Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 0° C. solution of 3,3-dimethylcyclobutanecarboxylic acid (1.35 g, 10.5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (4.01 g, 31.6 mmol) and 1 drop of N,N-dimethylformamide. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was concentrated in vacuo to give crude 3,3-dimethylcyclobutanecarbonylchloride (1.54 g) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25](=[O:27])[CH3:26])[CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(OCC)(=O)C.O>C(O)C>[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:27])[CH3:26])[CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 87.8 %

Procedure:
Sodium borohydride (0.03 g) was added to a solution (5 ml) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetylindoline (0.17 g) in ethanol and the resultant mixture was stirred at room temperature overnight. Then ethyl acetate and water were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Then the residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (150 mg) as a colorless oil (yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5](O)=[O:6].Cl.[O:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5]([NH:29][O:27][CH3:28])=[O:6]
Reactant: Cc1ccc(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)[nH]1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3ccc(C)[nH]3)CC2)c1

Procedure:
The title compound was synthesised by an analogous method to Example 45 starting from 2-chloro-6-(4-{[(5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 332) and methoxylamine hydrochloride.
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])C1C=CC=CC=1.[C:18](O)(=O)[CH:19]([CH3:21])[CH3:20].Cl>>[OH:8][C:9]1[C:10]2[N:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:12]([CH3:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CNc1cccc(OCc2ccccc2)c1N
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)c1nc2c(O)cccc2n1C
Yield: 6.6 %

Procedure:
A mixture of 3-benzyloxy-2-amino-N-methylaniline (600 mg), isobutyric acid (243 mg) and 4N hydrochloric acid (3.5 ml) was refluxed for 3 hours, and the solvent was removed in vacuo. Chloroform and saturated sodium bicarbonate solution were added to the residue. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatogrpahy (chloroform:methanol=50:1, v/v) to give 4-hydroxy-2-isopropyl-1-methyl-1H-benzimidazole (33 mg).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(S)c1
Yield: 50 %

Procedure:
2-(3-Mercaptophenyl)acetic acid (1.0 g, 6.0 mmol) was dissolved in dry methanol (40 mL). To this solution 10 drops concentrated sulfuric acid was added and the reaction mixture was heated to reflux for 36 hours. The reaction mixture was then concentrated to about half the volume, diluted with ethyl acetate, and the organic layer washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to afford methyl 2-(3-mercaptophenyl)acetate as an oil (0.55 g, 3.0 mmol, 50% yield). 1H NMR (CDCl3) 7.05 ppm, 3H, m; 6.88 ppm, 1H, m; 3.53 ppm, 3H, s; 3.38 ppm, 2H, s.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21]C(=O)OC(C)(C)C)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[NH2:21][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][N:10]([CH3:20])[C:11](=[O:12])[O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
(S)-tert-butyl 1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (5.78 g, 0.014 mol) was dissolved into a minimal volume of ethyl ether (100 mL) and added to a solution of TsOH (2.92 g, 0.0154 mol) in 20.0 mL of absolute EtOH. This solution was placed on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective de-protection of the BOC group proceeded concurrently with removal of the remainder of the solvent. The reaction was completed by 2 h and gave an off-white solid, which was washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basified with 1N NaOH (pH>10), and extracted with ethyl ether (3×50 mL). The combined organic extracts were washed with 1N NaOH (3×5 mL) and brine (3×5 mL),dried, decanted and stripped to give the free base of (S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (3.5 g, 80%). 1H NMR (400 MHz, CDCl3): 4.15 (t, J=8.4 Hz, 2H), 3.10 (m, 3H), 2.91 (s, 3H), 1.78-1.56 (m, 5H), 1.50-1.00 (M, 6H), 1.00-0.70 (m, 4H), 0.01 (s, 9H). MS (E/Z): 315 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH:6]([C:7]([O:9]CC)=[O:8])[C:5]1([CH3:13])[CH3:12])(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([C@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1C(C(C)=O)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)[C@H]1[C@H](C(=O)O)C1(C)C

Procedure:
Ethyl 3-acetyl-2,2-dimethylcyclopropane-1-carboxylate (36.0 g, 0.2 m) and N potassium hydroxide (391 ml) in ethanol (391 ml) was refluxed for two hours. Excess alcohol was removed in vacuo and the resulting solution acidified with concentrated hydrochloric acid (≈40 ml). This precipitated a solid which was extracted with ether (3×200 ml), the ether dried over anhydrous MgSO4 and evaporated in vacuo to give a cream solid m.p. 111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[N:11]=[N:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[N:11]=[N:10][C:9]([O:12][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1)c1ccccc1
Yield: 43.6 %

Procedure:
A solution of 6-(3,4-dichloro-phenoxy)-pyridazin-3-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.36 g, 2.10 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.24 g, 2.10 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 30:70), yielding the title compound (0.34 g, 44% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC=C)[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1.Cl[C:26]1[CH:31]=CC=C[C:27]=1Cl>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:19][C:15]3[CH:16]=[CH:17][C:18]([CH2:31][CH:26]=[CH2:27])=[C:11]([OH:10])[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1
Reactant: C=CCOc1cccc2oc(CCc3ccc(OC)cc3)c(C)c12
Reactant: Clc1ccccc1Cl
Product: C=CCc1ccc2oc(CCc3ccc(OC)cc3)c(C)c2c1O
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran (0.9 gm, 2.8 mmoles) in ortho dichlorobenzene (15 mL) was refluxed for 4.5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and was chromatographed on silica gel. Elution with 15% ethylacetate in hexane yielded 0.6 gm (67%) of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>ClCCl>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cc1ccccc1
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of aluminum chloride (6.67 g) in dichloromethane (70 ml) was added hexanoyl chloride (7.0 ml) at 0° C. After the mixture was stirred at 0° C. for 15 minutes, isobutylbenzene (7.9 ml) was added to the mixture. The mixture was stirred at 0° C. for 30 minutes and poured into ice water. The separated organic layer was washed with water, aqueous sodium bicarbonate and brine. The solution was dried over magnesium sulfate and evaporated to give 4'-isobutylhexanophenone (10.52 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[NH2:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:29]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])=[CH:32][CH:31]=1)#[N:28]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: N#Cc1ccc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)cc1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 4-(aminomethyl)benzonitrile (30 mg, 0.22 mmol). Yield: 66 mg (63%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1-c1ccc(COS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate and 8.4 g (83.0 mmol) of triethylamine were dissolved in methylene chloride (150 ml). Under cooling with ice, a solution of 5.7 g (50 mmol) of methanesulfonyl chloride in methylene chloride (25 ml ) was dropwise added thereto, followed by further stirring for one hour. The reaction liquid was poured into water, followed by the extraction with methylene chloride. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. 13.1 g of the title compound was obtained as a wax (yield 100%).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH2:21][CH:22]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:23]([O:25]CC)=[O:24])[CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[NH:3].[OH-].[Li+]>>[NH:1]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH2:21][CH:22]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:23]([OH:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)C(Cc1cccc(NS(=O)(=O)c2cccc(NC(=N)N)c2)c1)NC(=O)CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: N=C(N)Nc1cccc(S(=O)(=O)Nc2cccc(CC(NC(=O)CCc3ccccc3)C(=O)O)c2)c1

Procedure:
Corresponding to Example 4, 410 mg of (6f) were hydrolysed using lithium hydroxide. A white solid was obtained (yield: 221 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[C:9]([C:13]([OH:15])=[O:14])=[CH:8]2)=O.[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].ClCCl.CO>ClCCl.CO.O>[CH3:12][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][N:27]2[CH2:28][CH2:29][N:24]([C:22]([C@@H:18]3[CH2:19][CH2:20][CH2:21][N:17]3[CH3:16])=[O:23])[CH2:25][CH2:26]2)[CH:8]=[C:9]1[C:13]([OH:15])=[O:14]
Reactant: CN1CCCC1C(=O)N1CCNCC1
Reactant: Cn1c(C(=O)O)cc2cccc(C=O)c21
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN1CCC[C@H]1C(=O)N1CCN(Cc2cccc3cc(C(=O)O)n(C)c23)CC1

Procedure:
7-formyl-1-methyl-1H-indole-2-carboxylic acid and (1-methyl-pyrrolidin-2-yl)-piperazin-1-yl-methanone are used as reaction partners. After the reaction has ended the solvents are eliminated in vacuo and the residue is taken up in a little dichloromethane/methanol 80:20. The solution is added to a short layer of silica gel and sucked into a vacuum suction flask by the application of reduced pressure. Then dichloromethane/methanol/water 1:1:0.1 is added in several small batches and again the solution is sucked into a vacuum suction flask by the application of reduced pressure. The fractions containing the product are combined and evaporated down in vacuo.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.C1(C)C=CC=CC=1>[N+:11]([C:4]1[CH:3]=[C:2]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(OCCN2CCOCC2)c2occc2c1
Yield: 32 %

Procedure:
To a test tube was added 7-iodo-5-nitrobenzofuran (1.0 g, 0.00346 mol), 4-(2-hydroxyethyl)morpholine (0.91 g, 0.00692 mol), cesium carbonate (2.25 g, 0.00692 mol), 1,10-phenanthroline (0.25 g, 0.00138 mol) and CuI (130 mg, 0.692 mmol). Toluene (15 mL) was added and the solution was heated in a StemBlock for 72 h. After filtration through Celite, the crude material was purified by flash chromatography (EtOAc/DCM; 1:1). Yield: 32%, HPLC purity=90%, m/z=293 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCOCC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCOCC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydropyran-4-yl-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 461.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(=O)C.[Na+]>>[C:32]([O:14][CH:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH2:10][N:11]([C:15]2[N:20]=[CH:19][N:18]([CH2:21][C:22]3[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]=2)[CH2:12]1)(=[O:34])[CH3:33]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OC1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 94 %

Procedure:
To 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (20.0 mg, 0.0442 mmol) synthesized in Synthesis Example 190, at room temperature, acetic anhydride (2.0 mL) and sodium acetate (9.00 mg, 0.110 mmol) were added at room temperature and the resultant mixture was stirred at 100° C. for 40 minutes. After the completion of the reaction, the reaction solution was concentrated and to the resultant residue, water was added, followed by filtering a deposited colorless solid and by drying the solid to obtain the title compound (20.6 mg, yield: 94%).
Reaction SMILES: [CH3:1][C:2]12[N:7]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:6]1[CH2:5][CH2:4][CH2:3]2.[N-:18]=[N+:19]=[N-:20].[Na+]>CC(O)C.O>[N:18]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[N+:19]=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)N2C3CCCC32C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-methyl-6-(4-methylbenzenesulfonyl)-6-azabicyclo[3.1.0]hexane (55 g, 219.12 mmol) in IPA (1000 ml) and water (1000 ml) was added sodium azide (57.0 g, 876.92 mmol). The reaction mixture was stirred at room temperature for 17 hours. The reaction was cooled to room temperature and water (1000 ml) was added. The aqueous layer was extracted with diethyl ether (3×500 ml). The combined organics were washed with brine (250 ml), dried over sodium sulfate, concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])#[CH:2]>CN(C=O)C>[C:1]1([C:3]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:2]=[C:1]([C:3]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:2]=[C:1]([C:3]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:2]=1
Reactant: C#CC(=O)Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1cc(C(=O)Oc2ccccc2)cc(C(=O)Oc2ccccc2)c1

Procedure:
In the reaction, phenyl acetylenecarboxylate 12 is readily obtained by a simple condensation of phenol 11 and propiolic acid 9 using 1,3-dicyclohexylcarbodiimine (DCC), 4-(dimethylamino)pyridine (DMAP), 4-toluenesulfonic acid (TsOH) and Dichloromethane (DCM). Refluxing the obtained phenyl acetylenecarboxylate 12 in DMF for 24 hours under nitrogen yields the cyclotrimerized product of triphenyl benzene-1,3,5-tricarboxylate 13.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16]C(=O)OC(C)(C)C)=[O:10].O.O.[F-].[K+].[O:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1>C1COCC1.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].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:39]1[CH2:40][CH2:41][O:36][CH2:37][CH:38]=1)=[O:10]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1=CCOCC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 17.7 %

Procedure:
A mixture of tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (234 mg, 0.5 mmol), potassium fluoride dihydrate (155 mg, 1.65 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol) in THF (5 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2, 60 mg, 0.05 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 110° C. for 8 hr. Water (10 mL) was added and the mixture extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel chromatography (isohexane then 0-5% MeOH/EtOAc). The resulting intermediate was dissolved in MeOH (5 mL) and treated with a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at room temperature for 16 hr and the solvent removed under reduced pressure. Purification via preparative HPLC gave 101 as a brown solid (37 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.05 (s, 1H), 7.38-7.26 (m, 1H), 7.06-6.97 (m, 2H), 6.13 (s, 2H), 6.03-6.00 (m, 1H), 4.41 (d, J=2.8 Hz, 1H), 4.39 (d, J=2.8 Hz, 1H), 3.96 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 2.45-2.41 (m, 2H). LCMS (ES+) m/z 418 (M+1).
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cccnc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1)c1cccnc1F
Reaction time: 16 h
Yield: 14.3 %

Procedure:
2-Fluoro-nicotinic acid (0.793 g, 5.59 mmol) and phenethylamine (0.705 mL, 5.59 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (1.56 mL, 11.2 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.97 g, 7.83 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.196 g, 0.802 mmol, 14.3%). ESI-MS m/z calc. 244.1, found 245.2 (M+1)+. Retention time of 2.76 minutes.