Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CO[C@@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10.2 mg, 35%), MS (ISP) m/z=418.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and (S)-2-methoxypropanoic acid
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>>[CH3:18][NH:19][CH2:1][C:3]1([CH3:17])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: Cn1c2c(c3ccccc31)SCCC2(C)C=O
Reactant: CN
Product: CNCC1(C)CCSc2c1n(C)c1ccccc21
Yield: 97.4 %

Procedure:
In the same procedure as described in Example 2, 4-formyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole is allowed to react with methylamine to give the title compound: Yield 97.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:25]3[C:24]([Cl:23])=[CH:29][C:28]([Cl:30])=[CH:27][N:26]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=495.1 [M+H]+and 497.2 [M+2+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CO.[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]>COCCOC>[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH:32]([C:17]#[N:18])[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(C#N)CCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (30.4 mL, 1 M in tetrahydrofuran, 30.4 mmol) was added drop wise to a stirred and cooled (0° C.) solution of tosylmethyl isocyanide (4.74 g, 24.27 mmol) in dry DME (40 mL). After ten minutes, dry methanol (0.98 mL, 24.28 mmol) was added and followed by a solution of the product of Example 5B (3.11 g, 12.14 mmol) in DME (10 mL). The resulting solution was allowed to warm to room temperature and then heated (45° C.) for thirty minutes. After cooling, the reaction mixture was partitioned with diethyl ether and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 2-10% diethyl ether in hexanes to give the title compound as an oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CCCCCn1/c(=N/N=Cc2ccccc2)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of (2E)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (104 mg, 44 μmol), benzaldehyde (44.7 μl, 44 μmol) in ethanol (10 ml) was stirred at 70° C. for 3 hours. The reaction solution was concentrated in vacuo to give the desired product. LCMS calculated for C17H21N6O (M+H): 325.2. found: 325.2.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14]>N1C=CC=CC=1>[C:1]([O:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CO
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)COC(=O)CCc1ccccc1

Procedure:
33.7 g (0.2 mole) of hydrocinnamoyl chloride was added to a stirred solution of 18 g (0.2 mole) of ethyl glycolate in 20 ml of pyridine. The precipitated pyridine hydrochloride was filtered, washed with benzene, and discarded. The benzene solution of carboethoxymethyl hydrocinnamate was water washed, dried over sodium sulfate, and the solvent stripped off using a rotary evaporator. The yield of product was essentially quantitative. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It had nD30 1.4900 and d430 1.0919.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]2[NH:22][C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:14]=2[N:15]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]2[NH:22][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:14]=2[N:15]=1
Reactant: COc1ccc(-c2ncc3[nH]c4c(c3n2)CCCC4)c(F)c1
Agent: [Pd]
Product: COc1ccc(-c2ncc3[nH]c4ccccc4c3n2)c(F)c1
Temperature: 230 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-fluoro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]pyrimidine (300 mg) and palladium black (300 mg) in 3 mL of mesityline was stirred at 230° C. in a sealed tube for 1 h. The reaction mixture was filtered and the residue subjected to flash chromatography on silica gel with 30% ethyl acetate/hexane as the eluent. In this manner 2-(2-Fluoro-4-methoxyphenyl)-5H-indolo[3,2-d]pyrimidine (Compound 1), m.p. 202°-203° C. was obtained as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH:11][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@@H]1C[C@H](N)CCN1CC1CCCCC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CCN1CC1CCCCC1

Procedure:
(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]piperidine-2-carboxylic acid methyl ester was prepared from (2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>[Pd].C(O)C>[F:18][C:2]([F:17])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 75 °C
Reaction time: 8.5 h
Yield: 17.6 %

Procedure:
10% palladium on carbon (64 mg) was added to an ethanol solution (13 ml) of 4-(4-trifluoromethoxybenzyl)piperidine (1.28 g) and 1,4-cyclohexanedione (1.19 g), and the mixture was stirred at 70 to 80° C. for 8.5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After being dissolved in ethyl acetate, the residue was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→6:4) to afford the title compound as a black oil (305 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[NH:11][C@H:12]1[CH2:15][C@H:14]([NH:16][C:17]2[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=2)[CH2:13]1.C(N(CC)CC)C.[CH:31]1([C:34](Cl)=O)[CH2:33][CH2:32]1>O1CCCC1>[CH:31]1([C:34]2[N:16]([C@H:14]3[CH2:15][C@H:12]([NH:11][C:2]4[N:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:13]3)[C:17]3[C:22]([N:23]=2)=[CH:21][N:20]=[CH:19][N:18]=3)[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cncnc1N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc2nc(N[C@H]3C[C@H](n4c(C5CC5)nc5cncnc54)C3)ncc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N4-(Trans-3-(quinazolin-2-ylamino)cyclobutyl)pyrimidine-4,5-diamine (0.045 g, 0.146 mmol) and triethylamine (0.50 ml, 3.59 mmol) were dissolved in dry tetrahydrofuran (10 mL) and treated with cyclopropanecarbonyl chloride (0.050 ml, 0.546 mmol). The reaction was stirred at room temperature for 14 hours. The mixture was evaporated to dryness under reduced pressure and the residue dissolved in acetic acid (20 mL). It was sealed in a microwave vessel and heated at 125° C. for 20 minutes then to 145° C. for 1 hour. The solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-4% methanol in dichloromethane gradient) gave the desired N-(trans-3-(8-cyclopropyl-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (0.025 g, 0.070 mmol, 47.8% yield). M+1: 358.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15-1.24 (m, 2 H) 1.24-1.33 (m, 2 H) 2.02-2.12 (m, 1 H) 2.69-2.80 (m, 2 H) 3.68-3.81 (m, 2 H) 4.89 (m, J=7.70, 7.70, 4.10 Hz, 1 H) 5.54 (quin, J=8.36 Hz, 1 H) 5.92 (br. s, 1 H) 7.23-7.35 (m, 1 H) 7.59-7.67 (m, 1 H) 7.67-7.76 (m, 2 H) 8.95 (s, 1 H) 8.91 (s, 1 H) 9.03 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25].CCN=C=NCCCN(C)C>CO>[NH2:25][C:24]1[N:23]([CH2:26][CH2:27][CH3:28])[C:22](=[O:29])[N:21]([CH2:30][CH2:31][CH3:32])[C:20](=[O:33])[C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c(=O)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-benzyloxy-benzoic acid (0.868 g, 3.8 mmol), 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione (1.0 g, 3.8 mmol), methanol (15 ml), EDCI (0.95 g, 4.9 mmol), was stirred for 20 hours at room temperature. The reaction mixture was concentrated and water was added to obtain the intermediate N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide. It was dissolved in methanol (32 ml) and added 10% NaOH (24 ml). The mixture was heated at 80-90° C. for 3 hours. The mixture was cooled and solvent was removed. The residue was dissolved in water (20 ml) acidified with dil HCl to provide 8-(4-benzyloxy-phenyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (1.2 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]2[O:20][CH:9]2[CH2:10][CH2:11]1)(=[O:4])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N1CCC=CCC1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2OC2CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
11.7 g (0.067 mol) of 1-methanesulphonyl-2,3,6,7-tetrahydro-1H-azepine are dissolved in 230 ml of methylene chloride and the solution is treated with 23 g (0.13 mol) of m-chloro-perbenzoic acid in portions. A white suspension soon forms and this is stirred for a further 24 hours at room temperature. The m-chlorobenzoic acid which has precipitated is filtered off and the filtrate is washed with a saturated aqueous solution of sodium carbonate, then with aqueous iron-II sulphate solution, then with 0.1 N sodium hydroxide solution and finally with water and dried over sodium sulphate. On concentrating the solution under a water pump vacuum, while crystals of 1-methanesulphonyl-hexahydro-4,5-epoxy-1H-azepine are obtained and these are isolated by filtration; melting point 133°-134°.
Reaction SMILES: C(OCC1ON=C(CO[NH:13][C:14]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18](C3CCCCC3NS(C)(=O)=O)[CH:17]2C2C=CC(Cl)=CC=2Cl)=[O:15])N=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[O:26]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]([C:14]([NH2:13])=[O:15])[CH2:17][NH:18]1
Reactant: CC(=O)OCc1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)C1CNC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Oc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)c(Br)c1
Yield: 61 %

Procedure:
A mixture of 0.65 gm (3.43 mMol) 3-bromo-4-fluorophenol, 0.60 mL (6.86 mMol) allyl bromide, and 0.71 gm (5.15 mMol) potassium carbonate in 6 mL acetone was stirred at reflux for 13 hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 61% of the desired compound.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]1)(=O)=O.[OH:76][C:77]1[CH:84]=[C:83]([O:85][CH3:86])[CH:82]=[CH:81][C:78]=1[CH:79]=[O:80].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:86][O:85][C:83]1[CH:82]=[CH:81][C:78]([CH:79]=[O:80])=[C:77]([O:76][CH2:5][CH:6]2[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]2)[CH:84]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2cc(OC)ccc2C=O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol), 2-hydroxy-4-methoxybenzaldehyde (16.9 g, 0.11 mol) and potassium carbonate (25.6 g, 0.18 mol) were suspended in DMF (700 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (700 ml), washed twice with 0.5N hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with pure water (300 ml). The solvent was evaporated, and the residue was precipitated with methanol (700 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (73.56 g, 69.8 mmol, 97%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1.CN([CH:22]=[O:23])C.O>C1COCC1>[Br:9][C:10]1[C:11]([CH:22]=[O:23])=[C:12]([F:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78° C. for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78° C. for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)C(C)C.CN>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][NH:46][CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy) methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.2 mL) and DIPEA (17 μl, 0.10 mmol) was added methylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were contaminated with an impurity; the crude material was re-purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylamino) acetamide (Example 13) as a light brown solid (6 mg, 12%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.32 (3H, s), 2.39 (3H, s), 3.28 (2H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1H, m), 8.37-8.30 (3H, m), 8.59 (1H, s), 8.80 (1H, s).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3[CH:44]=C(C)C=CC=3)=[N:39][O:40][C:41]=2C)=NC=1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:39][CH:38]2[CH2:43][CH2:44][O:40][CH2:41][CH2:37]2)=[O:25])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(C)cc3)noc2C)nc1
Product: Cc1ccc(-c2noc(C)c2COc2ccc(C(=O)NC3CCOCC3)cn2)cc1
Yield: 84 %

Procedure:
As described for example 249f, 6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (250 mg, 0.73 mmol) was converted, instead of 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (260 mg, 84%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:14]2[C:10](=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=32)[S:9][N:8]=1)=[O:6].Cl>O1CCOCC1>[C:5]([C:7]1[N:14]2[C:10](=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=32)[S:9][N:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1nsc2nc3ccccc3n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a 6 mL solution of 1N NaOH, 3-(methoxycarbonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (1.0 g, 4.3 mmole) in 6 mL of dioxane, was added. The reaction mixture was stirred at room temperature until completion. The resulting mixture was then acidified with 3N HCl to pH ~2.0, and stirred at room temperature for an additional 0.5 h. The solid was filtered, washed with water, and dried under vacuum at 60° C. for 24 h to yield 0.74 g (78%) of the title compound as a colourless solid: mp 184-185° C. (dec); 1H NMR (DMSO-d6)δ 13.79 (br s, 1H), 8.59 (d, 1H) 7.78 (d, 1H), 7.51 (t, 1H), 7.40 (t, 1H); IR (KBr)ν 3435, 1705 cm-1 ; MS m/z 193 (M+ -OH), 175 (M- --CO2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[NH4+].[Cl-].O.[CH2:18]1COCC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](=[O:13])[CH3:18])=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
At −78° C., to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.45 g, 10 mmol) in dry THF (50 mL) was added MeMgCl THF solution (3.0 M, 4 mL, 12 mmol) slowly and the reaction mixture was allowed to stir at −78° C. for 45 min. Sat. aq. NH4Cl (2 mL) and water (4 mL) were added. The aqueous layer was extracted with EtOAc (2×10 mL), and the combined extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica chromatography eluting with EtOAc/hexanes (1/9) to give to give 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (675 mg, 30% yield). LC-MS m/z 225 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 2.65 (s, 3H).