. overnight. After cooling to room temperature, the reaction is filtered through Celite and the filtrate is diluted with 100 mL of EtOAc, sequentially washed with H2O, brine, and finally concentrated in vacuo. The crude product is purified by silica gel flash chromatography (5%-15% EtOAc in Hexanes as eluent) to afford 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CD3OD, 400 Mz): 7.59 (s, 1H), 6.96 (s, 1H), 5.67 (broad s, 1H), 4.73 (m, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.37 (m, 2H), 2.25 (s, 3H), 1.50 (s, 9H), 1.33 (d, J=6.0 Hz, 6H).
Reaction SMILES: BrBr.C(O)(=O)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]#[N:16])=[CH:10][CH:9]=1.[S-:18][C:19]#[N:20].[K+]>O>[NH2:20][C:19]1[S:18][C:13]2[CH:12]=[C:11]([CH:14]([CH3:17])[C:15]#[N:16])[CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: N#C[S-]
Reactant: CC(C#N)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C#N)c1ccc2nc(N)sc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
27.4 g of bromine in 87.5 ml of 95% v/v acetic acid were added dropwise to a stirred mixture of 25 g of 2-(p-aminophenyl)propionitrile [British Pat. No. 1,198,212], 66.8 g of potassium thiocyanate and 300 ml of 95% v/v acetic acid at ambient temperature. The mixture was then stirred at 50° C. for a further 2 hours before being poured into 1.5 liters of water. The solution obtained was filtered through celite and sodium bicarbonate was then added to the filtrate until no further precipitation occurred. The precipitate was collected and crystallized from methanol/water to give 19.4 g (56%) of 2-amino-α-methyl benzothiazole-6-acetonitrile as yellow prisms melting at 165.1° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[CH:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:22][CH:21]([CH3:23])[CH2:20][CH:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (133 mg, 0.56 mmol), methyl 6-(1-hydroxy-3-methylbutyl)nicotinate (150 mg, 0.67 mmol) and triphenylphosphine (147 mg, 0.56 mmol) in tetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (113 mg, 0.56 mmol). The reaction was stirred at room temperature overnight. The reaction was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yloxy)butyl)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 9.19 (s, 1H), 8.25-8.23 (d, 1H), 7.63-7.61 (d, 2H), 7.58-7.56 (d, 2H), 7.49-7.47 (d, 1H), 7.44-7.43 (d, 2H), 6.93-6.90 (d, 2H), 5.40-5.37 (m, 1H), 3.93 (s, 3H), 2.00-1.93 (m, 2H), 1.75-1.70 (m, 1H), 1.03-0.96 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](N2CCCCC2)=[CH:7]1)[CH3:2].[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH2:33][CH2:34]Cl>>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH2:33][CH2:34][N:11]1[CH2:12][CH2:13][CH:14]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: CCOCCn1cc(N2CCCCC2)c2cccnc21
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Product: CCOCCn1cc(C2CCN(CCOc3cc(OC)ccc3C(=O)OC)CC2)c2cccnc21
Yield: 87.6 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 3 g (10.9 mmol) of 1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-b]pyridine and 4 g (16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard work-up and purification, 2.3 g (44% yield) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[F:14])[CH3:2].[OH-].[Na+]>[Na+].[Cl-].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([O:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[F:14])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1ccc(OC)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)[C@H](OCC)c1ccc(OC)cc1F
Reaction time: 96 h
Yield: 29.7 %

Procedure:
An emulsion of (RS)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid ethyl ester (1.11 g) in 0.1M NaCl, 3 mM Natriumphosphat buffer pH 7.0 (260 ml) was cooled to 4–5° C. and treated with lipase from Rhizomucor miehei. The reaction mixture was stirred for 4 days at 4–5° while maintaining the pH at 7 by gradual addition of 0.1N NaOH (totally 25.5 ml), then extracted with CH2Cl2 and then EtOAc. The organic layers were dried over Na2SO4, then concentrated to give (R)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid ethyl ester (330 mg, 98.9% ee).
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[C@@H:4]([C:14]([NH2:16])=[O:15])[NH:5][C@H](C1C=CC=CC=1)C)[CH3:2]>[Pd]>[CH2:1]([CH:3]([CH2:17][CH3:18])[C@@H:4]([C:14]([NH2:16])=[O:15])[NH2:5])[CH3:2]
Reactant: CCC(CC)[C@H](N[C@@H](C)c1ccccc1)C(N)=O
Agent: [Pd]
Product: CCC(CC)[C@H](N)C(N)=O
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of 3-ethyl-N2-[(S)-1-phenylethyl]-L-norvalinamide (2.6 g, 10.5 mmol) and 5% Pd/C. (800 mg) was shaken for 24 h in a Parr apparatus under 3 atm of H2. The mixture was filtered through a plug of Celite and the solvent was removed in vacuo to give 3-ethyl-L-norvalinamide as a white solid (1.4 g, 93%), which was used in the next reaction without further purification. Mass Spectrum (+ESI): 145 (M+H)+.
Reaction SMILES: CS(C)=O.O.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1.Br[CH2:17][CH2:18][CH2:19]Br>CCOCC.CC(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2([C:14]#[N:15])[CH2:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2cccc(Cl)c2)CCC1
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
According to the procedure of Butler and Pollatz (Butler, D. E. and J. C. Pollatz, J. Org. Chem. 36:1308 (1971), a reaction flask fitted with a mechanical stirrer, pressure equalizing addition funnel and thermometer was charged, under nitrogen, with 162 ml of DMSO; 17.62 g (0.44 mol) of 60% Nail/oil dispersion was added in portions over 5 minutes. A 20° C. water bath was applied while a solution of 24.5 g (0.162 mol) of (3-chlorophenyl)acetonitrile and 35.9 g (0.195 mol) of 1,3-dibromopropane in Et2O (100 ml) was added during 75 minutes with good stirring at such a rate that the reaction temperature was kept below 33° C. The mixture was stirred at 20° C. for 2 hours when it was cooled in an ice bath and treated cautiously with 8 ml of 2-propanol. The mixture was stirred at 10° C. for 15 minutes when it was treated cautiously with 120 ml of H20 at such a rate that the reaction temperature was kept below 15° C. After 15 minutes, the layers were separated and the aqueous layer was extracted with 4 portions of Et2O. The extracts were combined with the organic layer and this mixture was dried (MgSO4) and concentrated. A red oil was separated from the mineral oil and distilled to give 15.8 g (51%) of the titled product, b.p. 106°-110° C. (0.9 mm Hg).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[CH3:33][CH2:34][N:35](C(C)C)C(C)C.BrCC#N>CN1C(=O)CCC1>[C:34]([CH2:33][N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)#[N:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: N#CCBr
Solvent: CN1CCCC1=O
Product: N#CCN1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (85 mg, 0.18 mmol) was dissolved in 3 mL NMP with DIEA (95 μL, 0.54 mmol). To it was added bromoacetonitrile (36 μL, 0.54 mmol). The mixture was stirred at RT for 40 m and quenched with TFA. The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (75 mg). MS found for C26H26F2N6O as (M+H)+ 477.4. UV: λ=256 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.19-7.08 (4H, m), 5.82 (1H, s), 4.55 (2H, s), 4.43 (2H, s), 3.67 (2H, d, J=11.6 Hz), 3.23 (2H, t, J=12.0 Hz), 2.95 (1H, m), 2.19-2.03 (4H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (5.0 g, 16 mmol) in tetrahydrofuran (100 ml) was added dropwise 2.0 M solution (20 ml) of phenylmagnesium bromide in tetrahydrofuran at −78° C. The temperature of the reaction mixture was raised, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)(phenyl)methanone (3.4 g, yield 65%) as a yellow oil.