Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 24 h
Yield: 32.5 %

Procedure:
94 mg (0.346 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dichloromethane (3.4 mL), and 70 μL (0.676 mmol) of benzylalcohol and 98 mg (0.511 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride were added, followed by stifling at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and subsequently the residue was diluted with ethyl acetate and washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 41.2 mg of the title compound (yield 33%). Enantiomeric excess: 99.8% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 33.2 min.).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:20][C@@H:21]2[O:47][C@H:46]([CH2:48][O:49][C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:22]2[O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:10][N:11](C(=O)CC)[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O>CO>[CH2:1]([C:8]1[C:9]([O:20][C@@H:21]2[O:47][C@H:46]([CH2:48][O:49][C:50](=[O:55])[C:51]([CH3:52])([CH3:54])[CH3:53])[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:36])[CH3:35])[C@H:22]2[O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:26])[CH3:27])=[N:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 4-benzyl-5-isopropyl-1-propionyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (3.00 g) in methanol (30 mL) was added sodium bicarbonate (0.654 g) under stirring at room temperature. The reaction mixture was stirred at room temperature for 17 hours. After confirming the completion of the reaction, water was added to the mixture to precipitate the crystals. The crystals were collected by filtration. The obtained crystals were washed with water and dried under reduced pressure to give 4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (2.67 g).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)CCC>[ClH:1].[NH2:2][CH2:3][C:4]1([CH2:9][C:10]([O:12][CH2:3][CH2:4][CH2:5][CH3:6])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCC1(CC(=O)O)CCCC1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CC1(CN)CCCC1

Procedure:
According to Example 7, 1-aminomethyl-1-cyclopentane-acetic acid hydrochloride is esterified with n-butanol to give n-butyl 1-aminomethyl-1-cyclopentane-acetate hydrochloride; m.p. 50° C.
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:13]#[C:14]CO)[C:5]2[C:10]([C:11]=1[F:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:13]#[CH:14])=[CH:3][CH:2]=1
Reactant: Cc1c(C)c(C#CCO)c2ccccc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1ccc(F)c2ccccc12
Temperature: 120 °C
Yield: 67.5 %

Procedure:
Dimethylhydroxymethyl-4-fluoro-1-naphthylacetylene (1.88 g, 8.23 mmol) and NaOH (396 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98% article, 9.90 mmol) were placed in a 30 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 20 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 946 mg of the desired compound as a yellow solid (yield: 67.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=C[N:6]3[CH:12]=[N:13][N:14]=[C:5]3[C:4]=2[CH:3]=1.[OH-].[K+].Cl>>[NH2:8][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]1[NH:14][N:13]=[CH:12][N:6]=1
Reactant: Clc1ccc2ncn3cnnc3c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(Cl)cc1-c1ncn[nH]1

Procedure:
To a flask containing 129.8 gms. of 9-chloro-1,2,4-triazolo[4,3-c]quinazoline is added 2600 ml. of a 10% KOH solution and the resulting mixture heated to reflux. A gentle reflux is maintained overnight after which time the mixture is neutralized to pH 7.0 with cooling and stirring by adding dropwise a 1:1 HCl solution and the resulting precipitate filtered off, washed several times with H2O and allowed to air dry. The residue was dissolved in methanol and evaporated in vacuo to dryness. The resultant residue is triturated with benzene and the precipitate filtered off to obtain 5-(2-amino-5-chlorophenyl)-s-triazole, m.p. 170°-175° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:15](Cl)(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:8]([S:15]([NH:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 39 mg of benzylsulfonyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to she reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzylsulfonamido)-4-phenethylbenzoate.
Reaction SMILES: N[C:2]1[C:3]([Cl:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[CH3:12])[C:5]([O:7]C)=[O:6].N([O-])=O.[Na+].[ClH:19]>Cl.Cl[Cu]>[Cl:14][C:3]1[C:2]([Cl:19])=[C:11]([CH3:12])[C:10]([F:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: COC(=O)c1cc(F)c(C)c(N)c1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of methyl 3-amino-2-chloro-5-fluoro-4-methylbenzoate are diazotized with NaNO2 /HCl in aqueous solution. This diazonium salt solution is added dropwise to a solution of 4.1 g of CuCl in 16 ml of concentrated HCl. The mixture is then warmed until no further gas is formed. After cooling, the solid which has precipitated is separated off and taken up in 30 ml of 50% strength EtOH. After addition of 2.3 g of NaOH, the mixture is boiled for 1 hour. After cooling to room temperature, the mixture is acidified with HCl and the solid which has precipitated is isolated. Melting point: 179°-80°. Yield: 5.2 g.
Reaction SMILES: C12CC(CC1)C[C@@H]2NC1SC(C)(CC2CCNCC2)C(=O)N=1.[CH:23]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][C@@H:24]2[NH:30][C:31]1[S:32][C:33]([CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([C:47]3[CH:48]=[C:49]([CH:61]=[CH:62][CH:63]=3)[O:50][CH2:51][CH2:52][NH:53]C(=O)OC(C)(C)C)=[O:46])[CH2:41][CH2:40]2)([CH3:37])[C:34](=[O:36])[N:35]=1>>[NH2:53][CH2:52][CH2:51][O:50][C:49]1[CH:48]=[C:47]([CH:63]=[CH:62][CH:61]=1)[C:45]([N:42]1[CH2:43][CH2:44][CH:39]([CH2:38][C:33]2([CH3:37])[S:32][C:31]([NH:30][C@H:24]3[CH2:25][CH:26]4[CH2:29][CH:23]3[CH2:28][CH2:27]4)=[N:35][C:34]2=[O:36])[CH2:40][CH2:41]1)=[O:46]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)N2CCC(CC3(C)SC(N[C@H]4CC5CCC4C5)=NC3=O)CC2)c1
Agent: CC1(CC2CCNCC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Product: CC1(CC2CCN(C(=O)c3cccc(OCCN)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-5-(piperidin-4-ylmethyl)thiazol-4(5H)-one by using tert-butyl 2-(3-(4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carbonyl)phenoxy)ethylcarbamate (689 mg, 1.18 mmol) as the starting material. The title compound was obtained as an off-white solid (531 mg). MS (ESI, pos. ion) m/z: 485 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[S:10])=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]([NH2:16])=[O:15]>CC(C)=O>[C:14]([NH:16][C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)=[S:10])(=[O:15])[NH2:13]
Reactant: NC(N)=O
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CC(C)=O
Product: NC(=O)NC(=S)NC(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
4-Chlorobenzoyl isothiocyanate (395 mg) and 600 mg urea (5 equiv) were mixed in 30 mL of acetone and stirred at reflux for 1 day. The reaction was concentrated and the residue slurried in diethyl ether. The residue was collected by filtration and washed with diethyl ether. The white solid was dissolved in ethyl acetate (10 ml) and the resultant solution washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated to a white solid (0.35 g, 1.4 mmol, 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1COCC1.C(C(O)=O)(F)(F)F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1Cl
Yield: 98.7 %

Procedure:
To a solution of the product of Step E (0.11 g; 0.34 mmol) in 1M BH3 in THF (0.68 ml; 0.68 mmol) CF3CO2H (1 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min) the reaction was quenched with H2O (0.5 ml) and the solvents were removed under reduced pressure. The residue was diluted to 15 ml with EtOAc and was washed with 1 M NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.11 g; 100%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 2.6 (broad s, 1H+H2O); 3.12 (tr, 2H, J=8.4 Hz); 3.66 (tr, 2H, J=8.4 Hz); 3.98 (s, 3H); 6.71 (d, 1H, J=8.1 Hz); 7.07 (d, 1H, J=8.7 Hz); 7.83-7.88 (m, 2H); 8.05 (dd, 1H, J=2, 8.7 Hz); 8.21 (d, 1H, J=2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:27]=O>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2/[CH:27]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Product: COc1ccc2[nH]cc(/C=C/C(=O)c3cc(OC)c(OC)c(OC)c3)c2c1
Yield: 52 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (1.2 g) and 5-methoxyindole-3-carboxaldehyde (1 g) except that the obtained crude crystals were recrystallized from 2-propanol, to give Compound 25 (1.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:20]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a stirred mixture of 14.9 grams (0.102 mole) of 4-chlorobenzamide in 800 ml of toluene was added 20.6 grams (0.051 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent). This mixture was stirred and heated at reflux for two hours. The reaction mixture was allowed to cool slowly to room temperature. Approximately 600 ml of toluene was evaporated from the mixture under reduced pressure, leaving a residual liquid. This liquid was purified by column chromatography on silica gel, eluting with methylene chloride:ethyl acetate (60:40), to yield 5.6 grams of 4-chlorophenylthiocarboxamide as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: CNS(=O)(=O)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred room temperature solution of 4-bromomethyl-N-methyl-benzenesulfonamide (2.70 g, 10.0 mmol) in DMF (15 mL) was added sodium azide (0.90 g, 13 mmol). The mixture was stirred at 40° C. for 16 hours. The solution was poured into water (60 mL) and diluted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to afford 4-azidomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][C@H:11]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCO)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 98.7 %

Procedure:
(S)-tert-Butyl (3-(benzyloxy)-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (0.65 g, 1.37 mmol) was dissolved in 33 mL methanol. Palladium on carbon (10%, 0.65 g, 6.11 mmol) was added and the mixture was hydrogenated at 30 psi overnight. The crude was filtered through a plug of Celite, washing several times with ethyl acetate. The combined filtrates were evaporated to give 0.52 g (99% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:33]4[N:32]=[C:31]([OH:30])[CH:36]=[CH:35][N:34]4[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccnc(N)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C

Procedure:
A mixture of crude {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (1.26 g) and 4-methoxypyrimidin-2-ylamine (0.67 g) in DMF (21 mL) was heated overnight at 90° C. (bath temperature). On cooling the mixture was partitioned between EtOAc and water and the organic phase washed with brine, dried and concentrated to give a mixture of the title compound and Int-2-0. Purification was achieved by preparative HPLC to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)[CH:3]=[CH2:4].CC(C[AlH]CC(C)C)C.C(O)(=O)C(C(C(O)=O)O)[OH:24]>C1COCC1>[OH:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:24])[CH:3]=[CH2:4]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: C=CC(O)c1cccc(C#N)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C=O)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
To the nitrile (Step 1) (17.0 g, 0.107 mmol) in THF (465 mL) at -78° C. was added dropwise a DIBAL solution (157 mL, 0.235 mmol). The resulting mixture was brought slowly to 0° C. After completion, the reaction mixture was poured over 10% aqueous tartaric acid solution (1 L). After stirring for a period of 1 hr., the title product was extracted with EtOAc and purified by flash chromatography (40% to 50% EtOAc in hexane) to afford 15 g (88%) of the aldehyde.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH2:8](Br)[CH:9]=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+].C(C(C)=O)C>CCOCC.[I-].[Na+]>[CH2:10]([CH2:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5])[CH:9]=[CH2:8]
Reactant: CNC(C)(C)C#N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: C=CCCNC(C)(C)C#N
Yield: 48.2 %

Procedure:
A mixture of 2-methylamino-2-methylpropionitrile (14.7 g., 0.15 mole) allyl bromide (18.0 g., 0.15 mole), sodium carbonate (15.9 g., 0.15 mole), sodium iodide (0.2 g., 0.001 mole) and methyl ethyl ketone (200 ml.) was heated under reflux for 40 hrs. The sodium carbonate was filtered off and the solvent was removed from the filtrate in vacuo to give a yellow oil, T.L.C. (Silica, ether), three components RF 0.8, 0.4 and 0.0. The oil was passed through a column of silica 40 × 3.5 cm. using ether as an eluent to give 2-allylmethylamino-2-methylpropionitrile (10.0 g., 48%).
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28]C(C)(C)C)=[O:27])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][P:9]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]([CH3:34])([CH3:33])[C:26]([OH:28])=[O:27])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(COCCCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 3-(3-((bis(benzyloxy)phosphoryl)oxy)propoxy)-2,2-dimethylpropanoate (54) (1.76 g, 3.57 mmol) in DCM (30 mL) was added TFA (1.38 mL, 17.9 mmol), and the reaction was allowed to stir at RT for 4 h. The volatiles were removed in vacuo and the crude product was purified by silica gel chromatography (40 g, 0-30% EtOAc in isohexane (+1% AcOH)) to afford 3-(3-((bis(benzyloxy)phosphoryl)oxy)propoxy)-2,2-dimethylpropanoic acid (55) (1.03 g, 58%) as a colourless oil: m/z 437 (M+H)+ (ES+); 435 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.49-7.26 (m, 10H), 5.08-4.95 (m, 4H), 4.03-3.96 (m, 2H), 3.42-3.35 (m, 2H), 3.31 (s, 2H), 1.77 (quin, J=6.2 Hz, 2H), 1.05 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[H][H].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>ClCCCl.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[CH:15]([OH:20])[C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Temperature: -30 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrine hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -30° C., a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. On raising the temperature of the resulting suspension from -30° C. to room temperature over 2 hours, 87 ml of hydrogen gas was generated. Thereafter, a solution of 0.39 g (1.2 mmoles) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane was added to this suspension at room temperature, and then stirring was carried out for 23 hours. Thereafter, 6 ml of 2M hydrochloric acid was added, followed by stirring for 2 hours. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. By gas-chromatographic analysis, it was found that the conversion was 96.4%, and the composition of the reaction product was: E-form alcohol, 98.3% and Z-form alcohol, 1.7% (Z-form alcohol was produced through isomerization of the ketone compound to the Z-form, followed by reduction of the carbonyl group).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>CN(C=O)C.C(OCC)C>[CH:1]([O:19][C:18]1[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=1[O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (40.0 mL; 421 mmol) was added to a suspension of K2CO3 (48.0 g, 348 mmol) and vanillin (40 g, 263 mmol) in DMF (150 mL) and the stirring slurry heated to 80° C. for 15 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (51.0 g, 100%) which required no further purification. The spectra of this material are identical with that previously reported (M. F. Comber and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1991, 2783).