Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[O:32][C:11]2=[C:12]3[O:17][CH:16]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15][CH2:14][C:13]3=[CH:30][CH:31]=[C:10]2[C:9]=1[CH3:33].C(O)(=O)C(O)=O>C(Cl)Cl.CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH:16]1[CH2:15][CH2:14][C:13]2=[CH:30][CH:31]=[C:10]3[CH:9]([CH3:33])[CH:8]([CH3:7])[O:32][C:11]3=[C:12]2[O:17]1
Reactant: Cc1oc2c3c(ccc2c1C)CCC(CNCCCNc1ncccn1)O3
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC1Oc2c(ccc3c2OC(CNCCCNc2ncccn2)CC3)C1C
Yield: 3.3 %

Procedure:
CH2Cl2 /CH3OH 85/15). The desired fractions were collected and the solvent was evaporated. The residue (1.8 g) was dissolved in ethanol and converted into the ethanedioic acid salt (1:2) with ethanedioic acid (0.010 mol). The precipitate was filtered off and dried, yielding 1.1 g (3.3%) (±)-N-2-pyrimidinyl-N'-[(3,6,7,8-tetrahydro-2,3-dimethyl-2H-furo[3,2-h][1]benzopyran-8-yl)methyl]-1,3-propanediamine ethanedioate(1:2); mp. 171.2° C. (comp. 8-a).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>CS(O)(=O)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[O:19][CH2:17][CH3:18])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOc1ccccc1C=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 44.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), o-ethoxybenzaldehyde (2.7 g, 18 mmol), methanesulfonic acid (5 drops), and xylenes (50 ml) was refluxed for 48 hours. The reaction mixture was stripped to dryness, and treated with 10% K2CO3 and CHCl3 (100 ml). The layers were separated and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo. The dark oil thus obtained was dissolved in CH2Cl2 (30 ml) and combined with silica gel (30 g). The preloaded silica gel was placed on a silica gel column and eluted with Et2O/hexanes (20/80) to Et2O (100%) to afford 1.41 g (45%) of 1-cyclopentyl-3-ethyl-6-(2-ethoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 146°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:18].[Na+]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][I:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCI

Procedure:
A solution of chloromethyl N-(3-(N-tert-butoxycarbonylamino)-propyl)carbamate (2 g) and sodium iodide (4.5 g) in acetonitrile (15 ml) was stirred for 1 hour at room temperature, evaporated in vacuo, redissolved in dichloromethane and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel with ethyl acetate/hexane (1:2) as eluent to yield the title compound as colourless crystals.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].ClC1C=C(C=C([F:25])C=1)C(O)=O>>[CH:12]1([C:9]2[CH:8]=[C:3]([CH:2]=[C:11]([F:25])[CH:10]=2)[C:4]([OH:6])=[O:5])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: COC(=O)c1cc(C2CC2)ccc1N
Product: O=C(O)c1cc(F)cc(C2CC2)c1
Yield: 16 %

Procedure:
Obtained (16% yield) following the procedure described in intermediate 8 (step A), starting from 3-chloro-5-fluorobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[S:5][C:6]=1[CH3:7]
Reactant: OCCO
Reactant: Cc1sc(C=O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1sc(C2OCCO2)cc1Br
Yield: 93 %

Procedure:
A mixture of 4-bromo-5-methylthiophene-2-carbaldehyde (6.0 g), ethylene glycol (100 mL), p-toluenesulfonic acid (2 mL) and toluene (100 mL) was heated under reflux for 5 hr with a Dean-Stark trap. The reaction mixture was washed with water and saturated brine, and the obtained organic layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 2-(4-bromo-5-methyl-2-thienyl)-1,3-dioxolane (6.96 g, yield 93%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:22])C>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-((4-(trifluoromethyl)benzyl)oxy)pyridine 1-oxide (350 mg) in acetic anhydride (6 ml) was heated under reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH (10 ml) and 2 M NaOH (10 ml), and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The DCM layer was concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) to give the title compound (110 mg) as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][C:25]([OH:33])([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: OC1(c2ccc3ccccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 24% overall yield as a foam. FDHS m/e=400 (H+ of free base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14]N.O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([NH2:14])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20.3 %

Procedure:
To a cooled mixture of 1.81 g (10 mmol) 4-chloro phthalimide in 20 mL ethanol (96%) was added 0.5 mL (10 mmol) hydrazine monohydrate. The reaction mixture was stirred for 2 min. at room temperature and 2 min. at reflux. By adding 50 mL cold water pale yellow crystals formed after 1 h. Resulting crystals was filtered and recrystallized from ethanol to give 0.4 g (20%)4-chloro-N-amino-phthalimide :top 172°-175° C.; 1H NMR (200 MHz, DMSO-d6) d 4.90 (s, 2H, NH2), 7.82-7.92 (m, 3H, C6H3); it solidifies after melting and melts again around 345° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27]>>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15])=[O:27]
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: O=C(c1cc2ccccc2o1)C1CCCCN1
Product: Cc1nc(C(=O)N2CCCCC2C(=O)c2cc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 1, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.1 g, 0.39 mmol) and (RS)-1-benzofuran-2-yl-1-piperidin-2-yl-methanone, D9 (0.1 g, 0.43 mmol) as a colourless solid (0.074 g, 43%)
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:11])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[OH:12]O>CC(O)=O>[CH2:1]([C:5]1[C:6]([CH3:11])=[N+:7]([O-:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ncccc1CC(C)C
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(CC(C)C)ccc[n+]1[O-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
3-Isobutyl-2-methyl-pyridine (Ishiguro et al. Yakugaku Zasshi 1958, 78, 220) (970 mg, 6.51 mmol) was suspended in a mixture of hydrogen peroxide (5 mL) and HOAc (45 mL) and the resulting mixture was stirred at 100° C. for 2.5 hours. The solvent was removed under reduced pressure and the resulting oily mixture was quenched with saturated NaHCO3 (60 mL) and extracted with CH2Cl2 (10×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to yield 3-isobutyl-2-methyl-pyridine-1-oxide as a colorless oil (821 mg, 76%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.84 (m, 1H), 2.51 (d, 2H, J=6.0 Hz), 2.52 (s, 3H), 7.03 (m, 2H), 8.18 (d, 1H, J=6.0 Hz).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4,6-trifluorobenzonitrile (288 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 172 mg, yield: 51%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1)=[O:30]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCCCCCc1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCCCCCCC(=O)O)cc1

Procedure:
By the reaction of ethyl 7-[4-(2-aminoethyl)-phenyl]-heptane-carboxylate hydrochloride (m.p. 137°-139° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained 7-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-heptane-carboxylic acid; m.p. 103°-106° C., after recrystallization from diethyl ether.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[C:26](O)=[O:27]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:26]([C:21]3[NH:22][C:23]([CH3:25])=[CH:24][C:20]=3[CH3:19])=[O:27])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Agent: Cl
Product: Cc1cc(C)c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)[nH]1

Procedure:
Title compound was synthesized by an analogous method to Example 18 using 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) and 3,5-dimethyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-[3-(4-chlorophenyl)-ureido]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (33%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 4.40 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.22 ml of 2-chloro-6-methylpyridine in 12.5 ml of tetrahydrofuran was added 1.4 ml of a hexane solution containing 1.58 M n-butyl lithium at 0° C., followed by stirring the reaction mixture at 0° C. for 30 minutes. After cooling down to −78° C., a solution of 403.7 mg of tert-butyl 4-oxo-1-piperidinecarboxylate in 1 ml of tetrahydrofuran was added to the solution, followed by gradually warming up the reaction mixture to −40° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extracting with chloroform. The resulting chloroform layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−3/2) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23]Br)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[C:18](=[O:27])[CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[C:18](=[O:27])[CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1cn[nH]c1
Reactant: Cc1cc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 1.0 g (2.2 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid and 0.6 g (8.8 mmol) of pyrazole in 15 ml of N-methylpyrrolidine was heated at 100°. After 2 h, the reaction mixture was cooled to room temperature, poured into brine, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The organic solution was adsorbed onto silica gel and purified by flash chromatography (gradient elution: hexane-18% ethyl acetate/hexane) to afford 0.71 g (73%) of Methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid (MH+=443).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([O:11][CH2:19][CH3:20])=[C:8]([CH3:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(C)cc([N+](=O)[O-])cc1C
Yield: 97.7 %

Procedure:
A mixture of 10 g (0.0598 mol) of 4-nitro-2,6-dimethylphenol, 16.5 g (0.1196 mol) of K2CO3 and 18.6 g (0.1196 mol) of ethyl iodide in 100 ml of acetonitrile was refluxed for 2.5 hours. The solid material was removed by hot filtration and was then washed with hot acetonitrile. The combined organic phase was evaporated and the resulting residue dissolved in ether. The ether phase was washed with water, dried (Na2SO4) and evaporated yielding 11.4 g (98%) of the product, M.p. 56° C.
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:28]2[O:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:28]2[O:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a mixture of ethyl 3-{methyl[(4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl]amino}propanoate (82.5 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (54.8 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(CC)CC.[CH3:22][CH2:23][OH:24]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([O:24][CH2:23][CH3:22])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.0 g, 22.0 mmol) in THF (25 mL) was added Et3N (3.1 mL, 22.0 mmol) followed by EtOH (1.3 mL, 22.0 mmol). This mixture was stirred at ambient temperature for 1 h and quenched with saturated, aqueous NH4Cl (10 mL). The layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in EtOAc) to give the title compound (4.8 g, 20.3 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.42 (t, J=7.1 Hz, 3H), 4.43 (q, J=7.1 Hz, 2H), 7.23-7.34 (m, 1H), 7.74-7.82 (m, 1H), 8.23 (dd, J=6.3, 2.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[C:5]([CH2:12][C:13]([OH:15])=O)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][N:29]([C:13](=[O:15])[CH2:12][C:5]4[N:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]5=[C:3]([C:2]([F:1])([F:17])[F:16])[N:4]=4)[C:28]=3[CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1nc(C(F)(F)F)c2ccccn12
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1nc(C(F)(F)F)c2ccccn12)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 72 %

Procedure:
The title compound was prepared from 2-(1-(trifluoromethyl)imidazo[1,5-a]pyridin-3-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 32 mg (72%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.36 (d, J=6.6 Hz, 1H), 8.35 (s, 0.9H), 8.06 (s, 0.1H), 7.63 (d, J=9.0 Hz, 1H), 7.50 (m, 0.3H), 7.42 (m, 1.7H), 7.12-7.22 (m, 2H), 7.01 (m, 1H), 6.79 (t, J=6.6 Hz, 1H), 4.51 (s, 0.2H), 4.38 (s, 1.8H), 4.08 (m, 1.7H), 3.90 (m, 0.3H), 2.86 (t, J=6.6 Hz, 0.3H), 2.80 (t, J=6.6 Hz, 1.7H), 2.02 (m, 2H); MS: (ES) m/z calculated for C22H18F4N5O [M+H]+ 444.1, found 444.1.
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:6]([O:5][CH2:1][C@H:2]([OH:4])[CH3:3])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)CO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Dimethylaminopyridine (82 mg, 0.67 mmol) was added to a solution of (R)-propane-1,2-diol (5.17 g, 67.9 mmol) and trityl chloride (19.2 g 68.9 mmol) in DCM (200 mL) at 0° C. Triethylamine (23.5 mL, 168.6 mmol) was then added dropwise to this mixture. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with 1.0 N aq HCl (50 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give (R)-1-(trityloxy)propan-2-ol (18.6 g, 86%) as a white solid. 1H NMR (DMSO-d6): δ 7.43-7.22 (m, 15H), 4.64 (d, 1H), 3.78 (m, 1H), 2.94 (dd, 1H), 2.70 (dd, 1H), 1.06 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(=S)=S>[C:18]1([CH2:24][C:25]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:2][CH:3]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)CCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a solution of 25.0 g of methyl 4-phenylbutyrate in 100 ml of carbon disulfide, 37.3 g of anhydrous aluminium chloride was added and then a solution of 43.3 g of phenylacetyl chloride in 25 ml of carbon disulfide was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed with aqueous potassium carbonate solution, dried, and then the solvent was removed. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1→methylene chloride) to afford 27.3 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 54°~54.5° C.