Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)NC=Cc1ccc(O)cc1
Temperature: 50 °C

Procedure:
12.5 g (0.045 mol) of p-(2-n-butoxycarbonylaminovinyl)-acetoxybenzene, after dissolving in 75 ml of absolute methanol, addition of a solution of 2.43 g (0.045 mol) of sodium methoxide in 50 ml of methanol, heating to 50°C for 15 minutes and subsequent evaporation to dryness in vacuo, yield the crude sodium salt of p-(2-n-butoxycarbonylaminovinyl)-phenol. This is heated to the boil with 45 ml of epichlorohydrin for 24 hours under a reflux condenser, whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. 1-[p-(2-n-Butoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 120°C (from ether) is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:15](F)(F)[C:16]1[CH:17]=[C:18](CBr)[CH:19]=[CH:20][CH:21]=1>>[C:16]1([CH2:15][O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1

Procedure:
When the bridging group n is --OCH2 --, 1,4-dioxaspiro[4.5]decan-8-ol (the preparation of which was previously described) is treated with sodium hydride and reacted with an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 3-trifluoromethylphenylmethyl bromide, affording the corresponding 8-phenylmethoxy-1,4-dioxaspiro[4.5]decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethoxycyclohexanone, which is in turn reacted with cyanoguanidine, yielding the targeted 2,4-diamino-6-phenylmethoxy-5,6,7,8-tetrahydroquinazoline. Example 11 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH2:8].[N+](N[C:13]1[NH:18][C:17](=[O:19])[C:16]([CH2:20][C:21]2[CH:22]=[N:23][C:24](C)=[CH:25][CH:26]=2)=[CH:15][N:14]=1)([O-])=O>C(O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][C:16]2[C:17](=[O:19])[NH:18][C:13]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:13]3[NH:18][C:17](=[O:19])[C:16]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:15][N:14]=3)=[N:14][CH:15]=2)[CH:22]=1
Reactant: NCCSSCCN
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: O=c1[nH]c(NCCSSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)ncc1Cc1cccnc1

Procedure:
Cystamine is reacted with 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by heating in ethanol to give 2-[5-(3-pyridylmethyl)-4-oxo-2-pyrimidylamino]ethyl disulphide which is reduced with dithiothreitol to give 2-(2-mercaptoethylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which is reacted with 5-dimethylaminomethyl-2-furylmethanol in cold aqueous hydrochloric acid to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:24]([O-])=[O:25].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: COCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Product: COCC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 23.1 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea and 1.5 g of sodium nitrite are treated in the same manner as described in Example 24. 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[CH2:10](Br)[C:11]#[CH:12]>CCCCCC.C1(C)C=CC=CC=1>[CH2:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[C:11]#[CH:10]
Reactant: O=C1CCCCN1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C#CCN1CCCCC1=O
Temperature: 15 °C
Reaction time: 19 h

Procedure:
Sodium hydride (5.76 g of 50% dispersion in oil, 0.12 mole) was washed three times with hexane and suspended in 645 ml of toluene. 2-Piperidone (11.88 g, 0.12 mole) in 100 ml of toluene was added to the well stirred sodium hydride suspension and heated to reflux for 2 hours. The reaction mixture was cooled to 15° C. and 2-propynyl bromide (14.28 g, 0.12 mole) in 55 ml of toluene added over 30 minutes. The mixture was then stirred at room temperature for 19 hours, filtered and mother liquor evaporated to yield a first batch of 1-(2-propynyl)-2-piperidone as an oil (7.87 g of about 55% purity by pnmr assay).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[CH2:25](I)[CH:26]([CH3:28])[CH3:27].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:11]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2cccc(O)c2)c(F)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2cccc(OCC(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Ethyl 3-{3,5-difluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (200 mg, 0.59 mmol) was dissolved in DMF (10 mL), isobutyl iodide (339 μL, 3.0 mmol) and sodium hydride (47 mg, 1.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (186 mg, yield 80%) as an oily matter.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([O:32]CC1C=CC=CC=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)O)C(=O)CCOCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CCO
Yield: 97 %

Procedure:
A magnetically stirred solution of 8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.37 g., 4.4 millimole) in ethanol (50 ml.) is subjected to hydrogenation at atmospheric pressure at 23° C. in the presence of a 10% palladium on charcoal catalyst (0.3 g.) for one hour. The hydrogen uptake is 2.4 ml. (100% theory). The catalyst is removed by filtration and the solvent is removed by evaporation in vacuo to give 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3 chloroformate as a viscous, colorless liquid (1.55 g., 97% yield); pmr (CDCl3) δ0.88 (3H,t), 2.03 (H,m), 2.32 (2H,t), 2.68 (2H,t, J=5.5 cps.), 3.65 (H, b.s.), 3.86 (2H,t, J=5.5 cps.), 5.50 (3H, exchangeable s) and 7.32 (1/3H,s).
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:39]([O:42][C:43](Cl)=[O:44])([CH3:41])[CH3:40]>C(Cl)Cl>[CH:39]([O:42][C:43]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:24])([F:25])[F:23])=[O:16])=[CH:12][N:13]=2)[CH2:3][CH2:4]1)=[O:44])([CH3:41])[CH3:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt (50 mg, 0.102 mmol) in methylene chloride (6 mL) was added triethylamine (0.1 mL). The clear solution was cooled in an ice bath and isopropylchloroformate (1M in toluene, 0.2 mL) was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hr. The solvents were evaporated and the residue was triturated with methanol. The precipitate was filtered and dried to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester (32.4 mg). LC-MS calcd for C24H24F3N5O4 (m/e) 503.2, obsd 503.8 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[F:11][C:12]([F:24])([F:25])[C:13]1[CH:14]=[C:15]([NH:16][C:8]([C:3]2[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1O
Yield: 45 %

Procedure:
Using 3-hydroxypyridine-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline, as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.N1C=CC=C(CC(O)=O)C=1>>[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([OH:11])=[O:10])[CH2:3]1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: O=C(O)CC1CCCNC1
Yield: 80.5 %

Procedure:
3-Pyridylacetic acid hydrochloride (13 grams) (74.9 mmoles) was hydrogenated as described in Preparative Example 5A to give a mixture of unreacted 3-pyridylacetic acid and the title compound (76:24) (8.63 grams, MH+ 144).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29](O)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O>[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29]([N:2]3[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]3)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)c2cnc(C#Cc3ccccc3)s2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
Example 75 was prepared via the process of Scheme 1, step 3, Method—B, supra, as follows: 2-Phenylethynyl-thiazole-5-carboxylic acid (0.100 g, 0.436 mmol) in tetrahydrofuran (1.7 mL) [Intermediate 1] was stirred, and N,N′-carbonyldiimidazole (0.079 g, 0.49 mmol) (Fluka Chemie AG) was added in one portion at room temperature. The mixture was stirred for 60 minutes and then 4-piperidone monohydrochloride (0.241 g, 1.78 mmol) (3B Pharmachem (Wuhan) International Co., LTD (Libertyville, Ill., USA)) was added, followed by the addition of triethylamine (192 uL, 1.38 mmol). The mixture was stirred for about 2 hours and was worked up by diluting with 25 mL of EtOAc and washing with 2×10 mL of 1.7% aq. HCl, 1×10 mL of water, 3×10 mL of 1.0 M K2CO3, and 1×10 mL of brine; dried (Na2SO4), and concentrated to give the title compound, 1-(2-phenylethynyl-thiazole-5-carbonyl)-piperidin-4-one (55 mg; 41%), as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.63-7.59 (m, 2H), 7.47-7.32 (m, 3H), 4.03 (t, J=6.3 Hz, 4H), 2.59 (t, J=6.3 Hz, 4H). LC/MS (Method 1), RT=1.05 min. Calculated [M+H]+=311; Observed [M+H]+=311.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[O:10]([CH2:17][CH:18]1[O:22][C:21](=[O:23])[NH:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][N:20]2[CH2:19][CH:18]([CH2:17][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:22][C:21]2=[O:23])=[CH:4][CH:3]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: O=C1NCC(COc2ccccc2)O1
Product: O=C1OC(COc2ccccc2)CN1Sc1ccc(Cl)cc1
Yield: 33 %

Procedure:
Analogously to Example 4, 33% yield of 3-(4-chlorophenylthio)-5-phenoxymethyloxazolidin-2-one with a melting point of 98° to 101° C. was obtained from 4-chlorophenylsulphenyl chloride and 5-phenoxymethyloxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:22]=[O:24])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(N=C=O)cc1
Temperature: 25 °C
Yield: 159.1 %

Procedure:
To a mixture of (4-Amino-phenoxy)-acetic acid methyl ester 15 (15 g, 82.87 mmol) and triethylamine (16.77 g, 165.73 mmol) in toluene (225 ml) under nitrogen atm. at 0° C. was added triphosgene (9 g, 30.33 mmol) in one lot. The reaction was exothermic and the temperature raised to 25° C. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was then cooled to room temperature, the solids were filtered off, and the toluene was distilled off under vacuum to get crude 28, which was vacuum distilled to get pure 28 (10 g, 58.3%) as a white powder. M.p: 50-53° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH:17][CH:19]([CH3:21])[CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)=O
Reactant: Nc1cccnc1Nc1ccc2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cccnc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
The N2-(benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (8.5 g, 37.1 mmol) was dissolved in dichloromethane (150 mL). Acetone (4.1 mL, 55.6 mmol), sodium triacetoxyborohydride (11.79 g, 55.6 mmol) and acetic acid (4.2 mL, 74.2 mmol) were added to it. This was stirred at ambient temperature for 18 h. The mixture was washed with 1N NaOH and then washed with water. The organic layer was concentrated in vacuo and chromatographed using a gradient of 0-10% ethyl acetate in dichloromethane to give N2-(benzo[d][1,3]dioxol-5-yl)-N3-isopropylpyridine-2,3-diamine (7.8 grams, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)CCC>[CH2:9]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH:23]1)[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Solvent: CCCCN
Product: CCCCn1cc(-c2ccc(C)cc2)c2c1CCNC2
Yield: 77.6 %

Procedure:
The title compound (292.8 mg) was prepared from 0.56 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL of butylamine, and 0.45 g of 1-methyl-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C18H24N2, 268.19; found, m/z 269.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.20-7.14 (m, 4H), 6.93 (s, 1H), 4.32 (s, 2H), 3.88 (t, J=7.1 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.77-1.70 (m, 2H), 1.41-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:21]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:22]=2)[CH2:14][CH2:13]1)=[O:10].O.NN>CCO>[NH2:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:17][CH2:16]2)[S:19][C:20]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate (Example 277; 1.43 g, 2.42 mmol) in EtOH (10 ml) was added hydrazine hydrate (0.174 ml; 3.63 mmol) and refluxed for 14 h. The reaction mixture cooled to room temperature and concentrated in vacuo, diluted with DCM and acidified with 10% HCl, washed with H2O. The precipitate was filtered and dried in vacuo to give the title compound (600 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 81.2 %

Procedure:
To a solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (323) (4.82 g, 9.74 mmol) in tetrahydrofuran (90 mL) and water (45 mL) was added LiOH.H2O (4.086 g, 97.37 mmol). The reaction mixture was heated to reflux for 20 h (the reaction was monitored by LC-MS). The tetrahydrofuran was removed in vacuo and the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 1N HCl to about pH 3. A white solid was separated by filtration and dried in vacuo to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (3.47 g, 81%).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([B:16]([OH:18])[OH:17])=[C:11]([CH3:19])[CH:10]=1)=[O:8])C.O.Cl>O1CCOCC1>[C:7]([C:9]1[CH:10]=[C:11]([CH3:19])[C:12]([B:16]([OH:17])[OH:18])=[C:13]([CH3:15])[CH:14]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1cc(C)c(B(O)O)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Lithium hydroxide monohydrate (0.089 g) was added to a mixture of 4-ethoxycarbonyl-2,6-dimethylphenylboronic acid (0.047 g), water (1 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.5 mL), and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.023 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[C:16]([CH3:25])=[CH:15][C:14]3=[O:26])[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([C:16]([CH3:25])=[CH:15][C:14](=[O:26])[N:13]2[CH2:12][CH2:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.5 mL of an ethanol solution containing 65 mg of 1-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one, 0.5 mL of an 80% aqueous trifluoroacetic acid solution was added under cooling with ice, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and water and ethyl acetate were added thereto. The reaction mixture was adjusted to pH 7.7 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 48 mg of a colorless oily substance, 7-methoxy-4-methyl-1-(2-(4-oxocyclohexyl)ethyl)quinolin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1F)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
2-Fluorophenylacetic acid (2.0 g, 13.14 mmoles) was dissolved in 20 ml dichloromethane. To this mixture, oxalylchloride (1.66 g, 13.14 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 20 ml dichloromethane. To this mixture, 4-fluoroanisole (1.10 g, 8.76 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.75 g, 13.14 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (1.17 g, 54% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.25(s,1H), 7.73(dd, J=9.5,3.2 Hz, 1H), 7.43(dt, J=8.8,3.1 Hz, 1H), 7.35(d, J=6.2 Hz, 1H), 7.31(d, J=7.2 Hz, 1H), 7.19(d, J=8.2 Hz, 1H), 7.03(dd, J=9.1,4.6 Hz, 1H),4.50(s, 2H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][NH2:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[N:21]=1.C(N(CC)CC)C>CC#N>[Br:22][C:20]1[N:21]=[C:16]([NH:13][CH2:12][C:11]2[C:2]([F:1])=[C:3]3[C:8](=[CH:9][C:10]=2[F:14])[N:7]=[CH:6][CH:5]=[CH:4]3)[C:17]([NH2:23])=[N:18][CH:19]=1
Reactant: NCc1c(F)cc2ncccc2c1F
Reactant: Nc1ncc(Br)nc1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1NCc1c(F)cc2ncccc2c1F
Temperature: 180 °C
Yield: 43.2 %

Procedure:
A mixture of (5,7-difluoroquinolin-6-yl)methanamine (2.7 g, 13.9 mmol), 3,5-dibromopyrazin-2-amine (2.4 mg, 9.49 mmol) and triethyl amine (4.8 g, 47.5 mmol) in CH3CN (6 mL) was heated under microwave irradiation at 180° C. for 40 min. The reaction mixture was concentrated in vacuo and purified by column chromatography (hexane:EtOAc) to provide 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.50 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.64 (m, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 6.21 (s, 2H), 4.69 (d, 2H). LCMS (method B): [MH]+=367.9, tR=2.36 min