Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[C:14]([Li])([CH3:17])([CH3:16])[CH3:15].O(C)[Li]>CCCCCC>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][Si:5]([C:14]([CH3:17])([CH3:16])[CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: [Li]C(C)(C)C
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: [Li]OC
Solvent: CCCCCC
Product: CO[Si](CCC(F)(F)F)(OC)C(C)(C)C
Temperature: 0 °C
Yield: 110.9 %

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to 0° C. and charged with 150 ml hexane and 3,3,3-trifluoropropyl trimethoxy silane (0.075 mol, 15 ml). A nitrogen purged addition funnel was fitted to the flask and charged with tert-butyllithium (0.075 mol, 34 ml). This was added dropwise to the cooled flask creating a cloudy, white precipitate (LiOCH3). After addition (1 hour), the addition funnel was washed with 20 ml of hexane. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The flask was fitted with a reflux condenser and the reaction mixture refluxed for two hours. After cooling to room temperature, the reaction mixture was filtered through a medium porosity filter tube, using Celite diatomaceous earth and glass wool as a filtering aid. A white solid was collected, which weighed 11.13 g wet (theoretical=3.0 grams of LiOCH3). The hexane was removed from the filtrate to give 20.33 g of a clear yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.C(Cl)(=O)C(Cl)=O.S(N)([NH2:23])(=O)=O.[OH-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:23]
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CCc1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 3-(2,3-difluorophenyl)-propionic acid (A1) (6.83 g, 36 mmol) in anhydrous dichloromethane (50 ml) containing a few drops of DMF was added oxalyl chloride (6.4 ml, 73 mmol) at 0° C. under argon. The solution was stirred at ambient temperature for 2 h and the solvent removed in vacuo. The residue was dissolved in sulfolane (30 ml) and added to sulfamide (4.23 g, 44 mmol) and the mixture heated at 120° C. for 3 h. The brown solution was cooled, poured into 2M sodium hydroxide solution (300 ml) and extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give the title compound as a brown oil (6.04 g, 98%). 1H-NMR (CDCl3) δ 2.68 (2H, t), 3.04 (2H, t), 7.01-7.15 (3H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=O)C.O.[NH2:22][NH2:23]>CO>[NH:22]([C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:3])[NH2:23]
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 74.7 %

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (10.0g.) was dissolved in methanol (150 ml.) and hydrazine hydrate (10.0g.) added dropwise with cooling. The mixture was stirred for fifteen minutes and the crystalline precipitate was filtered off, washed with methanol (10 ml.), and dried to give title compound (7.08 g), m.p. 211°-212° (decomp.) λmax. (EtOH) 302 nm (ε 10,100) νmax. (Nujol) 1680 cm.-1 (--CONH--).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][OH:23])=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NO)ccc1O2
Yield: 64.2 %

Procedure:
A solution of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (210 mg, 0.52 mmol) in DCM (6 ml) was treated with 4 M HCl in dioxane (1.0 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (106 mg, hydrochloride salt) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3[N:20](CCC#N)[N:19]=[N:18][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnnn1CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a suspension of (S)-tert-butyl 2-(3′-chlorobiphenyl-4-yl)-1-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)ethylcarbamate (300 mg, 0.662 mmol) in DCM (3 ml) at room temperature was added DBU (2 ml, 13.27 mmol), and the solution was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated reduced pressure. The obtained residue was purified by reverse phase HPLC [30 to 95% ACN-water (0.1% TFA) over 10 min by Sunfire C18 column] and gave the title compound: 250 mg (yield: 94%). LCMS (condition F): 400.1 (M+1); retention time=1.28 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[CH:19]1([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]([C:4]1[N:23]=[C:22]([CH:19]2[CH2:21][CH2:20]2)[S:24][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:18]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.07 min; [M+H]+=328.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][NH2:42])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:33]([O:37][C:38]([NH:39][CH2:40][CH2:41][NH:42][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:43])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Brc1cccc2cnccc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1cccc2cnccc12
Temperature: 80 °C
Yield: 70 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (416 mg, Spex), tris(dibenzylideneacetone)dipalladium(0) (92 mg), 2-(di-tert-butylphosphino)biphenyl (119 mg), N-(2-aminoethyl)carbamic acid tert-butyl ester (385 mg) and sodium tert-butoxide (269 mg) in toluene (5 ml) was stirred with heating at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and added with ethyl acetate (5 ml). The insoluble matters were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (402 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, 6-chloro-2-methylpyridin-3-amine (200 mg, 1.40 mmol) and triethylamine (217 μl, 1.56 mmol) were taken up in dichloromethane (7.0 ml) under argon. The solution was cooled to 0° C. and stirred for 20 minutes. Acetic anhydride (134 μl, 1.42 mmol) was added dropwise over 15 minutes. The mixture was allowed to warm to room temperature and left to stir for 22 hours. The reaction was quenched with aqueous sodium bicarbonate and washed with ethyl acetate three times. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:27])[C@H:3]([NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12]([C:13](OC)=[O:14])=[C:11]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[N:10]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH3:6][CH:5]([CH3:7])[CH2:4][C@@H:3]([NH:8][C:9]1[N:10]=[C:11]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[C:12]2[C:13](=[O:14])[NH:20][CH2:19][C:17]=2[CH:18]=1)[C:2]([NH2:1])=[O:27]
Reactant: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1-c1cnn(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@@H](Nc1cc2c(c(-c3cnn(C)c3)n1)C(=O)NC2)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of (R)-methyl 6-(1-amino-4-methyl-1-oxopentan-2-ylamino)-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (20.3 mg, 0.055 mmol) and palladium hydroxide (10 mg, 0.094 mmol) in MeOH (2 mL) and HOAc (2 mL) was stirred at RT for 3 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and EtOAc (20 mL) for 12 h. The mixture was extracted with EtOAc (2×20 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc/MeOH=15/1-10/1) to give the title compound as a white solid (10.2 mg, 54%). 1H-NMR (DMSO-d6) δ ppm 0.88-0.95 (m, 6H), 1.52-1.60 (m, 2H), 1.73-1.76 (m, 1H), 3.88 (s, 3H), 4.21 (s, 2H), 4.48 (br s, 1H), 6.43 (s, 1H), 6.90 (s, 1H), 7.03 (br s, 1H), 7.42 (s, 1H), 8.01 (s, 1H), 8.41 (s, 1H), 8.92 (s, 1H). [M+H] calc'd for C17H23N6O2, 343. found, 343.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4-oxo-azepane-1-carboxylic acid tert-butyl ester (13.6 g, 63.8 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) at 0° C. is added lithium borohydride (1.40 g, 63.8 mmol). The mixture is stirred at 0° C. for 60 minutes. Hydrochloric acid (1.0 M, 40 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (Na2SO4) and concentrated to a residue. The residue is purified on silica using a gradient of ethyl acetate in hexanes (40 to 80%) to yield the title compound (13.6 g, 99.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31](C)(C)C)=[O:29])[CH2:24][CH2:23]5)=[CH:18][C:17]=4[F:35])[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[O:5][C:4](=[O:36])[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(CC)CC)C.ClC(OC)=O>>[CH3:1][C:2]1([CH3:37])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]5)=[CH:18][C:17]=4[F:35])[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[O:5][C:4](=[O:36])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Agent: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate (25.0 mg, 0.0000485 mol) was treated with TFA. After stirring at rt for 30 min, the volatiles were removed in-vacuo and the residue was dried on high vaccum. The resultant TFA salt was dissolved in methylene chloride (0.25 mL, 0.0039 mol) and to this was added triethylamine (0.0203 mL, 0.000145 mol) followed by methyl chloroformate (0.00749 mL, 0.0000970 mol). The reaction mixture was stirred at rt for 1 h and then the volatiles were removed in-vacuo. The residue was diluted with methanol and applied directly on RP-HPLC to yield the desired product. LCMS (M+H) 474.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[NH:11][C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2=3)=[CH:23][CH:24]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1Cc2c([nH]c3ncccc23)C(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(n(CC(O)c3ccncc3)c3ncccc23)C(C)(C)C1
Reaction time: 12 h
Yield: 9.6 %

Procedure:
6,8,8-Trimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (100 mg, 0.465 mmol) was dissolved in DMF (2 mL) and sodium hydride (56 mg, 1.39 mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine (113 mg, 0.933 mmol) was added dropwise at RT and stirred for 12 h. After consumption of starting material (by monitoring TLC and LCMS), the reaction mixture was poured in to ice water and extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (5×10 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product purified by reverse phase chromatography to obtain 15 mg of 1-pyridin-4-yl-2-(6,8,8-trimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol. 1HNMR (CDCl3, freebase) δ (ppm): 8.63 (d, 2H), 8.22 (d, 1H), 7.75 (d, 1H), 7.45 (d, 2H), 7.09 (dd, 1H), 5.17 (d, 1H), 4.53 (dd, 1H), 4.47 (d, 1H), 3.71 (d, 1H), 3.44 (d, 1H), 2.5 (s, 3H), 2.49 (d, 1H), 2.44 (d, 1H), 1.47 (s, 3H), 1.32 (s, 3H). Separation by chiral HPLC provided enantiomers 17a and 17b. Optical rotations: Compound No. 17a, (+) 50.54 (c 0.56, Chloroform, 99.31% HPLC purity); Compound No. 17b, (−) 51.38 (c 0.55, Chloroform, 95.62% HPLC purity).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:15](=[O:17])[CH3:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:8](=[CH:9][C:10]=1[CH:11]([CH3:13])[CH3:12])[O:14][C:19]1([CH2:22][CH2:21][CH2:20]1)[CH2:16][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)c(C(C)=O)c1C
Reactant: O=C1CCC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C)C(=O)CC1(CCC1)O2
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 3-acetyl-4-hydroxy-6-isopropyl-2-methylphenyl acetate (8.5 g) and cyclobutanone (2.6 g) in toluene (150 mL) was added pyrrolidine (1.2 g). The solution was left at room temperature for 16 hours, refluxed for two hours, and then a Dean-Stark was used to remove the water. Work up and chromatography (silica gel, hexane-ethyl acetate 2% to 5%) gave 4 g of 7-isopropyl-5-methyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: Cc1cccc2c(O)cccc12
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1cccc2c(Oc3ccc(C#N)cn3)cccc12

Procedure:
Using the procedure outlined in Preparation 15, 5-methylnaphthalen-1-ol and 6-chloronicotinonitrile were converted to the title compound: RT=3.90 min; m/z (ES+)=261.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 12 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-O-ethylserine (5.3 g, 22 mmol) and potassium carbonate (6.3 g, 45 mmol) in DMSO (80 mL) was added iodomethane (6.5 g, 45 mmol) at room temperature. After 12 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford methyl N-(tert-butoxycarbonyl)-O-ethylserinate. MS ESI calc'd. for C11H22NO5 [M+H]+ 248. found 248. 1H NMR (400 MHz, CDCl3) δ 5.36 (d, J=8.0 Hz, 1H), 4.42-4.39 (m, 1H), 3.84-3.81 (m, 1H), 2.75 (s, 3H), 3.64-3.60 (m, 1H), 3.49-3.45 (m, 2H), 1.45 (s, 9H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([N:28]([CH2:32][CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:29]([CH3:31])[CH3:30])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:26]([N:28]([CH2:32][CH2:33][OH:34])[CH:29]([CH3:31])[CH3:30])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:18])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:25])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
5-(Benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-hydroxy-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (57) (62 mg, 107 μmol, Eq: 1.00) was stirred in tetrahydrofuran (2 ml), HCl (aqueous) (161 μl, 161 μmol, Eq: 1.5) was added. The reaction mixture was stirred at room temperature for 3.0 hours, 160 μl 1N NaOH was added and the reaction mixture was diluted with water, extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Trituration in hexanes/ether was conducted to give 5-(benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (58) (32 mg, 64%).
Reaction SMILES: C(OP([CH:9]([Cl:11])[Cl:10])(=O)OCC)C.[C:12]([CH:15]1[C:17]([CH3:19])([CH3:18])[CH:16]1[CH:20]=O)(=[O:14])[CH3:13].O>CN(C)C=O.O1CCCC1>[Cl:11][C:9]([Cl:10])=[CH:20][CH:16]1[C:17]([CH3:19])([CH3:18])[CH:15]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A solution of 12.3 g (0.11 mol) of potassium tert.-butylate in 30 ml of dimethylformamide was added dropwise, under an inert gas atmosphere (nitrogen or argon) at -20° to -25° C., to a solution of 24 g (0.180 mol) of dichloromethane-phosphonic acid diethyl ester and 14 g (0.1 mol) of 2-acetyl-3,3-dimethylcyclopropanecarboxaldehyde in 100 ml of tetrahydrofuran. The mixture was subsequently stirred for 3 hours without cooling, 200 ml of water were added and extraction was carried out twice with 100 ml of methylene chloride. The organic phase was washed with 50 ml of 10% strength sodium hydroxide solution and then with 3 times 50 ml of water, dried over sodium sulphate and evaporated in vacuo. 14.8 g (71% of theory) of 1-(2,2-dichlorovinyl)-2-acetyl-3,3-dimethylcyclopropane were obtained from the residue, by vacuum distillation, in the form of a pale yellow oil having a boiling point of 55°-57° C./0.3 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@@H:21]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].N1CCCC1.O>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@H:21]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: O
Solvent: C1CCNC1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)OCc1ccccc1
Yield: 31.3 %

Procedure:
A solution of the product from step (b) (0.16g), pyrrolidine (0.16ml) and 3A molecular sieves (0.2g) in acetonitrile (3.2ml) was stirred at room temperature for 3.5 hours. The mixture was poured into water and extracted with ether, dried over magnesium sulphate and evaporated. The residue was flash chromatographed to give the sub-title product (0.05g) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Cl-].C([Al+]CC)C.[C:21]1([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:24]2[CH:23]=[CH:22][C:21]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:26][CH:25]=2)=[CH:4][C:3]=1[S:11]([NH2:12])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: c1ccc(N2CCCCC2)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(N3CCCCC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
A solution of 300 mg of 4-chloro-3-sulfamoyl-benzoyl chloride (1.186 mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at room temperature as 2.37 mL of diethyl aluminum chloride (1.0 M in hexane) is added drop-wise. The reaction is stirred at room temperature for 10 minutes, then 229 mg of 1-phenyl piperidine is added. The reaction is stirred at room temperature for 30 minutes. The reaction mixture is poured onto ice-2 N HCl and extracted with dichloromethane. The aqueous layer is then basified with 2 N sodium hydroxide and extracted with dichloromethane. The combined organic extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 180 mg of product is obtained. 1H NMR (400 MHz, CDCl3): δ 1.69 (s, 6H), 3.18 (m, 1H), 3.42 (s, 3H), 5.18 (s, 2H), 6.86 (d, 2H, J=8 Hz), 7.62 (d, 1H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 8.42 (s, 1H). MS (m/z): 379 (M+1). Analytics calculated for C18H19ClN2O3S: C, 57.06; H, 5.05; N, 7.39. Found: C, 56.88; H, 5.04; N, 7.13.