Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.NC1C=CC=CC=1NC(=O)C1C=CC(CN2CC3C(=CC(OC)=C(OC)C=3Br)C2=O)=CC=1.B(O)(O)[C:62]1[CH:67]=[N:66][CH:65]=[N:64][CH:63]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:62]3[CH:63]=[N:64][CH:65]=[N:66][CH:67]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1cncnc1
Agent: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cncnc3)C2=O)cc1
Yield: 68 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyrimidin-5-yl-5-boronic acid instead of phenyl boronic acid to obtain the title compound (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH2:34]O)[CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[CH3:38][NH:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:36])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH2:34][N:39]([CH3:40])[CH3:38])[CH:29]=4)=[CH:26][CH:27]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CNC
Reactant: O=C(c1ccc(-c2ccnc(CO)c2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Reaction time: 24 h
Yield: 44 %

Procedure:
In the same manner as in Referential Example 178, the corresponding brome compound was obtained using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine (300 mg). To the resulting compound, dimethylamine hydrochloride (469 mg) and potassium carbonate (795 mg) were added, followed by stirring for 24 hours. The solvent was then distilled off under reduced pressure. Ethyl acetate and water were added to the residue to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (3 to 5% methanol—dichloromethane). Hydrochloric acid in ethanol was added and the resulting mixture was concentrated. Ethyl acetate was added to the concentrate. The colorless powder thus obtained was collected by filtration and dried, whereby the title compound (74 mg, 21%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][O:5][CH2:4]1.C([O-])=O.[NH4+:13]>[Pd].O.CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH2:13])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC1COCCC1=O
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CO[C@@H]1COCC[C@@H]1N
Yield: 50.8 %

Procedure:
A slurry of 3-methoxy-tetrahydro-pyran-4-one (0.4 g, 3 mmol—described in WO03/093266(A1)), ammonium formate (1.9 g, 30 mmol), 10% palladium on charcoal (1 g) in water:MeOH (1:5, 6 ml) was stirred overnight after which time it was filtered through Hyflo, the mixture concentrated to remove the MeOH, the residue taken up in Et2O, dried (Na2SO4) and concentrated to afford the title product (0.2 g, 49%) as a yellow oil (contaminated by 10-20% of the trans isomer). 1H NMR (300 MHz, CDCl3) (cis isomer) δ 1.60-1.80 (2H, m), 2.95-3.00 (1H, m), 3.22-3.43 (5H, m). 3.82-3.95 (1H, m), 4.01-4.13 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2.[OH-].[K+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc(OC)c3)c2c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2nc(SC)nc3ccc(C(=O)O)c(N)c23)c1
Temperature: 70 °C

Procedure:
Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-quinazoline-6-carboxylate (example 25d, 490 mg) was dissolved in 15 ml 1,4-dioxane and a 2 M aqueous KOH solution (3 ml) was added. The mixture was heated at reflux for 5 h and at 70° C. for 76 h. The mixture was cooled to room temperature and a 0.5 M HCl-solution in water was added. The mixture was extracted with CH2Cl2 (2×50 ml), the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[Cl:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Reaction time: 1 h

Procedure:
50 ml of chloroform was added to 1.30 g of 4-(4-aminophenyl)-2,6-diphenylpyridine obtained in Reference Example 3, and a solution containing 0.32 ml of chloroacetyl chloride in 10 ml of chloroform was dropwise added thereto with stirring while ice cooling. Stirring was continued at room temperature for further one hour. The reaction solution was washed successively with an aqueous sodium bicarbonate saturated solutions, water and an aqueous sodium chloride saturated solution in this order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residues were recrystallized from ethyl acetate-n-hexane, whereby 1.33 g of 2-chloro-N-[4-(2,6-diphenyl-4-pyridyl)phenyl]acetamide was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(CN2CCc3ccccc32)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Indoline (12.70 g, 106.5 mmol) was dissolved in MeOH (120 ml), stirred at room temperature and treated with potassium carbonate (14.70 g, 106.5 mmol). Benzyl bromide (18.20 g, 106.5 mmol) was then added and the mixture heated to reflux for 4 hr. The solution was cooled and filtered to remove the carbonate. The filtered solution was washed with water (2×100 ml) and extracted into DCM (2×100 ml), dried (MgSO4) and reduced under vacuum to give the title compound (18.65 g, 83%) as a brown semisolid. δH (d6 DMSO) 7.27 (5H, br m), 6.98 (1H, t), 6.95 (1H, t), 6.50 (2H, d), 4.18 (2H, s), 3.17 (2H, t, J 7.3 Hz), 2.84 (2H, t, J 7.2 Hz); m/z (ES+, 70V) 210 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[N:5]1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36].[I-].[Na+]>O1CCCC1>[CH2:30]([S:27]([N:24]1[CH2:25][CH2:26][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH2:3][CH2:2][N:33]([CH2:34][CH2:35][OH:36])[CH3:32])[CH:8]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:22][CH2:23]1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCCl)c4)cc23)CC1
Reactant: CNCCO
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN(C)CCO)c4)cc23)CC1
Yield: 27.5 %

Procedure:
A solution of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.065 mmol), 2-(methylamino)ethanol (500 μL, 6.5 mmol) and sodium iodide (3 mg, 0.016 mmol) in tetrahydrofuran (1 mL) was reacted in a microwave for 2 h at 130° C. An aqueous work-up was performed on the resulting mixture. This was then purified by Gilson Preparatory HPLC to give 9 mg of the title compound (17%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:18])=[C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:27]=[O:28])[CH:11]=2)[N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8]1)([CH3:14])[CH3:13]
Reactant: Cc1cc2c(cc1Br)N(C(C)C)CCN2C(C)C
Reactant: COc1ccc(C=O)cc1B(O)O
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: O
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)N(C(C)C)CCN2C(C)C
Temperature: 25 °C

Procedure:
A mixture of 7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (469 mg, 1.51 mmol), 2-methoxy-5-formylphenylboronic acid (407 mg, 2.26 mmol), potassium carbonate (834 mg, 6.03 mmol) and water (2.5 mL) in anhydrous 1,2-dimethoxyethane (30 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium (0) (349 mg, 0.30 mmol). The reaction mixture was heated under reflux for 8.5 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), saturated aqueous NH4Cl (100 mL), saturated aqueous NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40S cartridge, eluting with 10% ethyl acetate/90% hexane. The title compound was isolated as bright yellow solid (315 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 82 %

Procedure:
(1R*,2S*,4R*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (916 mg) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and a 1N aqueous solution (3.3 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (3.3 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (712 mg) as a colorless solid.
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26]([F:29])([F:28])[F:27].[OH-:30].[Na+].OO>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:30])=[CH:22][CH:23]=2)=[CH:13][C:12]=1[C:26]([F:27])([F:28])[F:29]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
9-BBN (158 mL, 79 mmol) was added to a solution of 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxy)benzene (15.75 g, 52.7 mmol) in THF (160 mL) at 0° C. The resultant reaction mixture was stirred at room temperature overnight. To the mixture was added water (16 mL), 3M NaOH solution (80 mL) and 30% hydrogen peroxide (80 mL). It was stirred at 50° C. for 2 h, concentrated in vacuo, and diluted with ethyl acetate (200 mL). The organic phase was collected, washed with water (100 mL×2) & brine (100 mL), dried over sodium sulfate, and concentrated. Purification via a column chromatography then provided the title compound as a colorless oil (12.13 g, 71.7% yield). LCMS: rt=2.08 min, [M+H+]=299
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.ClC(OCC)=O.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1.Cl>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]([NH:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1)=[O:16]
Reactant: Nc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CC(=O)Nc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl) acetic acid (0.40 g, 1.8 mmol) dissolved in 5 mL of CH2Cl2 was cooled to 0°-5° C. Triethylamine (0.46 mL) and then ethyl chloroformate (0.30 mL) were each added dropwise. After stirring at 15 minutes at 0° C. to assure complete conversion of the acid to the intermediate mixed anhydride, a solution of 5-(4-aminobenzyl) thiazolidine-2,4-dione (0.71 g, 3.2 mmol; Chem. Pharm. Bull. Japan, v. 30, p. 3580, 1982) and 0.24 mL triethylamine in 15 mL were added dropwise as the temperature was maintained at 0°-5° C. The resulting solution was then stirred for 18 hours at room temperature, stripped of solvent and the residue distributedbetween 25 mL 2N HCl and 25 mL ethyl acetate. The aqueous layer was extracted with 25 mL additional ethyl acetate, and the organic layers combined, washed sequentially 1×30 mL water, 1×30 mL saturatedNaHCO3 and 1×30 mL saturated NaCl, dried (Na2SO4) andstripped to yield 0.84 g of solids. The latter was flash chromatographed onsilica gel using 1:2 ethyl acetate:hexane as eluant to yield 0.23 g of impure title product suitable for rechromatography and 0.20 g of purified title product.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[N:17][C:10]=2[N:9]([CH3:36])[C:8]1=[O:37])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:37])[N:9]([CH3:36])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:26])[CH3:27])=[CH:34][CH:33]=1
Reactant: CC(C)c1ccccc1Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a solution of 3-(5-(4-fluorobenzyl)-6-(2-isopropylphenoxy)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (68 mg, 0.135 mmol) in THF (1 ml) and water (1 mL) was added LiOH.H2O (14 mg, 0.33 mmol). The reaction was stirred at RT for 15 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenoxy)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 85.4% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.23 (s, 1H), 7.38-7.35 (m, 1H), 7.23-7.18 (m, 2H), 7.14-7.10 (m, 2H), 7.03 (t, J=8.8 Hz, 2H), 6.61-6.58 (m, 1H), 4.71 (s, 2H), 4.49 (t, J=5.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.56 (s, 3H), 3.49-3.43 (m, 2H), 3.11-3.07 (m, 1H), 1.75-1.71 (m, 2H), 1.12 (d, J=6.4 Hz, 6H). LCMS: MH+ 478 and TR=3.356 min.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][NH:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:6]([N:5]1[CH2:2][CH2:1][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:4]1)[CH3:7]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCc2c([nH]c3ccccc23)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethyl iodide (2.4 ml) was added to a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (5.17 g) and sodium hydrogencarbonate (3.0 g) in 50 ml of acetonitrile and the solution was stirred at 70° C. over a bath for 3 hrs. After removal of the solvent by evaporation, water (60 ml) was added and the solution was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. Purification of the crude product by silica gel column chromatography and crystallization from ethyl acetate of the eluates with methanol/chloroform (1/4) gave 1.5 g of 2-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]1.Cl>CO>[ClH:8].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:18]1[CH2:23][CH2:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]1
Reactant: COC(=O)C1=CCCNC1
Reactant: ClCc1ccccc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(Cc2ccccc2Cl)C1
Reaction time: 24 h
Yield: 98.1 %

Procedure:
Triethylamine (2.2 g.) and 2-chlorobenzyl chloride (1.63 g.) were added to a solution of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.63 g.) in methanol (10 ml.). The solution obtained was kept for 24 hours at 20°-25° C. and then evaporated. Water (20 ml.) and 10% w/v sodium carbonate solution were then added to the residue to give a mixture of pH 10. This mixture was extracted with ether (2×20 ml.). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residual oil was dissolved in acetone to give a solution which was treated with a slight excess of ethereal hydrogen chloride. The solid which precipitated was collected by filtration and washed with acetone to give methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.5 g.) m.p. 171°-175° C.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[Sn](Cl)(Cl)Cl.[CH3:17][O:18]C(Cl)Cl>ClCCl>[CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(2,2-Dimethylpropyl)benzene (9.33 g, 63 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. on an ice bath. With vigorous stirring, SnCl4 (28.66 g, 110 mmol) was added all at once via syringe, followed by dropwise addition of dichloromethyl methyl ether (7.24 g, 63 mmol) over 10 min. After 20 min, the ice bath was removed, and the mixture was quenched by the addition of ice-water (100 mL). The aqueous layer was discarded and the organic phase was washed with water (3×25 mL), 3 N hydrochloric acid (3×25 mL), and aqueous saturated sodium chloride (2×25 mL). The organic phase was then treated with activated carbon, dried (magnesium sulphate), filtered and concentrated in vacuo. This afforded the title compound. Yield 7.49 g (62%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:31])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([N:18](C)C)=O)=[C:14]([C:23]2[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=2[CH3:28])[CH:13]=1.CN(C[N:36]1[C:40]2=[N:41][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([N:51]([CH3:53])[CH3:52])[CH2:47][CH2:46]3)=[CH:43][CH:44]=[C:39]2[N:38]=[CH:37]1)C>>[CH3:52][N:51]([CH3:53])[CH:48]1[CH2:49][CH2:50][N:45]([C:42]2[N:41]=[C:40]3[NH:36][C:37]([C:11]([C:12]4[CH:22]=[CH:21][C:15]([C:16]#[N:18])=[C:14]([C:23]5[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=5[CH3:28])[CH:13]=4)=[O:31])=[N:38][C:39]3=[CH:44][CH:43]=2)[CH2:46][CH2:47]1
Reactant: COC(=O)c1ccc(C(=O)N(C)C)c(-c2c(C)nn(C)c2C)c1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using N,N-Dimethyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-terephthalamic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 529.3036 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>ClCCl>[NH3:1].[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH:3]=2)([CH3:20])[CH2:9][CH2:10]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CCC(C)(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CCC(C)(c2cccc(NS(C)(=O)=O)c2)CC1
Product: N
Temperature: 25 °C
Reaction time: 16 h
Yield: 136.6 %

Procedure:
To 4-(3-aminophenyl)-N-hexyl-4-methylpiperidine (Preparation 56, 70.0 mg, 0.27 mmol) in dichloromethane (3 ml) was added methanesulfonyl chloride (61 mg, 0.53 mmol) in dichloromethane (0.5 ml) and pyridine (42 mg, 0.53 mmol) in dichloromethane (0.5 ml) at room temperature. The solution was stirred at room temperature for 16 h, then it was concentrated in vacuo to give the crude product. This was purified by silica column chromatography eluting with a gradient of ethyl acetate:hexane:0.88 ammonia (90:10:1 to 98:2:1) to give the title compound as a colourless oil (65 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([O-])(=[O:14])[CH3:13].[Na+].O>C(O)(=O)C>[C:12]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCc1ccc(C(=O)O)cc1
Yield: 72.5 %

Procedure:
A mixture of 4-aminomethylbenzoic acid (Aldrich, 1.51 g, 0.01 mol) and anhydrous sodium acetate (1.5 g, 0.018 mol) in glacial acetic acid (5 mL) was heated at reflux for 18 h. On cooling, the mixture was poured into cold water (50 mL). The precipitate was separated by filtration and washed several times with cold water. The cake was recrystallized from water to give 1.4 g (72.5%) of the title compound as a white powder, mp 195° C.