Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:13](OC(=O)C)(=[O:15])[CH3:14]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:13](=[O:15])[CH3:14])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C

Procedure:
5-Chloro-2-methyl-4-nitroaniline was treated with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in CH2Cl2 to provide N-(5-chloro-2-methyl-4-nitrophenyl)acetamide, which was reacted with vinyl magnesium bromide at −40° C. to room temperature to give N-(7-chloro-4-methyl-1H-indol-5-yl)acetamide. Deprotection of the acetyl group by heating in an aqueous HCl solution at the reflux temperature provided 5-amino-7-chloro-4-methylindole.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21](=[O:22])[N:23]([CH3:25])[CH3:24])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)CBr
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCC(=O)N(C)C)c12
Reaction time: 8 h
Yield: 90 %

Procedure:
To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), α-bromo-N,N-dimethylacetamide (1.1 eq.) potassium carbonate (5 equiv.), and 10 ml of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 ml) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 ml), washed with brine (20 ml), dried over MgSO4. Filtration and evaporation of the solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[C:7]3[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCNC(=O)c2cccc(N)c21
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCNC3=O)ncc1Cl
Temperature: 110 °C
Yield: 6.3 %

Procedure:
9-Amino-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (40 mg, 0.21 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (68 mg, 0.23 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (57 μL) was added, and the resulting mixture was heated to 110° C. in the microwave for 20 min. The resulting mixture was filtered, washed with CH2Cl2 and acetone. The ppt was dissolved in H2O, neutralized with NaHCO3, and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-10% MeOH in CH2Cl2) to obtain 2-[5-Chloro-2-(1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (6 mg, 5%). mp 282-284° C.; LCMS: m/z=452.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.30 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.26 (m, 1H), 7.06 (m, 1H), 6.88 (m, 1H), 6.69 (m, 1H), 6.21 (m, 1H), 4.43 (m, 1H), 3.55 (m, 2H), 3.42 (m, 2H), 3.18 (s, 3H), 3.02 (m, 3H).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][C:8]#[N:9].[C:10]1([C@H:20]([NH:22][C@H:23]2[CH2:27][CH2:26][C@@H:25]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[CH2:24]2)[CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:10]1([C@H:20]([NH:22][C@H:23]2[CH2:27][CH2:26][C@@H:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:7][C:8]#[N:9])=[CH:32][CH:33]=3)[CH2:24]2)[CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC#N)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 120 h
Yield: 68.7 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (3 mL) and chloroacetonitrile (0.11 mL, 1.8 mmol) were added to 4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenol (500 mg, 1.5 mmol) obtained in Example 10 (Step 3) and potassium carbonate (250 mg, 1.8 mmol), and the mixture was stirred for 5 days at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (NH silica; ethyl acetate/hexane:20/80-50/50) to give the title compound (382 mg, 68%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[CH:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:3]1
Reactant: Cn1ccc(=O)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
1-Methyl-4-quinolone (2 g) was heated with chlorosulphonic acid (5 ml) at 125° for 2.5 hours. The reaction mixture was cooled to room temperature and then carefully poured onto crushed ice (300 ml). The precipitated solid was collected by filtration and then dried to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. 313°-315°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ncnc(Cl)c1-c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ncnc(Cl)c2-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
To a mixture of 4,6-dichloro-5-phenylpyrimidine (675 mg, 3.0 mmol), 4-chlorophenylboronic acid (704 mg, 4.5 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) in toluene (10 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 3 mL, 6 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 5 h, after which time analysis by HPLC/MS indicated that the the reaction was complete. After cooling the reaction mixture to room temperature, water (15 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain 571 mg of the title compound as a white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =301.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]3[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1.[Sn](Cl)Cl>CO.CCOC(C)=O>[NH2:23][C:22]1[C:17]([NH:16][C@@H:13]2[CH2:12][CH2:11][C@H:10]([C:8]([N:7]3[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][C@H:2]3[CH3:1])=[O:9])[CH2:15][CH2:14]2)=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:20][CH:21]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-tert-butyl 3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate (0.2 g, 0.348 mmol) in MeOH (3.48 mL) was added tin(II) chloride (0.264 g, 1.392 mmol). The resulting suspension was stirred at 80° C. for 2 hours. The mixture was cooled to RT, diluted with EtOAc and washed with 1N aqueous NaOH. The organic layer was collected, dried over sodium sulfate and concentrated to afford (R)-tert-butyl 4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate as a tan solid (190 mg, 100%). MS m/z=545.4 [M+H]. Calc'd for C29H48N6O4: 544.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>ClCCl.C(N(CC)CC)C>[CH3:12][S:13]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(benzyloxy)ethanol in 320 ml of dichloromethane, 35 ml of triethylamine and 19.5 ml of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was added with ice water and then extracted with dichloromethane. After the extract was washed with a saturated solution of sodium chloride, the extract was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, whereby 49 g of 2-(benzyloxy)ethyl methanesulfonate were obtained (yield: stoichiometric).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][O:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][CH3:23])[C:16]=2[C:15]2[CH:14]=[C:13]([OH:28])[CH:12]=[CH:11][C:10]=2[N:9]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>CN(C=O)C>[N:29]1([C:35]([O:28][C:13]2[CH:12]=[CH:11][C:10]3[N:9]=[C:8]([NH2:7])[C:17]4[N:18]=[C:19]([CH2:24][O:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][CH3:23])[C:16]=4[C:15]=3[CH:14]=2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC(=O)N4CCOCC4)cc3c21
Yield: 88.3 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol, prepared in Parts A and B of Example 566) in anhydrous DMF (30 mL). The reaction was stirred for ten minutes, and 4-morpholinecarbonyl chloride (275 mg, 1.83 g) was then added. The reaction was stirred overnight at ambient temperature and poured into deionized water (300 mL). The resulting mixture was stirred for one hour and then extracted with chloroform (3×100 mL). The combined organic fractions were concentrated under reduced pressure, and the resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-20% CMA in chloroform). The resulting solid was recrystallized from acetonitrile and dried under vacuum to yield 606 mg of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl morpholine-4-carboxylate as a white, crystalline solid, mp 193-196° C. Anal. calcd for C21H27N5O4: C, 61.00; H, 6.58; N, 16.94. Found: C, 61.01; H, 6.51; N, 17.21.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:2].[CH2:18]=CCCCC.CCCCC=CCCCC.C(OCCCCCCCCC=C)(=O)C>>[C:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:2])[CH3:18]
Reactant: C=CCCCC
Reactant: CCCCC=CCCCCCCCCOC=O
Agent: C=CCCCCCCCCOC(C)=O
Agent: CCCCC=CCCCC
Product: CCCCC=CCCCCCCCCOC(C)=O

Procedure:
A process for preparing 9-tetradecenyl formate by reacting 1-hexene or 5-decene with 9-decenyl acetate in accordance with the method of claim 7 to obtain 9-tetradecenyl acetate, then reacting the acetate with water to obtain the corresponding alcohol and then reacting the alcohol with formic acid to obtain the formate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[NH:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[N:31]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 28 h
Yield: 43.4 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (100 mg) and 2-chloromethylpyridine hydrochloride (29 mg) in N,N-dimethylformamide (2 ml) was added potassium carbonate (93 mg) at ambient temperature, and the mixture was stirred for 28 hours at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=12:1, V/V; chloroform:methanol=12:1, V/V) to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-pyridylmethyl)-1H-benzimidazole (50 mg) as an amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21]C)=[O:20])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([OH:21])=[O:20])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(CN(C(=O)OC(C)(C)C)C2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of methyl 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)benzoate (550 mg, 1.57 mmol) in MeOH (5 mL) was added aqueous of NaOH (2.0 mL, 40% w/w). The mixture was stirred at 25° C. for 4 h. The reaction solution was concentrated, and the residue was dissolved in water and adjusted pH to 5-6 with 2N of HCl and extracted with EA. The organic layer was concentrated to give the desired product (300 mg, Yield 57%). LCMS (m/z): 336.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:20]4[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]4)[N:18]=[CH:19][C:14]3=[C:13]([N:27]3[CH2:33][CH:32]4[O:34][CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[N:12]=2)=[CH:7][CH:6]=1.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:35])[NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:20]4[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]4)[N:18]=[CH:19][C:14]3=[C:13]([N:27]3[CH2:33][CH:32]4[O:34][CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[N:12]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(O)CC4)c3n2)cc1
Reaction time: 1 h

Procedure:
To a solution of methyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate (63 mg) (0.13 mmol) in THF (2.0 mL) was added an excess of sodium borohydride. The mixture was stirred for 1 hr. at 50 C. The reaction was then cooled and quenched with water and extracted three times with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo. The resulting oil was triturated with diethyl ether to give a white solid. The solid was filtered and washed the diethyl ether to give (44 mg) MS m/z=479.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:17]3)=[O:15])=[C:8]([CH3:10])[N:9]=2)[CH2:2]1.Cl[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C.O>CN(C)C=O.CC#N>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH:18]2[CH2:17][N:16]([C:14]([C:13]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:11]([C:7]4[NH:6][C:5]([CH:3]5[CH2:4][N:1]([C:33]([O:35][CH3:36])=[O:34])[CH2:2]5)=[N:9][C:8]=4[CH3:10])[CH:12]=3)=[O:15])[CH2:19]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CNC2)nc1C
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CC(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 189.2, 100 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL). Methyl chloroformate (33 μL, 0.42 mmol) and triethylamine (34 μL, 0.25 mmol) were added to the reaction. The reaction mixture was stirred for 2 h at room temperature, then was quenched with 10 mL of water. The aqueous phase was extracted with 3×5 mL of ethyl acetate. The combined organic layers were washed with 3×3 mL of brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water with 50 mmol NH4HCO3 and MeCN (33.0% MeCN up to 45.0% in 7 min, up to 100.0% in 2 min, down to 33.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 21.5 mg (19%) of the title compound as a white solid. m/z (ES+) 470 (M+H)+.
Reaction SMILES: F[C:2]1C=CC(N2C(C(O)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([O-:41])=[O:40])=[CH:37][N:36]=[C:35]2[NH:42][CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=2[F:52])=[CH:30][CH:29]=1>C1COCC1.CO>[CH3:2][C:37]1[N:36]=[C:35]([NH:42][CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=2[F:52])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:38]=1[C:39]([OH:41])=[O:40]
Reactant: O=C([O-])c1cnc(NCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(NCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(=O)O

Procedure:
Methyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylic acid (69) was prepared in a similar manner as that described for the synthesis of compound 11 using 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylate (68) (60 mg, 0.158 mmol), 1NLiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.[BH4-].[Na+]>CO>[C:24]1([CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][CH2:1][C:3]3[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:18][CH2:19]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 8.2 g (0.0398 mol) of N-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide and 7.6 g (0.04 mol) of 4-amino-1-(phenylmethyl)piperidine in 80 ml of methanol was combined in batches with a total of 1.7 g (0.045 mol) of sodium borohydride and refluxed for a total of 24 hours. The solvent was removed in vacuo, the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and freed from solvent. The residue was triturated with diisopropylether and suction filtered. 6.0 g (39.6% of theory) of colourless crystals of melting point 138° C. were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7](CC2C=CC([N+]([O-])=O)=CC=2)[C:6]([O:18][CH3:19])=[N:5][CH:4]=1.[C:20]([C:23]1[CH:47]=[CH:46][CH:45]=[CH:44][C:24]=1[C:25]([NH:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32]N2C(CO)=CN=C2OC)=[CH:30][CH:29]=1)=[O:26])([OH:22])=[O:21]>>[C:20]([C:23]1[CH:47]=[CH:46][CH:45]=[CH:44][C:24]=1[C:25]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][C:4]2[N:5]=[C:6]([O:18][CH3:19])[NH:7][C:3]=2[CH2:2][OH:1])=[CH:42][CH:43]=1)=[O:26])([OH:22])=[O:21]
Reactant: COc1ncc(CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Reactant: COc1ncc(CO)n1Cc1ccc([N+](=O)[O-])cc1
Product: COc1nc(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2)c(CO)[nH]1

Procedure:
By repeating Example 72, Parts C and D, but substituting 5-hydroxymethyl-2-methoxy-1-(4-nitrobenzyl)imidazole as starting material in Part C, the compound 1-[4-(2-carboxybenzamido)benzyl]-5-hydroxymethyl-2-methoxyimidazole can be prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:40]1([CH2:46][NH2:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:46][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: NCC1CCCCC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC2CCCCC2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and cyclohexanemethylamine.