Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][C:13](=[O:17])[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11]1=[O:27].C(N(C(C)C)CC)(C)C.[N:37]([CH2:40][C:41]([O:43]CC)=[O:42])=[C:38]=[O:39]>ClCCl>[OH:17][C:13]1[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11](=[O:27])[N:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15](=[O:16])[C:14]=1[C:38]([NH:37][CH2:40][C:41]([OH:43])=[O:42])=[O:39]
Reactant: COc1ccccc1CN1C(=O)CC(=O)N(Cc2ccccc2OC)C1=O
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2OC)c1=O
Reaction time: 5 h

Procedure:
N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,34-tetrahydro-5-pyrimidinyl)carbonyl]glycine. A mixture of 1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.64 g, 4.45 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (500 uL, 4.45 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (1.0 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s., 1 H), 10.11 (t, J=4.93 Hz, 1 H), 7.20-7.28 (m, 2 H), 7.00 (d, J=7.83 Hz, 2 H), 6.86-6.96 (m, 4 H), 5.00 (s, 4 H), 4.10-4.18 (m, 2 H), 3.82 (s, 6 H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Reactant: CI
Product: CCOC(=O)C(C)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate and methyl iodide and by reaction and purification in the same manner as in the method described in Example 121, step 1, ethyl 2-(2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)propanoate was obtained as a colorless oil
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]=1[CH3:25].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([Br:16])=[C:18]([CH3:25])[CH:19]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (2.0 mL) was added dropwise to a solution of 4-bromo-3,5-dimethylphenol (CAS No. 7463-51-6) (2.0 g) and TEA (1.94 mL) in DCM (20 mL) under ice-cooling over three minutes. The reaction mixture was stirred at room temperature for 30 minutes. Ice and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5%) to give the title compound (3.20 g).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:18]1[S:19][C:20](=[NH:35])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]>O>[C:16]([C:18]1[S:19][C:20](=[N:35][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=NC(=O)c3ccccc3)n1CC2

Procedure:
5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline, and the mixture is refluxed for 0.5 hours. After cooling, the mixture is diluted with water. 0.6 g. of 1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a] isoquinoline is obtained in crystalline state; m.p.: 274°-276°C (after recrystallization from a mixture of dimethylformamide and butanol).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[N:30]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[S:27][CH:28]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cccnc2)n1
Yield: 79.7 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.060 g, 0.215 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.044 g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g, 0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example 274 affording 0.080 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.20 (d, 3H), 4.40 (m, 2H), 4.51 (m, 1H), 7.02 (d, 1H), 7.81 (d, 1H), 7.94 (m, 3H), 8.33 (s, 1H), 8.38 (d, 1H), 8.54 (d, 1H), 8.71 (d, 1H), 9.25 (bs, 1H).
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH3:16])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[C@@H:1]1([NH:12][C:13]([N:15]([CH3:16])[N:17]=[O:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
1-(β-D-mannopyranosyl)-3-methyl-urea (200 mg) was dissolved in a mixture of 1.5 ml of glacial acetic acid and 3.5 ml of water, and the resulting solution was admixed with 99 mg of sodium nitrite. The mixture so obtained was agitated for 3 hours at ambient temperature to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove sodium cation therefrom. The reaction mixture so treated was then concentrated by distillation under reduced pressure at a temperature of less than 30° C to remove the solvent, so that a crystalline product was deposited. This crystalline product was collected by filtration and washed with n-propanol, affording 180 mg of the titled compound. Yield 78%. mp. 103° C (with decomposition). [α]D26 -12.6° (c 0.99, H2O).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[CH2:30][CH2:29]2)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>O1CCCC1>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]([CH3:37])([CH3:38])[CH2:35][O:36][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32][CH2:33]2)[CH:16]=[C:15]([C:14]([F:39])([F:13])[F:40])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 5 h
Yield: 67.1 %

Procedure:
Triethylamine (0.75 g), followed by methylsulphonyl chloride (0.85 g) were added to a solution of 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidino]-prop-1-yne (3.0 g) in tetrahydrofuran (50 ml). After stirring for 5 hours, the precipitate of triethylamine hydrochloride was filtered off, and the filtrate was evaporated in vacuo to give a brown gum. This gum was purified by medium pressure chromatography using a mixture of dichloromethane and ethyl acetate (85:15) as eluent to give 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-methylsulphonyloxyethyl)piperidino]prop-1-yne (2.4 g) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH:36]=[CH:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:35][CH:36]=[CH:37][CH3:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CC=CCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Product: CC=CCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 99.1 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:15]1[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]1=[O:22])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 2.3 %

Procedure:
A mixture of 0.5 g 5-methoxy-1-indanone, 1.23 g oxindole and 2.7 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a greenish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Chromatography afforded 20 mg of 3-(5-methoxyindan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2F)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (480 mg, 1.4 mmol) and indole-6-carboxylic acid (242 mg, 1.5 mmol) afforded, after purification (SiO2: 0 to 40% 2 N ammonia/methanol solution in DCM), 355 mg (53%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a cold (0° C.) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (example 68 step 4, 500 mg) and triethyl amine (836 mg) in dichloromethane (5 mL) was added toluene-4-sulfonyl chloride (1.53 g). The reaction mixture was stirred overnight at room temperature then partitioned between hydrochloric acid (1N) and dichloromethane. The aqueous layers was extracted with dichloromethane and the combined organic layers were washed with half saturated aqueous solution of sodium hydrogenocarbonate and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (1:0 to 19:1 v/v) as eluant to afford the title compound (602 mg, 80%) as a yellow liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH3:13][N:14]=[C:15]=S.C(Cl)CCl>N1C=CC=CC=1>[CH3:13][NH:14][C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1
Reactant: CN=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CNc1nc2cc([N+](=O)[O-])ccc2n1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A solution of diamine 248 (1.88 g, 11.2 mmol) in pyridine (20 mL) was treated with methyl isothiocyanate (970 mg, 12.9 mmol) and the mixture was stirred at 80° C. for 30 minutes, cooled down to 15° C., treated with solid EDC (3.03 g, 15.8 mmol, 1.40 eq) and the heating continued at 80° C. for 16 h. After removal of pyridine in vacuo, the residue was purified by flash chromatography (eluent 5% MeOH in CH2Cl2) to afford the title compound 268 (1.44 g, 62% yield). 1H NMR: (CD3OD) δ (ppm): 8.12 (d, J=2.2 Hz, 1H), 7.94 (dd, J=2.2, 8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.44 (bs, 2H), 3.51 (s, 3H), 3.04 (s, 3H). LRMS: (calc.) 206.2; (obt.) 207.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: C1CCNC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 22.6 h
Yield: 38.5 %

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.2 g, 0.65 mmol) in DMF (1.3 mL) was added pyrrolidine (0.046 g, 0.65 mmol) followed by potassium carbonate (0.180 g, 1.3 mmol). The reaction was stirred at 100° C. for 22.6 h. After which, the reaction mixture is cooled to rt and water was added. The crude reaction was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline (0.09 g, 0.250 mmol, 38.6% yield). Mass Spectrum (ESI) m/e=360.0 (M+1).
Reaction SMILES: [OH-].[CH2:2]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O:14][Si:15]([O:22]CC)([O:19]CC)[O:16]CC)C>O>[Si:15]([O-:22])([O-:19])([O-:16])[O-:14].[CH2:2]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:2]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:2]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:2]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCCCCC[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Hexyltrimethylammonium hydroxide, (30.03%), 492.96 g, was diluted with 1073.86 g deionized water and to it there were added 650.0 g of tetraethylorthosilicate, (98%) with stirring. After hydrolysis was complete, the solution was placed on a rotary evaporator to remove the alcohol. A total of 518.6 g of liquid was removed, after which 150 g of deionized water was added. Elemental analysis showed the solution to contain 5.10 wt % Si.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:18][CH:17]=1.Cl>CCCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24]/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: O=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of n-buthyllithium in hexane (47.0 ml of a 1.6M solution) was added dropwise to a solution of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (6.35 g) in dry THF (100 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-one (7.49 g) in THF (15 ml) was added dropewise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was then poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (6.2 g). M.p. 177-179° C.; Retention Time HPLC 2.19 min; MS (ES+) 461 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (20 mg), ethyl glycinate (10 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (21 mg). The reaction was stirred at 20° C. for 1 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was evaporated to give ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycinate (D89) as a brown oil (20 mg), which was used directly in the next hydrolysis step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([CH:19]=[O:20])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O.O.CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:22])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 65 °C
Yield: 61.4 %

Procedure:
Intermediate 28 (1.1 gm, 0.0034 mol) in acetone (5 ml) was heated to 60-70° C. for 10 min. To the above suspension was added dropwise a hot solution of potassium permanganate (1.07 gm, 0.0068 mol) in water:acetone (1: 3) (15 ml) for 10 min. The reaction was heated to 60-70° C. for 10 min., cooled to room temperature and filtered. The residue washed with acetone and the filterate was extracted with 10% sodium hydroxide solution. Acidification, followed by filteration and washing of the precipitate yielded 4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (0.6 gm) as white solid, mp: 178° C. (dec.)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3].CS([C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:17]([O:18][C:24]3[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=3)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3]
Reactant: CCOc1oc(-c2c(O)cccc2Cl)nc1C(C)C
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1oc(-c2c(Cl)cccc2Oc2nc(OC)cc(OC)n2)nc1C(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5 ml DMF solution containing 0.27 g 4-(2-propyl)-5-ethoxy-2-(2-chloro-6-hydroxyphenyl)oxazole, 0.20 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.41 g pottasium carbonate was stirred for 3 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective oily substance in an amount of 0.3 g.