Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[CH3:18][O:19]C(Cl)Cl>ClCCl.C(OCC)(=O)C.Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]([CH:18]=[O:19])=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:15])([CH3:16])[O:7]2
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)CC2=O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1cc2c(c(O)c1C=O)C(=O)CC(C)(C)O2
Reaction time: 0.08 h

Procedure:
At −50° C., 13.19 ml (13.19 mmol) of a 1 M solution of titanium(IV) chloride in dichloromethane are added dropwise to a solution of 1.03 g (4.40 mmol) of 5-hydroxy-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 17A) in 50 ml of dichloromethane, and the mixture is stirred at this temperature for 5 min. 437 μl (4.84 mmol) of dichloromethyl methyl ether are then slowly added dropwise. Over a period of 2.5 h, the mixture is allowed to thaw to −25° C. The mixture is then diluted with ethyl acetate and 1 M hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 16:1).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[C:12]1([C:22]([OH:24])=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[C:12]1([C:22]([NH2:3])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cccc2ccccc12
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 240.5 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 1-Naphthoic acid (0.34 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 14 h 45 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (80% ethyl acetate-hexanes) to give the naphthalene-1-carboxylic acid amide derivative (0.7 mg, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:38]([NH:37][CH3:36])=[O:39])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CN=C=O
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 25 mg of the product of Step D (0.06 mmol) in 3 mL dry methylene chloride was added 0.01 mL pyridine (0.12 mmol) and 0.007 mL methylisocyanate (0.12 mmol). The resulting reaction mixture was stirred at RT for 1 hr, then the volatiles were removed under vacuum. The residue was purified by prep TLC eluting with methylene chloride/methanol (9/1) to give 25 mg of yellow glass. Further purification was achieved by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (95/5) to obtain a minor isomer A and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.86 (2s, 3H), 3.32-3.5 (m, 3H), 3.75-3.90 (m, 3H), 4.20 (br. s, 1H), 4.53 (q, 1H, 6.5 Hz), 6.95 (t, 2H), 7.04 (m, 2H), 7.57 (s, 2H), 7.77 (s, 1H)ppm. MS: 479.1 (MH+) observed.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNCC2COc3ccc4c(c3O2)CC(=O)N4)cc1
Temperature: 85 °C
Yield: 56.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g, 2.66 mmole) and 4-methoxybenzylamine (1.40 ml, 10.7 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.51 g, 64%) was obtained as an oil upon concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.44 g of the (S) enantiomer of the title compound as an off-white solid fumarate, one-quarter hydrate, m.p. 205-205.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Reaction time: 20 h

Procedure:
A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54 mmol) and N-methylpiperazine (17 mL) was stirred at room temperature for 6 hours. The reaction mixture was then diluted with water (800 mL) and maintained under magnetic stirring for 20 hours. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 40° C. The title compound was obtained as yellow solid (16.4 g, 94% yield) and it was used in the next step without any further purification.
Reaction SMILES: ClC1N2C(=[O:11])NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:44][CH:45]([OH:11])[CH2:46]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:35][CH:36]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CC(O)C3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.173 min, [M+H]30 =456.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[C:12]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[N:13][CH:14]=[CH:15][CH:16]=1.[N-]1C=CN=C1>O1CCCC1.C(#N)C>[NH2:21][C:19](=[O:20])[CH2:18][NH:17][C:12]1[C:11]([NH:10][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(=O)CNc1ncccc1N
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Solvent: CC#N
Product: NC(=O)CNc1ncccc1NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.2 %

Procedure:
While bubbling nitrogen through a solution of picolinic acid (1.23 g, 0.01 mole) in 100 ml of tetrahydrofuran, solid 1,1-carbonyldiimidazole (1.62 g, 0.01 mole) was added in portions. The reaction mixture was allowed to stir at room temperature for 5 hours. Then, a solution of 2-[(3-amino-2-pyridinyl)amino]acetamide (1.66 g, 0.01 mole) in acetonitrile was added in portions to the imidazolide solution and the reaction mixture was allowed to stir at room temperature overnight. The solvents were evaporated. The residue completely solidified upon standing. The solid was washed with methylene chloride and the solid was filtered off. The solid was recrystallized from ethyl acetate to give several crops of crystals, which were combined and recrystallized from ethyl acetate to give 0.52 g of title compound, mp 188°-90° C. with decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:3][CH:2]=1.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccncc3)c2n2ccnc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccncc1)c1ccccc1-2
Yield: 24.8 %

Procedure:
The procedure is performed as in Example 13, but starting with 0.8 g of 10-(4-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide and 80 mg of 10% palladium on charcoal, with addition also of 10 ml of acetic acid. 0.2 g of 10-(4-pyridylmethyl)-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one is obtained, in the form of a pale yellow solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.3, H: 4.3, N: 17.8).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH:9](OC)(OC)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9]
Reactant: Nc1cnccc1Br
Reactant: COC(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-pyridin-3-ylamine (2 g, 11.56 mmol, CAS RN 239137-39-4) in trimethyl orthoformate (19 mL, 173.4 mmol, CAS RN 149-73-5) and a catalytic amount of TFA (1 drop) was heated to reflux for 2 hours. Volatiles were removed in vacuo, the resultant dark brown material was dissolved in THF (40 mL), treated portionwise with LiAlH4 (440 mg, 11.56 mmol) at 0° C. and then left stirring at 0° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL), filtered through a bed of celite, and the residue further washed with EtOAc (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The residue was purified by column chromatography over alumina (10% EtOAc in n-hexane) to afford the title compound. Light yellow oil (875 mg, 40%). MS (ESI): m/z=187.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O>[NH:8]([C:6]1[CH:7]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:15][CH2:16]2)[N:3]=[CH:4][N:5]=1)[NH2:9]
Reactant: NNc1cc(Cl)ncn1
Reactant: COCCN1CCNCC1
Solvent: O
Product: COCCN1CCN(c2cc(NN)ncn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g (6.9 mmol) of the compound from Example 7A and 1.1 g (7.6 mmol) 1-(2-methoxyethyl)piperazine in 10 ml water is stirred at 100° C. for 2 h. A further 0.9 g (6.2 mmol) 1-(2-methoxyethyl)piperazine is added and the reaction mixture is stirred further at 100° C. for 16 h. After concentration in vacuo, the residue is stirred in acetonitrile. The solid which has precipitated out is filtered off, washed first with ethanol and then with diethyl ether and dried in vacuo.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:7](=[O:21])[C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([CH2:17][CH3:18])=[C:10]([CH2:19][CH3:20])[CH:9]=2>C(O)C>[N:1]([C:15]1[C:14](=[O:16])[C:13]2[C:8]([C:7](=[O:21])[CH:6]=1)=[CH:9][C:10]([CH2:19][CH3:20])=[C:11]([CH2:17][CH3:18])[CH:12]=2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc2c(cc1CC)C(=O)C(Cl)=CC2=O
Agent: [Na+]
Solvent: CCO
Product: CCc1cc2c(cc1CC)C(=O)C(N=[N+]=[N-])=CC2=O

Procedure:
An aqueous solution of sodium azide (6.15 g; 0.095 mole) was added in one portion to a stirred, refluxing solution of 2-chloro-6,7-diethyl-1,4-naphthoquinone (18.0 g; 0.073 mole) in ethanol (180 ml) and the mixture refluxed for a further 2 mins. The red solution was cooled and the orange solid filtered off and washed with cold ethanol then water. After drying the product weighed 13.87 g (75%) and had m.p. 73°-76° C. (d). Recrystallisation from ethanol gave long orange needles of m.p. 74°-76° C. (d). (Found; C, 65.64; H, 5.27; N, 16.66; C14H13N3O2 requires; C, 65.87; H, 5.13; N, 16.46%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccccc3)c21
Temperature: 80 °C
Yield: 59.2 %

Procedure:
To a stirred solution of 7-chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.600 g, 0.1.98 mmol) in anhydrous dioxane (8 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.036 g, 0.04 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene HCl (0.036 g, 0.08 mmol). Phenylmagnesium bromide (1.18 mL, 3.56 mmol, 3M in diethyl ether) was added and the reaction heated to 80° C. for 3 hours. After this time an additional equivalent of reagents was added and the reaction heated for an additional 18 hours. The reaction mixture was treated with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.405 g, 1.18 mmol, 59%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2ccncc2)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5 g of ethyl nipecotate, 4.8 g of 4-chloropyridine hydrochloride, 6.6 g of triethylamine and 100 ml of xylene was stirred at 100° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent in an ordinary manner, and the obtained residue was purified by the silica gel chromatography (ethyl acetate/ethanol) to obtain the title compound.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]1[NH:11][C:10](=[O:12])[CH:9]=[C:8]1[OH:13]>C(O)(=O)C>[Br:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]1[NH:11][C:10](=[O:12])[C:9](=[N:1][OH:3])[C:8]1=[O:13]
Reactant: O=C1C=C(O)C(=C(Br)c2ccccc2)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=C(Br)c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(bromophenyl-methylene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H. -D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(bromophenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 158° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].[Br:6][C:7]1C(O)=NC=[C:11]([I:13])[CH:12]=1.IC.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:4](=[O:5])[N:2]([CH3:3])[CH:1]=[C:11]([I:13])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Oc1ncc(I)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(I)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 214a (6.0 g, 20.0 mmol), iodomethane (4.26 g, 30.0 mmol), and K2CO3 (5.52 g, 40.0 mmol). The mixture was stirred at room temperature for 2 h and diluted with water (200 mL). The resulting white solid was collected by filtration to afford 214b (5.97 g, 95%) as a white solid. MS-ESI: [M+H]+ 314
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:22]([Li])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12](=[O:14])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C(=O)C(C)(C)C)c(F)cn1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-5-(hydroxymethyl)benzoate T6.3 (0.307 g, 1 mmol) in THF (11 mL) at −78° C. was added tert-butyl lithium (2 mL, 3 mmol). The resulting mixture was stirred for one hour. The reaction was then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was then purified on silica gel (0-40% EtOAc in hexanes) to yield T6.4 as a colorless solid (0.28 g, 84% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[C:4]([Cl:16])[CH:3]=1.O.[NH2:18][NH2:19]>CN(C=O)C>[Cl:16][C:4]1[N:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]2[C:8](=[O:9])[NH:18][NH:19][C:2]=2[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH][nH]c2cc(Cl)nc(C(F)(F)F)c12
Temperature: 150 °C

Procedure:
A solution of methyl 4,6-dichloro-2-(trifluoromethyl)nicotinate (535.9 mg, 1.956 mmol) in DMF (2 ml) was charged with hydrazine hydrate (190 μL, 3.92 mmol) and heated to 150° C. for 30 min under microwave irradiation. Concentrated in vacuo and washed residue with DCM. Purified via flash chromatography (0-20% MeOH/DCM) to provide 6-chloro-4-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-3(2H)-one MS: [M+H]+ m/z 238.
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][NH:5]1)[CH3:3].[CH:17](O)=O.[OH-].[Na+].Cl.C(O)C>C=O.O>[ClH:1].[CH2:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][N:5]1[CH3:17])[CH3:3]
Reactant: O=CO
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1Cc2ccc([N+](=O)[O-])cc2CN1C

Procedure:
To a stirred solution of 3-ethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.0 g, 8 mmol) in formaldehyde (15 ml) was added formic acid (7.0 ml) and the reaction was then refluxed for 1.5 h. The reaction was cooled and poured into water (300 ml) and made basic with 50% NaOH. The aqueous phase was then extracted with dichloromethane (3×100 ml), and the organic phase dried over MgSO4. Evaporation of the solvent yielded a crude oil. A hydrochloride salt was made from ethanol-HCl, (1.8 g), m.p. 240-241° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:18]([O:23][CH3:24])(=[O:22])[C:19]#[C:20][CH3:21].[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:19]([C:18]([O:23][CH3:24])=[O:22])=[C:20]([CH3:21])[N:9]([C@@H:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[C:3]=2[N:4]=1
Reactant: CC#CC(=O)OC
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n([C@H](C)c2ccccc2)c2nc(Cl)ncc12
Temperature: 120 °C
Yield: 15.2 %

Procedure:
A solution of (R)-5-bromo-2-chloro-N-(1-phenylethyl)pyrimidin-4-amine (5 g, 16 mmol), methyl but-2-ynoate (3.1 g, 32 mmol), lithium chloride (690 mg, 16 mmol), potassium carbonate (5.5 g, 40 mmol) and palladium acetate (360 mg, 1.6 mmol) in N,N-dimethylformamide (50 mL) was degassed and back-filled with nitrogen for three times, then heated at 120° C. for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo, extracted with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous magnesium sulfate and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give (R)-methyl 2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a yellow oil (800 mg, 15%). LRMS (M+H+) m/z: calcd 329.09. found 329. 1H NMR (300 MHz. CDCl3): δ 9.16 (s, 1H), 7.39-7.18 (m, 5H), 6.45-6.42 (m, 1H), 3.96 (s, 3H), 2.57 (s, 3H), 2.05 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].O.[OH-].[Li+].O>C(#N)C>[OH:14][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[C:10]([F:9])([F:19])[F:20])[CH:7]1[O:6][C:5](=[O:8])[CH:4]=[C:3]1[O:2][CH3:1]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC1=CC(=O)OC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC1=CC(=O)OC1C(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-methoxy-5H-furan-2-one (2.00 g, 17.5 mmol), 2-(trifluoromethyl)-benzaldehyde (3.05 g, 17.5 mmol) and lithium hydroxide monohydrate (0.148 g, 3.53 (mmol) in acetonitrile is stirred at room temperature for 0.5 h, treated with water, stirred for 0.5 h and concentrated in vacuo. The resultant residue is diluted with water and filtered. The filtercake is dried in vacuo to give the title product as a white solid, 3.00 g (59% yield), mp 126-128° C., identified by NMR and mass spectral analyses.