Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN(C(C)C)C(C)C.[NH2:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]1[OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:13])[NH:23][CH:24]1[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]1[OH:33])=[CH:5]2
Reactant: NC1Cc2ccccc2C1O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1Cc2ccccc2C1O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (116 mg, 0.67 mmol) was dissolved in DCM (10 ml) containing DIPEA (0.21 ml, 1.19 mmol) and 2-aminoindan-1-ol (Method 1; 101 mg, 0.67mmol) and HATU (247 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for approximately 18 hours. The resulting solution was washed with water (20 ml) and the aqueous layer extracted with DCM (2×20 ml). The organic extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (195 mg, 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[O:14][CH3:15].[CH3:16]O.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH3:16][O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:4]=[C:3]([O:14][CH3:15])[C:2]([OH:1])=[C:7]([O:8][CH3:9])[CH:6]=1
Reactant: CO
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(OC)c(O)c(OC)c1
Yield: 75 %

Procedure:
(4-Hydroxy-3,5-dimethoxy-phenyl)-acetic acid (9.5 g, 0.042 mmol) was added to methanol (260 mL) and sulfuric acid (8 mL). After completion of addition the reaction was heated at reflux overnight. The next day, the reaction mixture was cooled down and concentrated to yield a crude oil. The oil was re-dissolved in ethyl acetate, washed with water, brine, and dried over sodium sulfate, and filtered to be concentrated again. The crude material was purified using silica gel chromatography (50%:50% ethyl acetate:pentane) to yield the desired product (1.5 g, 75% yield based on recovered starting material).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21]>C(Cl)(Cl)Cl>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CC(C)CO
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccc1
Reaction time: 96 h

Procedure:
N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHCl3 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.
Reaction SMILES: C(O[CH:5]1[CH:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][CH:8]2[CH:7]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:6]1)(=O)C.I[Si](C)(C)C.[CH:25]([O:28][P:29]([O:34]C(C)C)[O:30][CH:31]([CH3:33])[CH3:32])([CH3:27])[CH3:26]>ClCCl>[CH:25]([O:28][P:29]([CH:5]1[CH:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][CH:8]2[CH:7]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:6]1)([O:30][CH:31]([CH3:33])[CH3:32])=[O:34])([CH3:27])[CH3:26]
Reactant: CC(=O)OCC1OC(OC(C)=O)C2OC(C)(C)OC12
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(=O)OCC1OC(P(=O)(OC(C)C)OC(C)C)C2OC(C)(C)OC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of acetic acid 6-acetoxy-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester (623 mg, 2.27 mmol) in dichloromethane (3 mL) was added iodotrimethylsilane (0.35 mL, 2.49 mmol) at −78° C. and the reaction mixture brought to RT. After confirming the disappearance of starting material by TLC, triisopropylphosphite (1.18 mL, 5.68 mmol) was added at −78° C. The reaction mixture was left to warm to RT and stirred overnight. The reaction was quenched with sodium bicarbonate, extracted with dichoromethane, the organic layers concentrated, dried and chromatographed. Elution with 50% ethylacetate/hexanes gave acetic acid 6-(diisopropoxy-phosphoryl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester as a colorless syrup (467 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][OH:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C2NNC(=O)C=2C)CC1)=O)(C)(C)C.CI.C(I)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][O:22][CH3:24])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Reactant: CCn1nc(CO)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCI
Solvent: CI
Product: CCn1nc(COC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-hydroxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Piperidine 19, Step C) using a procedure analogous to that described for Piperidine 15, Step E, except methyliodide was substutited for ethyliodide. RF: 0.47 (3:2 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.39 (t, J=7.2, 3H), 1.49 (s, 9H), 1.69–1.71 (m, 2H), 1.85–1.94 (m, 2H), 2.08 (s, 3H), 2.75–2.81 (m, 3H), 3.39 (s, 3H), 4.12 (q, J=7.2, 2H), 4.14–4.27 (m, 2H), 4.38 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([OH:17])=[CH:15]3)=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([O:17][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15]3)=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2cc(O)ccc12
Product: CCOC(=O)COc1ccc2c(C(=O)OC)c(C)c(C(=O)c3ccc(N)c(OC)c3)n2c1

Procedure:
This compound is obtained by carrying out the procedure according to the preparation described in the example above, by alkylating methyl [3-(4-amino-3-methoxybenzoyl)-6-hydroxy-2-methylindolizin-1-yl]carboxylate with ethyl bromoacetate.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1-n1cccn1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (240 mg, brown solid) from 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.74 mmol, Intermediate-70) and phenyl formate (180 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: COC(=O)c1cccnc1F
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncccc3C(=O)OC)C[C@H]2OC)nc1Cl
Yield: 81.3 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (62.51 mg, 0.19 mmol), methyl 2-fluoropyridine-3-carboxylate (68 mg, 0.39 mmol) and diisopropylethylamine (75 mg, 0.58 mmol), to obtain 65.2 mg of the title compound as a yellow brown oily substance (80%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:13].[OH-].[Na+].[ClH:16].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[ClH:17].[ClH:16].[ClH:17].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:13][C:2]1[NH:1][C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Sc1nc2cc3c(cc2[nH]1)CCN3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4c(cc3[nH]2)CCN4)nc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To 2.5 g of 1,5,6,7-tetrahydropyrrolo-(2,3-f)benzimidazole-2-thiol, suspended in 40 ml of alcohol, were added dropwise while stirring 1.2 g of sodium hydroxide in 20 ml of water and, after 30 minutes, there were added 2.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. The solution obtained was washed with 100 ml of 3N sodium hydroxide and three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product, dissolved in methanol, was treated with 30 ml of hydrochloric acid in ethyl acetate and the precipitated crystals were removed by filtration under suction. There were obtained 1.6 g (31.3% of theory) of 1,5,6,7-tetrahydro-2-[(2-pyridylmethyl)thio]pyrrolo(2,3-f)benzimidazole trihydrochloride of melting point 207°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 98.6 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (16.2 g, 40.2 mmol) was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 15.4 g (99% yield) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid. MS found: (M+H)+=389.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([NH2:20])[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8]
Reactant: [H][H]
Reactant: O=C1NCCCCC1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1cc(N)cc(C(=O)C2CCCCNC2=O)c1

Procedure:
A mixture of 3,5-dinitrobenzoyl caprolactam (2.00 g, 4.07 mmol), 0.08 g of 5 percent palladium on carbon and 30 ml of absolute ethanol is stirred with hydrogen under a pressure of 1 atmosphere at 10° C. When the theoretical quantity of hydrogen (0.024 mol) has been absorbed, the solution is filtered through celite. White crystals form when the filtrate is kept in a freezer, and the final product is obtained by recrystallization from CH2Cl2 to yield 65 percent of white crystals: mp 122°-124° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].Cl.N(CC)(CC)CC>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27]
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCCCc1ccccc1

Procedure:
5-Phenylvaleric acid (2.67 g, 15 mmol) in distilled THF was reacted with CDI (15 mmol) followed by glycine ethyl ester.HCl (15 mmol) and (C2H5)3N (15 mmol) as described in Example 35 Part A. The crude material (3.25 g, 82%) was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethylquinoline hydrochloride (380 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (660 mg, yield: 83%). This was recrystallized from acetone-hexane. Melting point: 147–148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)c1
Yield: 94.1 %

Procedure:
Reaction of 4-aminobenzophenone (100 mg, 0.51 mmol) in THF (6 mL) with m-anisoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-3-methoxy-benzamide (160 mg, 0.48 mmol, 94% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([F:27])[C:24]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[C:25]([F:27])[C:24]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
A mixture of 0.24 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(benzyloxycarbonyl)methoxypyridine [present compound 7-82], 10 mg of 10% palladium/carbon and 1 ml of ethyl acetate was stirred for 1.5 hours at room temperature under hydrogen atmosphere. There action system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-carboxymethoxypyridine [present compound 7-6].
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](OCC)=[O:35]>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[O:35])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: CCOC(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccn1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 28 g. (0.13 mole) of 3-phenyl-N,5-dimethyl- isoxazole-4-carboxamide and 330 milliliters of tetrahydrofuran is cooled to -65° C. and 180 milliliters of 1.6M n-butyllithium in hexane (0.288 mole) is added dropwise, maintaining the temperature between -60° and -70° C. After the addition is complete, the organic suspension is stirred for 11/2 hours at -60° to -70° C., and then 19.6 g. (0.13 mole) of ethyl picolinate in 196 ml. tetrahydrofuran is added drop-wise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-phenyl-5-(2-pyridylcarbonylmethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 146° to 149° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CC(O)C>[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Oc1ccc(N)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: Cc1cccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 170 °C

Procedure:
A mixture of 4-(3-methylpyridin-2-yloxy)benzenamine (1.00 g, 4.99 mmol) and 2-chlorobenzimidazole (0.860 g, 5.64 mmol) in 10 mL of iPrOH was heated at 170° C. for 30 min in the microwave. The reaction mixture was evaporated onto silica gel. Purification by flash chromatography (2M NH3 in MeOH:CH2Cl2) afforded N-(4-(3-methylpyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as solid. MS (ESI, pos. ion) m/z: 317.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([C@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N+:43]=[N-:44]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.) in DMF (0.13 M) was added NaN3 (5.0 equiv.). The solution was submerged in an 80° C. oil bath and left stirring under Ar for 24 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate in 60% yield. LC/MS (m/z)=548.4 (MH+), Rt=0.94 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.97-1.13 (m, 3 H), 1.33-1.52 (m, 30 H), 2.03-2.19 (m, 1 H), 2.66-2.87 (m, 2 H), 3.16 (dd, J=12.72, 2.15 Hz, 1 H), 3.22-3.32 (m, 1 H), 3.81-4.01 (m, 2 H), 4.78 (d, J=9.00 Hz, 1 H), 6.76-6.88 (m, 1 H), 8.05-8.18 (m, 1 H), 8.26-8.37 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][C@H:9]2[OH:22])=[C:6]([O:23][CH3:24])[CH:5]=[C:4]([O:25][CH3:26])[C:3]=1[C:27](=[O:29])[CH3:28].[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]1[O:1][C:2]2[C:3]([C:27](=[O:29])[CH:28]=1)=[C:4]([O:25][CH3:26])[CH:5]=[C:6]([O:23][CH3:24])[C:7]=2[C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[OH:22]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c(C(C)=O)c3O)[C@H](O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@H](O)C2)cc1

Procedure:
Compound of example 121 (2.0 g, 5.0 mmol) in dry DMF (25 mL) was reacted with methyl 2-chlorobenzoate (2.55 g, 15 mmol) in the presence of NaH (50%, 1.19 g, 25 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:13][CH2:14][CH3:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:16](#[N:18])[CH3:17]>>[OH:9][CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:13][CH2:14][CH3:15])[CH:6]=1)[CH2:17][C:16]#[N:18]
Reactant: CCCC(O)COc1cccc(C=O)c1
Reactant: CC#N
Product: CCCC(O)COc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-hydroxypentyloxy)benzaldehyde gave 3-hydroxy-3-(3-(2-hydroxypentyloxy)phenyl)propanenitrile as a yellow oil. Yield (0.25 g, 12%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.34 (m, 1H), 6.94-7.00 (m, 2H), 6.88 (dd, J=8.0, 2.0 Hz, 1H), 5.01 (t, J=5.6 Hz, 1H), 3.96-4.06 (m, 2H), 3.83 (dd, J=8.8, 7.6 Hz, 1H), 2.76 (d, J=6.0 Hz, 2H), 1.52-1.60 (m, 2H), 1.40-1.49 (m, 2H), 0.97 (t, J=6.8 Hz, 3H).