Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:38].O>CN(C)C=O>[CH3:38][O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodomethane (0.187 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (382 mg, yield: 80%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[C:11](OC)([O:14]C)[C:12](=[O:13])[CH:6]1[CH:7]=[C:8]2[Br:18])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[C:11](=[O:14])[C:12](=[O:13])[CH:6]1[CH:7]=[C:8]2[Br:18])=[O:4]
Reactant: COC(=O)C1CC2C(Br)=CC1C(=O)C2(OC)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CC2C(=O)C(=O)C1C=C2Br

Procedure:
3 g (9.4 mmol) of 5-bromo-8,8-dimethoxy-7-oxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester (J.O.C. (202), 67, 6493) are stirred in a mixture of 15 ml of trifluoroacetic acid and 1 ml of water for 12 hours at room temperature. Extraction is then carried out with dichloromethane against water. The organic phase is dried over sodium sulfate and yields, after removal of the solvent, the 5-bromo-7,8-dioxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester in the form of an orange-coloured oil and as a pure isomer.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:96]=[CH:97][CH:98]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([O:84][CH3:85])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:96]=[CH:97][CH:98]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([O:84][CH3:85])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperidine-1-carboxylate (200 mg, 0.271 mmol) was hydrolyzed by lithium hydroxide (57 mg, 1.358 mmol) in THF/methanol/water (5/2/2 ml) to yield crude 100 mg (63.2% yield) of the titled compound. MS: m/z=582.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](Br)[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([N:37]4[C:36](=[O:38])[C:35]5=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]5[C:33]4=[O:43])[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(Br)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 3.01 g of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(1-bromoethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole in 10 mL of N,N-dimethylformamide, 1.26 g of potassium phthalimide was added and the resultant mixture was stirred at 80° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 20 mL of water was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate (70 mL×1). The organic phase was washed with water (20 mL×1) and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (a gradient from 1:10 to 1:5) to obtain 2.80 g of the objective substance as a colorless resinoid.
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:20])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:34]1C=CC=C[CH:35]=1>C(OCC)(=O)C.CN>[CH3:20][C:13]1([CH3:21])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:34][CH3:35])[C:12]1=[O:22]
Reactant: c1ccncc1
Reactant: CC1(C)C(=O)N([C@@H](CCO)c2ccccc2)c2ccccc21
Agent: CN
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Reaction time: 16 h

Procedure:
1-[(1S)-3-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.2 g, 4.1 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.84 g, 4.4 mmol) was added. Stirred for 16 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A portion of the crude product (100 mg, 0.21 mmol) was immediately dissolved in methylamine (8M in ethanol, 10 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 0-15% methanol saturated with ammonia in chloroform) to give 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one as a colorless oil. The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (1.0 equivalent). The white precipitate was collected and dried under vacuum to give 44 mg 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [CH2:1]1[C:5]2(CCCC[C:6]2=[O:11])[CH2:4]CC1.C1(=O)CCCCC1.C[Mg]Cl.[Cl-].[NH4+].[CH3:24][C:25]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2>O1CCCC1>[C:6]([O:35][C:25]1([CH3:24])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:11])[C:5]([CH3:1])=[CH2:4]
Reactant: CC1(O)CCCCC12CCCC2
Reactant: O=C1CCCCC12CCCC2
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C1CCCCC1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)CCCCC12CCCC2
Temperature: 25 °C
Yield: 87 %

Procedure:
With stirring under nitrogen atmosphere at room temperature, a mixture of 100 g of spiro[4.5]decan-6-one (which had been synthesized from cyclohexanone by a method as described in A. P. Krapcho, Synthesis, 1974, p 383 and references cited therein) and 200 ml of tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 1.28 mol methylmagnesium chloride (which had been prepared from 31.1 g of metallic magnesium, 400 ml of tetrahydrofuran and chloromethane), during which time the temperature was kept below 60° C. The reaction mixture was refluxed for 30 minutes, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent vacuum distillation, there was obtained 93.3 g (yield 87%) of the target compound, 6-methylspiro[4.5]decan-6-ol.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH2:1]([C:3]1[N:4]([CH2:15][C:16]2[CH:35]=[CH:34][C:19]3/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=4[O:23][CH2:24][C:18]=3[CH:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCc1nc(-c2ccccc2)c[nH]1
Product: CCc1nc(-c2ccccc2)cn1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 92.9 %

Procedure:
Using 2-ethyl-4-phenyl-1H-imidazole (Tetrahedron Letters, 1967, p 265, 47 mg, 0.273 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (90 mg, 0.273 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (114 mg, 92%) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C(OC(=O)NC1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)(C)(C)C.[C:45]([O:49][C:50](=[O:65])[C:51]([O:54][C:55]1[CH:60]=[CH:59][C:58]([CH2:61][C:62]([OH:64])=O)=[CH:57][CH:56]=1)([CH3:53])[CH3:52])([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:49][C:50](=[O:65])[C:51]([CH3:52])([O:54][C:55]1[CH:56]=[CH:57][C:58]([CH2:61][C:62](=[O:64])[N:2]([CH3:1])[C:3]2[C:4]([CH3:19])=[N:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)=[CH:59][CH:60]=1)[CH3:53])([CH3:46])([CH3:47])[CH3:48]
Reactant: CNc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)OC(C)(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N(C)C(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 124C], methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-amine (prepared from [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (example 125B] by N-methylation followed by Boc-cleavage in analogy to the procedures described in examples 5E] and 5F]) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-[4-({methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22](O)=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[CH3:25][N:26]1CCOCC1.Cl.CN.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO.C1COCC1.CN(C=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22]([NH:26][CH3:25])=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1OCC(=O)O
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ({2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-yl}oxy)acetic acid (1.8 g, 5.4 mmol) in the mixed solvents of DMF (36 mL) and THF (36 mL) were added NMM (2.3 g, 21 mmol), methylamine hydrochloride (0.44 g, 6.5 mmol), HOBt (1.47 g, 11 mmol) and EDCl (2.08 g, 11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. TLC(CH2Cl2/MeOH=2:1) indicated the reaction was complete. The mixture was concentrated in vacuo. The residue was taken up with CH2Cl2 (100 mL), washed with 5% aq. Na2CO3 (30 mL×2) and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (CH2Cl2˜CH2Cl2/MeOH=100:1 to CH2Cl2/MeOH=80:1) to give the title compound (1.2 g, 63.2%) as a light yellow solid. 1H NMR (MeOD) δ (ppm) 8.90 (1H, s), 7.39 (1H, d), 7.40 (1H, m), 4.689 (2H, s), 3.84 (1H, m), 3.67 (1H, m), 2.94 (3H, s), 2.40 (3H, s), 2 54 (4H, m), 1.39 (4H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.C[O:18][B:19](OC)[O:20]C.O>C(OCC)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:19]([OH:20])[OH:18])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cnc2ccccc2c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A solution of 3-bromoquinoline (14.6 g (0.07 mole)) in 50 ml of diethylether was added at -40° under argon to a solution of 2 M n-BuLi (37.5 ml (0.075 mole) (in cyclohexane)) in 50 ml Et2O. The reaction mixture was stirred 15 minutes and 0.075 mole (7.8 g, 8.5 ml) trimethylborate was added rapidly over 2 minutes. The mixture was stirred 15 minutes at 0° C. and 4 ml of H2O was added and stirring continued for 30 minutes. The volatiles were evaporated in vacuo to a yellow tar resi-due. The residue was dissolved in 150 ml ethyl alcohol to which was added 4 ml of acetic acid and reflux-ed for 45 minutes. The volatiles were evaporated in vacuo to a yellow oily residue. The residue was stirred with 40 ml of ether to give a yellow solid which was filtered, washed with ether and dried to give 11.14 g of a solid. The solid was stirred in 100 ml of water and filtered to give 3.26 g of a solid after air drying. The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.[CH3:20][C:21]1([CH3:31])[NH:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][N:23]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:22][C:21]3([CH3:31])[CH3:20])=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: CC1(C)CN(C2COC2)CCN1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
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: CC1(C)CN(C2COC2)CCN1C(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (100 mg, 0.33 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (62 mg, 0.36 mmol), HATU (278 mg, 0.37 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (3 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) affording the title compound as a yellow solid. LCMS (method H): RT 2.67 min, [M+H]+ 453.3
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5]N[CH2:3][CH2:2]1.[C:10]([Si:14]([CH3:34])([CH3:33])[O:15][Si:16]([CH:26]([CH2:29][CH:30]1[CH2:32][O:31]1)CC)([CH3:25])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[O:15]([Si:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:25])[CH2:26][CH2:29][CH2:30][O:31][CH2:32][CH:8]([OH:9])[CH2:7][N:1]1[CH2:6][CH2:5][CH:26]([CH2:29][CH2:30][OH:31])[CH2:3][CH2:2]1)[Si:14]([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:34])[CH3:33]
Reactant: CCC(CC1CO1)[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[Si](C)(CCCOCC(O)CN1CCC(CCO)CC1)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
2-piperazin-1-yl-ethanol (0.61 g) and ethanol (20 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,5-Di(tert-butyl)-3-(oxiranylmethylpropyl)-1,1,3,5,5-Pentamethyltrisiloxane (2.0 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, the ethanol was removed by rotovap, and the mixture was distilled under reduced pressure to remove impurities.
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13]CC2CCCCC2)[C@H:11]([CH2:21][CH2:22][C:23]2([C:33]([O:35]CC)=[O:34])[S:28](=[O:30])(=[O:29])[CH2:27][CH2:26][CH2:25][S:24]2(=[O:32])=[O:31])[O:10][C:9]1([CH3:39])[CH3:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].O1[CH2:47][CH2:46]OCC1>>[C:1]([N:8]1[C@@H:12]([CH2:13][CH:47]2[CH2:46][CH2:13][CH2:12][CH2:11][CH2:21]2)[C@H:11]([CH2:21][CH2:22][C:23]2([C:33]([OH:35])=[O:34])[S:28](=[O:29])(=[O:30])[CH2:27][CH2:26][CH2:25][S:24]2(=[O:31])=[O:32])[O:10][C:9]1([CH3:39])[CH3:38])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)C1(CC[C@@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CCC2CCCCC2)S(=O)(=O)CCCS1(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CCC2(C(=O)O)S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Reaction time: 3 h

Procedure:
A mixture of 1 g of 2-[2-((4S,5S)-3-BOC-4-cyclohexylethyl-2,2-dimethyl-5-oxazolidinyl)-ethyl]-2-ethoxycarbonyl-1,3-dithiane 1,1,3,3-tetroxide, 50 ml of dioxane and 20 ml of 2 N NaOH (aqueous) is stirred at 20° for 3 h. The usual working up gives 2-[2-((4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl)-ethyl]-2-carboxy-1,3-dithiane 1,1,3,3-tetroxide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
3 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole and 1.5 g of triethylamine were dissolved in 50 ml of dichloromethane, to which a solution of 1 g of acetyl chloride in 20 ml of dichloromethane was added dropwise under ice cooling. After stirring at room temperature for 8 hours, the mixture was washed with water and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was treated by column chromatography to obtain 2.7 g of 4-acetoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 76.5%). n20D=1.4752.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:5])=[O:44])([CH3:55])[CH3:54]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: CC(C)(CN)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCC(C)(C)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CB29) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown glassy foam (0.084 g, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([OH:24])=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:27](Cl)(=O)C(Cl)=O.CN(C)C=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([O:24][CH3:27])=[O:23])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (148 mg) was dissolved in 2 ml of dry methylene chloride, and 0.2 ml of oxalyl chloride and a catalytic amount of dimethylformamide were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled to remove the solvent, and dry benzene was added thereto, followed by distillation of benzene. After two times repetition of the above procedure, the residue was dissolved in 2 ml of dry methylene chloride. The solution was added to a mixture of methanol (125 mg), triethylamine (81 mg) and dry methylene chloride (1 ml) under nitrogen stream with ice-cooling and stirred at the same temperature for 2 hours. The reaction mixture was washed successively with water and dilute hydrochloric acid, dried over anhydrous sodium sulfate and distilled to remove the solvent to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-methoxycarbonylmethyl-4-acetylthiopyrrolidine.