Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]#[N:7])=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[Cl-:11].[NH4+:12]>>[ClH:11].[S:1]1[C:5]([C:6](=[NH:12])[NH2:7])=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ncns1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: N=C(N)c1ncns1

Procedure:
1,2,4-thiadiazole-5-carbonitrile (1.11 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61, Step B to give the title compound as an offwhite solid (1.32 g, 80%). The compound was characterized by the following spectroscopic data:
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]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[F:28][C:29]([F:36])([F:35])[CH2:30][S:31]([NH:21][CH2:20][CH:18]1[CH2:19][C:17]1([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: O=S(=O)(CC(F)(F)F)NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 79.4 %

Procedure:
(2-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine (71 mg, 0.15 mmol) was coupled with 2,2,2-trifluoroethanesulfonyl chloride (50 mg, 0.5 mmol) using General Coupling Method B to give 60 mg (86% yield) of 2,2,2-trifluoro-N-((2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methyl)ethanesulfonamide. MS found: (M+H)+=504.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9].Br[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:32]([CH:34]1[CH2:36][CH2:35]1)=[O:33].C(N(CC)CC)C.[Cl-:51].[Na+]>C(#N)C>[ClH:51].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])[C:32]([CH:34]2[CH2:35][CH2:36]2)=[O:33])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COC(=O)CCn1nncc1/C=C1\CNCCC1SC(C)=O
Reactant: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)piperidine hydrogen trifluoroacetate (3.5 g) in acetonitrile (100 ml) were added 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (4.1 g) and triethylamine (3.3 ml), and the resulting mixture was stirred at room temperature for 15 minutes. After addition of aqueous sodium chloride solution, products was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:2:1) as the eluent to afford a free base of the title compound (1.97 g) as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[OH:8][C:1]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1
Reactant: COCCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCC(O)(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A stirred solution of tert-butyl 3-benzoylpyrrolidine-1-carboxylate (489 mg, 1.78 mmol) in dry THF (10 mL) was cooled to −70° C. and 2 M 4-methoxybutylmagnesium chloride in THF (8 mL, 16 mmol) was added. The mixture was stirred at −70° C. for 1 h and poured into satd aq NH4Cl (100 mL). The mixture was extracted with ether (2×100 mL) and the combined ether extracts were dried over Na2SO4. Removal of the solvent left an oil which was purified by flash chromatography on a 40-g silica cartridge eluted with a 0 to 100% ethyl acetate in hexanes gradient to afford tert-butyl 3-(1-hydroxy-5-methoxy-1-phenylpentyl)pyrrolidine-1-carboxylate (290 mg, 44%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[C:24]([NH2:27])(=[S:26])[CH3:25].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:27]=[C:24]([CH3:25])[S:26][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(N)=S
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 10.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (570 mg), thioacetamide (0.20 g) and N,N-dimethylacetamide (15 ml) was stirred at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-4:6), the obtained crude product was purified by preparative HPLC, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (64 mg, yield 11%) as colorless needle crystals. melting point 161-162° C. MS:390 (MH+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.[CH2:27]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][S:34][CH2:33][NH:32]1)[CH3:28]>C(Cl)Cl>[CH2:27]([O:29][C:30](=[O:36])[C@@H:31]1[CH:35]([C:12](=[O:14])[CH2:11][CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[S:34][CH2:33][NH:32]1)[CH3:28]
Reactant: O=C(O)CC1CCc2ccccc2C1
Reactant: CCOC(=O)[C@@H]1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a mixture of 2.85 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 13.45 g of WSC.HCl was added 45 ml of methylene chloride under ice-cooling. The mixture was stirred for 5 minutes at room temperature. To this was added a solution of 2.4 g of L-thioproline ethyl ester in 7 ml of methylene chloride at room temperature, and the mixture was stirred for a further 18 hours at the same temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 3.4 g of 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline ethyl ester as a colorless oil (yield: 68%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].O.C(O)(=O)[CH2:20][C:21]([CH2:26]C(O)=O)([C:23](O)=O)O>O>[C:21]([O:13][C:12]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:15])([CH3:26])([CH3:23])[CH3:20]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2.00 g (13.2 mmol) of 4-(aminomethyl)benzoic acid suspended in water (20 ml) was mixed with 3.81 g (27.6 mmol) of potassium carbonate and then with 3.57 g (16.4 mmol) of di-tert-butyl bicarbonate under cooling with ice. The mixture was allowed to react at 40° C. for 2.5 hours and stirred at room temperature overnight. Then, water (7 ml) and 5.6 g of citric acid monohydrate were gradually added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (3.05 g, yield 92%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16].Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccsc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cn1cncc1C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-Bromo-1-methyl-imidazole (18.8 g, 117 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 38.9 mL, 117 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-methoxy-N-methylthiophene-3-carboxamide (20.0 g, 117 mmol) was added dropwise. The mixture was stirred for 3.5 h at room temperature. The mixture was worked-up by addition of water (400 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (3×100 mL), the organic layers were washed with water (100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1-methyl-1H-imidazol-5-yl)(3-thienyl)methanone [11.6 g, yield 41%; HPLC/MS: m/z=193 (M+H); log P(HCOOH)=0.43].
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)=[O:22])=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:37](=O)[CH3:38])=[CH:12]1)=O)C1C=CC=CC=1.Cl.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43]([NH2:45])=[NH:44].[CH3:48]N(C)C=O>>[C:42]([C:43]1[N:45]=[C:37]([C:13]2[C:14]3[C:19](=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:25][CH2:24]4)=[O:22])[CH:15]=3)[NH:11][CH:12]=2)[CH:38]=[CH:48][N:44]=1)([CH3:47])([CH3:46])[CH3:41]
Reactant: CC(=O)c1cn(C(=O)OCc2ccccc2)c2cc(Cl)c(C(=O)N3CCC(Cc4ccc(F)cc4)CC3)cc12
Reactant: CC(C)(C)C(=N)N
Reactant: CN(C)C=O
Agent: Cl
Product: CC(C)(C)c1nccc(-c2c[nH]c3cc(Cl)c(C(=O)N4CCC(Cc5ccc(F)cc5)CC4)cc23)n1
Temperature: 75 °C
Yield: 9 %

Procedure:
To a solution of 3-Acetyl-6-chloro-5-[4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-indole-1-carboxylic acid benzyl ester (150 mg, 0.27 mmol) in N,N-dimethylformamide (1 mL) was added dimethylformamide (N,N)-di-tert-butyl acetal (0.5 mL, 2.1 mmol) and the solution was heated to 75° C. for 5 h. The material was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. This material was filtered and concentrated to give an orange oil. This was dissolved in N,N-dimethylformamide (1 mL), added 2,2,2-trimethylacetamidine hydrochloride 85° C. for 18 h. The slurry was cooled to ambient temp and partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to an orange oil and purified by silica gel chromatography using ethyl acetate/heptane to afford the title compound as a yellow semi-solid (12.1 mg, 9%). MH+, m/z=505.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>>[CH:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:46]=[CH:47][C:38]=1[CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl]-piperidine-1-carboxylate as white crystals; MS: 624 (M+H)+.
Reaction SMILES: OO.[Cl:3][C:4]1[S:8][C:7]([S:9][CH2:10][CH2:11][CH:12]=[C:13]([F:15])[F:14])=[N:6][CH:5]=1.C(O)(=[O:18])C.[OH-:20].[Na+]>O>[Cl:3][C:4]1[S:8][C:7]([S:9]([CH2:10][CH2:11][CH:12]=[C:13]([F:15])[F:14])(=[O:18])=[O:20])=[N:6][CH:5]=1
Reactant: CC(=O)O
Reactant: [OH-]
Reactant: FC(F)=CCCSc1ncc(Cl)s1
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=S(=O)(CCC=C(F)F)c1ncc(Cl)s1
Temperature: 5 °C
Yield: 82 %

Procedure:
Hydrogen peroxide (0.77 g) was added to a mixture of 5-chloro-2-(4,4-difluorobut-3-enylthio)thiazole (1.94 g) and glacial acetic acid (21 g) at a temperature of 55-60° C. and the resultant mixture maintained at this temperature for 6 hours. After cooling the mixture to 5° C. and adding sufficient 47% sodium hydroxide solution to adjust the pH to 6 the mixture was diluted with water (20 ml) and extracted with chloroform (3×20 ml). The combined extracts were washed with water (20 ml), sodium bisulfite solution (20 ml), and water (20 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure yielded 5-chloro-2-(4,4-difluorobut-3-enylsulfonyl)thiazole (1.95 g, 82%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[CH2:28]([C:14]1[C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:36])[N:9]([CH3:35])[C:10]=2[N:17]=[CH:16][C:15]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)c1cccc(Oc2cnc3c(c2Cc2ccccc2)c(=O)n(CCCOC=O)c(=O)n3C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(Oc2cnc3c(c2Cc2ccccc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a solution of 3-(5-benzyl-6-(3-isopropylphenoxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.10 mmol) in THF (3 ml) and water (3 mL) was added LiOH.H2O (10 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by Prep HPLC to give 5-benzyl-3-(3-hydroxypropyl)-6-(3-isopropyl phenoxy)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 45% yield) as a solid. 1H NMR (CDCl3) δ: 8.32 (s, 1H), 7.29 (s, 2H), 7.25-7.12 (m, 4H), 6.99 (d, J=7.9 Hz, 1H), 6.76 (s, 1H), 6.68 (dd, J=8.0, 2.3 Hz, 1H), 4.80 (s, 2H), 4.24 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 3.52 (dd, J=11.8, 6.2 Hz, 2H), 3.10 (t, J=7.0 Hz, 1H), 2.85 (dt, J=13.9, 6.9 Hz, 1H), 1.98-1.83 (m, 2H), 1.22 (d, J=6.9 Hz, 6H). LCMS: MH+ 460 and TR=3.376 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1>CO.[Pt]>[CH3:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1=CCC(C(=O)O)OC1
Agent: [Pt]
Solvent: CO
Product: CC1CCC(C(=O)O)OC1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (40 mg, 0.28 mmol) in MeOH (2.0 mL) was added 5% Pt—C (20 mg), hydrogenated for 16 h at 20 psi. The reaction mixture was filtered off through celite, washed with MeOH and concentration of the filtrate gave 2:1 ratio of geometrical isomers of 5-methyl-tetrahydro-pyran-2-carboxylic acid (37 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:28][CH3:29])[CH:20]=1>>[ClH:1].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:3]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c(OC)cc1Cl
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar to Example 117 and isolated as a brown solid (55 mg, 68%). 1H NMR (CDCl3): 8.78 (dd, J=1.8, 4.8 Hz, 2H), 8.31 (dd, J=1.8, 4.8 Hz, 2H), 8.24 (s, 1H), 7.52 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 3.98 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](=O)([O-])[O-].[Na+].[Na+].[CH:20]([Cl:23])(Cl)Cl>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]12([C:11]([O:13][CH:20]([Cl:23])[CH3:14])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CC(Cl)OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 1-adamantanecarboxylic acid (1.50 g) in water (22 mL), sodium carbonate (3.53 g) was added, and the mixture was stirred at 100° C. for 20 minutes. After cooling to 0° C., tetrabutylammonium hydrogen sulfate (1.00 g), chloroform (30 mL) and 1-chloroethyl sulfochloridate (1.94 g) were added to the reaction mixture, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 12 hours. To the reaction solution, water was added, and the mixture was extracted twice with chloroform. The combined organic layer was washed with brine and then dried over anhydrous sodium sulfate. The insoluble was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate=100:0-50:50) to give 1-chloroethyl adamantane-1-carboxylate (A-2-1, 1.10 g) as a colorless oil.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:31][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:31][CH:12]1[CH2:13][CH2:14]2)[CH3:9]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C2CCC(C2)CC1c1cccc(OC(=O)C(C)(C)C)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add H2O (9 mg, 0.5 mmol) and TMSCl (39 mg, 0.357 mmol) to a solution of 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester (102 mg, 0.297 mmol) in 2-butanone (50 mL). Then stir the reaction mixture at ambient temperature for 4 hours. Evaporate the mixture under vacuum to give 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester hydrochloride as white solid (112 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J=15.6, 1H), 7.20-7.22 (d, J=7.6, 1H), 7.05 (s, 1H), 6.94-6.96 (m, 1H), 3.08-3.14 (m, 1H), 2.79 (s, 3H), 2.66 (s, 3H), 2.53-2.57 (m, 2H), 2.36 (s, 2H), 2.23 (m, 1H), 1.61-1.85 (m, 8H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=[CH:11][C:10]=1CC(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:32]([NH:34][C@H:35]([C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1)=[O:41])[CH2:36][C:37](=[O:39])[NH2:38])=O)(C)(C)C>>[CH2:16]([O:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:32]=1[NH:34][C@H:35]([C:40]([N:42]1[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]1)=[O:41])[CH2:36][C:37](=[O:39])[NH2:38])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC1
Product: CN1CCN(C(=O)[C@H](CC(N)=O)Nc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Yield: 88.6 %

Procedure:
Condensation of 2,4-dibenzyloxyphenylacetic acid (923 mg) and 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-methylpiperazine (1.0 g) was carried out in the same manner as in Example 12 (i) to obtain colorless crystalline powder 1-(2,4-dibenzyloxyphenyl-L-asparaginyl)-4-methylpiperazine (1.18 g). Melting point: 83°-85° C.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccccc1F
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2F)C1=O
Yield: 77.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 2-fluoroaniline (0.851 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.511 g (78%) of a yellow solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH:18]=[O:19].C[O-].[Na+]>C1(C)C=CC=CC=1>[OH:19][CH:18]([P:7](=[O:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[C:16]([CH3:15])=[CH:23][C:22]([CH3:24])=[CH:21][C:20]=1[CH3:25]
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Yield: 98 %

Procedure:
To 101 g (0.5 mol) of diphenyl phosphine oxide and 74 g (0.5 mol) of 2,4,6-trimethylbenzaldehyde in 150 mL of toluene there were added 0.5 g of a 30 wt % strength sodium methylate solution. The product began to crystallize after 10 minutes and was isolated in the usual manner. Yield: 98%.