Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS(N=C=O)(=O)=O.COC1C=CC(CO)=CC=1.[CH3:18][O:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]([NH:28][S:29](Cl)(=[O:31])=[O:30])=[O:27])=[CH:22][CH:21]=1.[CH3:35][O:36][C:37]1[CH:73]=[CH:72][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH2:71])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH:71][S:29](=[O:31])(=[O:30])[NH:28][C:26]([O:25][CH2:24][C:23]2[CH:33]=[CH:34][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:27])=[O:44])=[CH:72][CH:73]=1
Reactant: COc1ccc(COC(=O)NS(=O)(=O)Cl)cc1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Agent: COc1ccc(CO)cc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)NS(=O)(=O)NC[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc(OC)cc2)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of chlorosulfonyl isocyanate (3.95 ml: 45.4 mmole) in dichloromethane (70 ml), p-methoxybenzyl alcohol (5.66 ml: 45.4 mmole) is added at -50° C. The mixture is stirred at -50° C. for 15 minutes. The resulting solution of p-methoxybenzyloxycarbonylsulfamoyl chloride is added to a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (obtained in the above Steps 6 or 8) (12.21 g: 22.7 mmole) and triethylamine (6.38 ml: 45.6 mmole) in dichloromethane (300 ml) at -78° C., and the mixture is stirred for 10 minutes, successively washed with dilute hydrochloric acid and brine, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylsulfamoylaminomethyl-4-tritylthiopyrrolidine (16.31 g). Yield: 91.6%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH2:12](P(CCCC)CCCC)CCC.C[Mg]Br.Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH3:12])=[C:4]([Cl:11])[CH:3]=1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -22 °C
Reaction time: 0.67 h

Procedure:
5 g of crude 4-bromo-2-chlorobenzoyl chloride (from step 1) are dissolved in 120 ml anhydrous THF. 45.6 ml of tributylphosphine is added dropwise at −22° C., and after 20 minutes 141 ml of methyl magnesium bromide is added dropwise and the reaction mixture is stirred for 40 minutes at −22° C. The reaction mixture is poured into 1N aqueous HCl solution and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are washed with a saturated solution of sodium chloride, dried over MgSO4 and evaporated to dryness under reduced pressure. The remaining residue is purified by flash chromatography (n-hexane/ethyl acetate, 9/1 (v/v)) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)=[N:11][C:8]=3[O:9][CH2:10][C:5]2=[N:4][N:3]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[N:6]2[C:7]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:12]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5([NH2:31])[CH2:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)=[N:11][C:8]=3[O:9][CH2:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 55.5 %

Procedure:
Tert-butyl (1-(4-(1-methyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (11 mg, 0.022 mmol) was dissolved in TFA (1 ml) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and the residue was dried to give the desired product as an off-white solid (5 mg, 55% yield). LCMS (Method A): RT=3.71 min, M+1=411. 1H-NMR (500 MHz, CD3OD) δ 8.11 (1H, s), 7.49-7.44 (2H, d), 7.42-7.37 (2H, d), 7.35-7.30 (3H, m), 7.29-7.25 (2H, m), 5.63 (2H, s), 2.84 (3H, s), 2.80-2.70 (2H, m), 2.61-2.51 (2H, m), 2.28-2.17 (1H, m), 2.01-1.88 (1H, m).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:24]=[C:25]=[S:26])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH:1]1([NH:6][C:25]([NH2:24])=[S:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: NC1CCCC1
Product: NC(=S)NC1CCCC1

Procedure:
Cyclopentyl-thiourea was prepared following procedure D using cyclopentyl amine (2.4 g, 28 mmol), and Fmoc-isothiocyanate (5.6 g, 20 mmol). Purification (Silica gel, ethyl acetate/hexane 1:1, 100%) provided the product (1.6 g) as white a solid. LCMS m/z: 145 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13]([OH:15])=[O:14])[C@@H:10]([OH:16])[C@H:9]([OH:17])[C@H:7]2[N:8]=1)[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH2:1]([N:3]([CH3:18])[C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13]([OH:15])=[O:14])[C@@H:10]([OH:16])[C@H:9]([OH:17])[C@H:7]2[N:8]=1)[CH3:2]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)O)O[C@@H]2S1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5 mL sure seal vial was added (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylic acid (53.00 mg; 0.20 mmol; 1.00 eq.) in N,N-dimethylformamide (2.00 ml) followed by dipotassium carbonate (55.85 mg; 0.40 mmol; 2.00 eq.) and iodomethane (29.69 μl; 0.40 mmol; 2.00 eq.). The mixture was stirred at room temperature for overnight before it was concentrated, purified by Yamazen C1 (40 g column, 220 nm) and dried with lyophilize to afford 7.3 mg (9.3%) monomethylated compound as white solid and two sets of peaks were found on NMR, ratio=3:1.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:32](O)([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:19]=[C:13]1[O:12][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:15]([C:16]([O:18][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:17])[CH2:14]1
Reactant: CC(C)(C)O
Reactant: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6.53 g of (2RS,3SR)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid was dissolved in 70 ml of chloroform, and 4.53 g of 4-dimethylaminopyridine, 7.11 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4.70 ml of tert-butyl alcohol were sequentially added thereto, followed by stirring at room temperature for 14 hours. The reaction solution was poured into 1N hydrochloric acid cooled with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to obtain 5.16 g of the above-identified compound as a white solid.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:21]([N:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@@H:24]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]1)=[O:22])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C]>[OH:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:21]([N:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@@H:24]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]1)=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3)c2COCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3)c2CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.2 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[({5-[(benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (2.92 g) and palladium(II) hydroxide-carbon (500 mg) were suspended in methanol, and the mixture was stirred under a hydrogen atmosphere (5 atom) at room temperature for 10 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (2.39 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][CH2:32][F:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH2:30][CH2:31][CH2:32][F:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCCF)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OCCCF)nc1Cl
Yield: 64.6 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(3-fluoropropoxy)piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (129a) (0.20 g, 0.49 mmol), 2 N lithium hydroxide (6 mL, 12 mmol) and methanol (5 mL), to obtain 0.15 g of the title compound as a light brown solid (79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Mg]Br)[CH2:25][CH:26]=[CH2:27].[Cl-].[NH4+]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12](=[O:13])[CH2:27][CH2:26][CH:25]=[CH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 62 %

Procedure:
To a solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (Org. Lett. 2004, 5, 1469; 450 mg, 1.41 mmol) in THF (10 mL) was added 3-butenylmagnesium bromide solution (0.5 M in THF, 3.38 mL, 1.69 mmoL) at −40° C., then after 3 h sat. aq. ammonium chloride solution (5 mL) was added. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 2:1) afforded the title compound (329 mg, 62%). Colourless oil, MS: 376.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:19]([C:21]#[N:22])=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:13]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)C3(CCN(Cc4ccccc4)C3)c3c(C#N)cccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CN2CC3(CCN(Cc4ccccc4)C3)c3c(CN)cccc32)cc1
Yield: 17.1 %

Procedure:
A solution of 1′-benzyl-1-(4-methoxybenzyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-4-carbonitrile (3.00 g, 7.08 mmol) in LAH (1.0M in THF, 35.4 mL, 35.4 mmol) was heated at reflux for 12 hours. The reaction mixture was quenched with Na2SO4-10H2O, dried and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by chromatography (hexanes/ethyl acetate gradient) to give (1′-benzyl-1-(4-methoxybenzyl)spiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine (500 mg, 1.21 mmol, 17%). LCMS (APCI+) M+H+414 (100%); Rt=3.23 min.
Reaction SMILES: [CH2:1]([O:6][C@@H:7]1[CH2:12][O:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]34[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH3:29])([CH2:23][CH2:24]3)[CH2:21][CH2:20]4)=[CH:15][CH:14]=2)[CH2:9][O:8]1)/[CH:2]=[CH:3]/[CH2:4]C.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCCC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)/C=C/C.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCCC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)C/C=C\CC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)CC/C=C/C.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)CO1)CCCC=C.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)CO1)/C=C/C.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCC.C(O[C@@H]1CO[C@@H](C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)CO1)/C=C/CCCCC>>[CH2:1]([O:6][C@@H:7]1[CH2:12][O:11][C@@H:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]34[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][CH3:29])([CH2:21][CH2:20]3)[CH2:25][CH2:26]4)=[CH:17][CH:18]=2)[CH2:9][O:8]1)/[CH:2]=[CH:3]/[CH3:4]
Reactant: CC/C=C/CO[C@@H]1CO[C@@H](c2ccc(C34CCC(CCC)(CC3)CC4)cc2)CO1
Agent: C/C=C/CCCO[C@@H]1CO[C@@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CO1
Agent: C/C=C/CO[C@@H]1CO[C@@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CO1
Agent: C/C=C/CO[C@@H]1CO[C@@H](c2ccc(C34CCC(CCCCCCC)(CC3)CC4)cc2)CO1
Product: C/C=C/CO[C@@H]1CO[C@@H](c2ccc(C34CCC(CCC)(CC3)CC4)cc2)CO1

Procedure:
1-[4-(trans-5-[(E)-Pent-2-enyloxy]dioxan-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Hept-2-enyloxy]dioxan-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Oct-2-enyloxy]dioxan-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-But-2-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Pent-2-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Hept-2-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Oct-2-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(Z)-Hex-3-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Hex-4-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[Hex-5-enyloxy]dioxan-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-But-2-enyloxy]dioxan-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Pent-2-enyloxy]dioxan-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Hept-2-enyloxy]dioxan-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(trans-5-[(E)-Oct-2-enyloxy]dioxan-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:32]1[CH2:31][CH2:30][C:29]([F:28])([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:26]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 53.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (100 mg, 0.28 mmol) obtained in Example 88, step 2 and 4-fluoro-4-(4-fluorophenyl)piperidine hydrochloride (79 mg, 0.34 mmol), the title compound (80 mg, 54%) was obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Cl[C:34]1[N:39]=[C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]2[CH3:46])[CH:37]=[C:36]([CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[N:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.C(O)C>[CH3:9][C:4]1[CH:3]=[C:2]([C:34]2[N:39]=[C:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]3[CH3:46])[CH:37]=[C:36]([CH2:47][S:48]([CH3:51])(=[O:49])=[O:50])[N:35]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1cc(Br)ccc1N
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1N
Temperature: 90 °C
Reaction time: 4 h
Yield: 14.3 %

Procedure:
4-Bromo-2-methylaniline (1.00 g, 5.37 mmol), potassium acetate (1.59 g, 16.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.64 g, 6.45 mmol) were dissolved in 1,4-dioxane (20 mL) and the solution degassed for 5 minutes. Dichlorobis(triphenylphosphine)palladium (264 mg, 0.32 mmol) was added and the reaction stirred at 90° C. for 4 hours. 2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.65 g, 5.37 mmol), ethanol (1.5 mL), 2M sodium carbonate aqueous solution (3 mL) and dichlorobis(triphenylphosphine)palladium (264 mg) were added. The reaction was maintained at 90° C. for 18 hours then allowed to cool to room temperature. Water (15 mL) and ethyl acetate (15 mL) were added and the mixture was filtered to remove the insoluble impurities. The phases were separated and the aqueous layer extracted with a second portion of ethyl acetate (15 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-3% methanol in DCM, to give the desired compound as a beige foam (290 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH3:21]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([NH2:21])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: N
Reactant: COC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Solvent: CO
Product: COC(=O)C1CCC(c2cc(N)n3nccc3n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(7-Chloro-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid methyl ester (2.5 g, 8.51 mmol) was dissolved in 15 mL ˜7N ammonia in methanol in a sealed vessel. The reaction mixture was heated at 80° C. for 16 hours. After 16 hours, the reaction mixture is cooled to room temperature and concentrated in vacuo to yield a brown solid (2.58 g). The title compound was used in the next step without further purification. LC-MS: 275 [M+H].
Reaction SMILES: O.Cl.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]#N.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+]>CO>[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]1[S:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[N:3]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CSC(c2ccc(O)cc2O)=N1
Temperature: 70 °C
Reaction time: 54 h
Yield: 65.8 %

Procedure:
D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared in Example 1, in a mixture of degassed methanol (105 ml) and 0.1 M phosphate buffer, pH 5.95 (70 ml). NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was stirred at 70° C. under Ar for 54 hours. Volatile components were removed under reduced pressure and the solution was acidified with 1 N HCl to pH 2. The resulting brown precipitate was vacuum filtered and the solid was washed with water (40 ml) and ethanol (20 ml). The crude product was dissolved in saturated NaHCO3 (700 ml) and the aqueous solution washed with ethyl acetate (2×200 ml). The aqueous layer was filtered through a fine frit and acidified with 1 N HCl to pH 2. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4×400 ml), the combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The remaining solid was combined with the precipitated product and dried under high vacuum at 40° C. for 12 hours to give 4,5-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4(S)-carboxylic acid (4.08 g, 66%), mp 266–268° C. (dec) [Ind. J. Chem., Vol. 15B, Kishore et al, pages 255–257 (1977) for (L)-isomer: 261–262° C.]. 1H NMR (300 MHz, DMSO-d6) δ 3.61 (m, 2H), 5.38 (dd, 1H, J=7.2/9.4 Hz), 6.31 (d, 1H, J=2.3 Hz), 6.38 (dd, 1H, J=2.3/8.6 Hz), 7.25 (d, 1H, J=8.6 Hz), 10.25 (br s, 1H), 12.60 (br s, 1H), 13.15 (br s, 1H). Anal. calc. for C10H9NO4S: C, 50.20, H, 3.79, N, 5.85. Found: C, 50.13; H, 3.82; N, 5.85.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4].S(Cl)(Cl)=O>C1C=CC=CC=1>[F:1][C:2]1([F:10])[CH2:6][C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CC(F)(F)C(=O)O1
Yield: 83 %

Procedure:
A mixture of 2,2-difluorosuccinic acid (1.15 g, 7.46 mmol), thionyl chloride (4 mL, 20.6 mmol) and benzene (4 mL) was heated at reflux for 2.5 h. The mixture was filtered and the filtrate was concentrated to afford the title product as an oil that crystallized on standing (838 mg, 6.16 mmol, 83% yield).