Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>O1CCOCC1>[ClH:23].[CH2:1]([O:8][N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1=[NH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C1CCCCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyl benzyloxy(4-cyanobutyl)carbamate was dissolved in a solution of 4 M HCl in 1,4-dioxane and the mixture was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate and diethyl ether. A solid formed which was washed with diethyl ether, filtered and dried under high vacuum to give 1-(benzyloxy)piperidin-2-imine hydrochloride as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]=[O:12].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=1)[CH3:10]
Reactant: CN(C)CCc1ccco1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCc1ccc(CO)o1

Procedure:
N,N-Dimethyl-2-furanethanamine (9.8 g), 30% aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated at 70° for 5 hr. The reaction was cooled, basified with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil b.p. 90°-100° (0.5 mm). Found: C, 64.0; H, 8.9; N, 8.0. C9H15NO2 requires: C, 63.9; H, 8.9; N, 8.2%.
Reaction SMILES: [Na].C(OC(C[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=O)C.[CH:17]1([N:22]2[C:26]([NH2:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]([CH2:31][CH3:32])=[N:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.O.[CH2:34](O)[CH3:35]>C(O)(=O)C>[CH:17]1([N:22]2[C:26]3=[N:27][C:34]([CH2:35][C:9]4[NH:8][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=4)=[N:30][C:28](=[O:29])[C:25]3=[C:24]([CH2:31][CH3:32])[NH:23]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)Cn1cnc2ccccc21
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCO
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3nc4ccccc4[nH]3)nc(=O)c1-2
Yield: 75 %

Procedure:
Sodium (338 mg) was dissolved in ethanol (30 mL) and 1-(ethoxycarbonylmethyl)benzimidazole (3.0 g, 14.7 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.6 g) were added. The reaction mixture was refluxed overnight, the solvent was stripped and the residue was treated with water and acetic acid. A precipitate formed which was collected by filtration and washed with water to afford 1.96 g (75%) of 1-cyclopentyl-3-ethyl-6-[1-benzimidazolylmethyl]pyrazolo-[3,4-d]pyrimidin-4-one, m.p. 256-259° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-6-methyl-pyrimidine (3.61 g, 22.15 mmol), triethylamine (7.02 mL, 50.34 mmol) in DMF (15 mL) was slowly added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 5.00 g, 20.13 mmol). The resulting reaction solution was stirred at rt for 2 h, then diluted with ethyl acetate (400 mL), washed with water (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20–80% ethyl acetate in hexane) to give 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):375.36
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH2:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28])[CH3:24]>>[CH2:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)[CH3:24]
Reactant: CCc1ccccc1CN
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CCc1ccccc1CNCCn1cnc(-c2cc(C(=O)O)ccn2)c1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-ethylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.11 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.6 Hz), 2.92 (2H, t, J=6.1 Hz), 3.71 (2H, s), 4.09 (2H, t, J=5.9 Hz), 7.11-7.16 (3H, m&s), 7.27 (1H, d, J=7.6 Hz), 7.44 (1H, dd, J=6.2 and 1.4 Hz), 7.69 (1H, s), 7.71 (1H, s), 8.21 (1H, s), 8.36 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[CH2:32][NH:31][CH2:30][CH2:29]2>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[C:10]([N:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][C:35]([O:36][CH3:37])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:32]2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3cc(OC)c(OC)cc13)CC2
Reaction time: 16 h

Procedure:
To 26.59 g of 2,4-dichloro-6,7-dimethoxyquinazoline and 20.39 g of triethylamine in 250 ml of warm dimethylacetamide was added to 23.1 g of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline in 300 ml of dry dimethylacetamide and the reaction mixture stirred at room temperatures under exclusion of moisture for 16 hours. The precipitate was filtered and the filtrate concentrated to dryness under reduced pressure. The residual product was recrystallized from methanol, 40.6 g, m.p. 183°-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH2:21][CH3:22])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Yield: 55.8 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 6.6 ml (0.1 mol) of ethylamine were stirred in 15 ml of ethanol in an autoclave at 130° C. for 3 hours. The reaction mixture was freed from solvent, the residue was suspended in 8 ml of ethanol and treated in an ultra-sound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 01N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.18 g (56%) of 4-amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 252° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>FC1C=CC=CC=1CN.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:3]4[CH:4]=[CH:5][CH:20]=[CH:21][C:2]=4[F:1])=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: NCc1ccccc1F
Solvent: CCO
Product: O[C@H](CNCc1ccccc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-fluorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:7]=1.[OH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:8]([N:6]1[C:5](=[O:15])[N:4]([CH3:16])[C:3](=[O:17])[C:2]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=2)[O:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:7]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCCO)c1
Reactant: CCCCCCCn1nc(Br)c(=O)n(C)c1=O
Product: CCCCCCCn1nc(OCCCc2cccc(OC(C)(C)C(=O)OCC)c2)c(=O)n(C)c1=O

Procedure:
Compound 5 (oil) is prepared from triazine 4b and from intermediate 12a according to synthesis method 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Reaction time: 168 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 0.814 mmol) in ethyl acetate/methanol 20/20 mL was added palladium hydroxide (160 mg) and stirred under hydrogen atmosphere for 7 days. The catalyst was filtered through celite and the solvent was distilled off to get 320 mg (99.37% yield) of the titled compound. MS: m/z=396.3 (M+1).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O.CN(C)C=O.Cl>ClCCl>[C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirrer and a nitrogen inlet-outlet was charged with 4-(N,N-diphenylamino)cinnamic acid (1.0 g, 3.2 mmol) in 15 mL dichloromethane. Thionyl chloride (0.35 mL, 4.8 mmol) was added followed by 12.4 □L N,N-dimethylformamide. Hydrogen chloride gas evolution began immediately and then ceased within one hour of stirring. The solution was stirred for 3 h and then concentrated on a rotary evaporator. The product was transferred to a high vacuum line and residual solvent was removed under vacuum. The product was obtained as a brown solid and stored under nitrogen without any further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[OH-].[K+].[C:16](=[O:18])=[O:17]>>[OH:11][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
A stirred autoclave is charged with 1220 parts of β-naphthol, 608 parts of aqueous caustic soda solution (50% by weight) and 27 parts of aqueous caustic potash solution (85% by weight). The mixture is well mixed under nitrogen, heated to an internal temperature of 260° C and kept for 30 minutes at this temperature. The dehydration is then practically complete. Carboxylation is carried on for 3 hours at a temperature of 260° C with dry carbon dioxide at a pressure of 7 atmospheres. The absorption of CO2 is monitored by a gas meter. After the absorption is ended 350 parts of β-naphthol is distilled off at 20 mm of Hg and then in the manner above described carbon dioxide is again forced in and the mixture carboxylated for 2 hours. A total of 300 parts of carbon dioxide is absorbed in a carboxylation period of 300 minutes. The reaction mixture is stirred with 5000 parts of water and dissolved. The solution is cooled to 80° to 90° C, acidified with 50% by weight sulfuric acid to a pH of 6.5 and then extracted for fifteen minutes with a total of 800 parts of a mixture of m-xylene and p-xylene in the ratio 2.3:1. The phases are then separated and the aqueous phase is acidified to a pH of 3 at 90° C with 50% by weight sulfuric acid. The precipitated 2-hydroxynaphthalene-3-carboxylic acid is separated by filtration from the hot solution at 80° C. 530 parts of 2-hydroxynaphthalene-3-carboxylic acid is obtained. This is 73% of theory based on reacted naphtholate deducting the β-naphthol obtained. It contains 99% by weight of 2-hydroxynaphthalene-3-carboxylic acid and 0.5% by weight of β-naphthol. The melting point is 218° to 220° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Br[CH2:24][C:25]([C:27]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]1)=O>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][CH:24]=[C:25]([C:27]4([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]4)[N:2]=3)[CH2:5][C@H:6]2[O:21][CH3:22])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(N)=S)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Product: CCOC(=O)C1(c2csc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)n2)CC1

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-methoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained by the method described in Example (65c) (40 mg, 0.12 mmol) and ethyl 1-(bromoacetyl)cyclopropanecarboxylate obtained according to a method known in the literature (Heterocycles, 63, 3, 2004, 699-706) (60 mg, 0.26 mmol), to obtain 23.5 mg of the title compound as a colorless oily substance (42%).
Reaction SMILES: [OH:1][C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=O.CS(O)(=O)=O.C(N(CC)CC)C.O>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:15]=[C:16]([CH:17]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:1][C@@H:2]([CH2:35][O:36][Si:37]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:39])[CH3:40])[CH:44]([CH3:46])[CH3:45])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:13]=1)[O:18][C:19]1[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
N-{(2S)-2-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (558 mg, 0.82 mmol) synthesized in Example (101b) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (287 mg, 1.65 mmol) and triethylamine (0.34 mL, 2.47 mmol) were added, followed by stirring at 50° C. for 6 hours under nitrogen atmosphere. To the reaction solution, water (40 mL) was added, and extraction was carried out twice with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (496 mg, yield 94%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:34])([F:33])[C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[C:20](=[O:27])[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:33])([F:34])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[CH:20]([OH:27])[CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(O)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of LiAlH4 (200 mg) in anhydrous ether (15 ml) is added at 0° a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (400 mg) in ether (5 ml). After addition is complete, the reaction mixture is stirred at RT for about one hour. Excess of the hydride is decomposed using wet ether and water, the mixture is filtered and filtrate concentrated. The oily product is purified by prep. thin layer chromatography to give 4-[4-(4-trifluoromethylphenoxy)phenoxy]-pentane-1,3-diol, MS m/e 500 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Yield: 50.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(oxazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.47 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.3 g, 51%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O-:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)C[Cl:19].C1C=NC2N(O)N=NC=2C=1.[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[ClH:19].[ClH:19].[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: ClCCCl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(C(=O)C2CCNCC2)CC1
Product: Cl
Reaction time: 0.08 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylate (5 g) in DMF (60 ml) was treated with EDC (5.5 g) followed by HOAT (0.1 g). After 5 min, N-isopropylpiperazine (2.8 g) in DMF (5 ml) was added and the reaction was left stirring for 18 h. The reaction was then diluted with EtOAc (150 ml) and washed with saturated brine/sodium hydrogen carbonate (1:1, 200 ml) followed by brine (3×200 ml). The EtOAc layer was evaporated to near dryness and the residue treated with TFA/water (40 ml, 95:5) for 5 h prior to evaporation and re-evaporation from toluene (3×60 ml). The residue was taken up into a minimum volume of EtOAc and treated with HCl (30 ml, 2N solution in diethyl ether) for 1 h. The resulting sub-titled compound was filtered off and washed with diethyl ether before drying under vacuum (4.8 g).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=[O:6].B(Br)(Br)Br.C(=O)=O.CC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(Oc2ccccc2)cc(C)c1C=O
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(Oc2ccccc2)cc(O)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A light yellow solution of 2-methoxy-6-methyl-4-phenoxy-benzaldehyde (6.33 g, 26.13 mmol) in DCM (250 mL) was treated with boron tribromide (1.0 M solution in DCM, 76 mL, 76 mmol) dropwise at −78° C. (dry ice/acetone bath). The red/brown mixture was stirred at −78° C. for 30 minutes, 0° C. (ice-water bath) for 30 minutes, then rt for 3 h. The mixture was quenched with ice water, then extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to a brown residue. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-hydroxy-6-methyl-4-phenoxy-benzaldehyde (5.06 g, 85%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1H), 10.14 (s, 1H), 7.42 (t, J=7.42 Hz, 2H), 7.30-7.21 (m, 1H), 7.08 (d, J=7.42 Hz, 2H), 6.35 (s, 1H), 6.21 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CCOCC>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[CH:3][C:2](=[O:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: COP(=O)(CC(=O)c1cccnc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150 mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 15 mg of sodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension was warmed in a 45° C. oil bath for 30 min. After the mixture had cooled to rt, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol) was added in THF (1.5 mL). After stirring overnight at rt, the mixture was diluted with ether (20 mL) and washed with 2.5 N NaOH (20 mL) followed by saturated aq. brine (20 mL). The aq. layers were extracted in succession with ether (20 mL), and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer) as a yellow syrup. For the title compound: 1H NMR (500 MHz, CDCl3) δ9.17-9.13 (bs, 1H), 8.81 (bd, J=4, 1H), 8.27 (d, J=8, 1H), 7.49 (dd, J=8, 4, 1H), 7.07 (dd, J=15, 7, 1H), 6.85 (dd, J=15, 1, 1H), 4.25-4.13 (bs, 2H), 2.87-2.78 (m, 2H), 2.51-2.41 (m, 1H), 1.83 (d, J=12, 2H), 1.49 (s, 9H), 1.45 (qd, J=12, 4, 2H). ESI-MS 261 (M+H-56), 217 (M+H-100); HPLC A: 1.73 min.