Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([O:11]C)([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:18]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CCCCCC>[OH:28][CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([O:9][CH3:10])=[O:11]
Reactant: O=Cc1ccccc1Cc1ccccc1
Reactant: C#CCCCC(OC)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)CCCC#CC(O)c1ccccc1Cc1ccccc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred mixture of 2.19 g (12.73 mmol) 1,1,1-trimethoxy-5-hexyne in 15 ml dry tetrahydrofuran (THF) at -78° under nitrogen was added 8.37 ml of 1.52M n-butyllithium (12.73 mmol) in hexane dropwise. The mixture was stirred at -78° for 1 hour and 2.0 g of 2-benzylbenzaldehyde (10.20 mmol) in 10 ml dry THF was added dropwise at -78°. The mixture was stirred at room temperature for 12 hours and poured into water. The reaction mixture was extracted with ether (2×75 ml) and the combined organic layers were washed with water (50 ml), saturated sodium chloride (50 ml), and dried (MgSO4). Filtration and evaporation left an oil that was purified by flash chromatography to give the title compound in 56% yield (2.02 g). NMR (CDCl3, 200 MHz) δ: 1.80 (m, 2H), 2.25-2.50 (m, 5H), 3.67 (s, 3H), 4.18 (br s, 2H), 5.60 (s, 1H), 7.12-7.75 (m, 9H). Mass spectrum: m/z=322 (M+).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[I:13][C:14]1[CH:15]=[N:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18]([CH:22]=1)[C:19]([OH:21])=O.[NH2:28][C:29]1[C:30]([CH2:41][CH3:42])=[N:31][N:32]([CH2:37][CH2:38][O:39][CH3:40])[C:33]=1[C:34]([NH2:36])=[O:35].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:36][C:34]([C:33]1[N:32]([CH2:37][CH2:38][O:39][CH3:40])[N:31]=[C:30]([CH2:41][CH3:42])[C:29]=1[NH:28][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([I:13])[CH:15]=[N:16][C:17]=1[O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:35]
Reactant: CCCCOc1ncc(I)cc1C(=O)O
Reactant: CCc1nn(CCOC)c(C(N)=O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCOc1ncc(I)cc1C(=O)Nc1c(CC)nn(CCOC)c1C(N)=O
Yield: 133.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (434 mg, 2.26 mmol) was added to a stirred solution of 5-iodo-2-butoxynicotinic acid (615 mg, 1.92 mmol), 4-amino-3-ethyl-1-(2-methoxyethyl)-pyrazole-5-carboxamide (370 mg, 1.74 mmol), 1-hydroxybenzotriazole hydrate (346 mg, 2.26 mmol) and diisopropylethylamine (0.9 mL, 5.22 mmol) in tetrahydrofuran (12 mL) at room temperature under a nitrogen atmosphere. After 20 h the solvent was evaporated and the product was extracted from 10% sodium bicarbonate solution with dichloromethane (3×100 mL). The organics were dried (MgSO4) and concentrated to give a fawn solid. The solid was triturated with di-isopropylether to give an off-white solid (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH2:8][O:7][C:6](=[O:10])[C:5]=2[S:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.ClCCl>[Br:11][C:3]1[S:4][C:5]2[C:6](=[O:10])[O:7][CH2:8][C:9]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2c1COC2=O
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)sc2c1COC2=O

Procedure:
In a 50 mL round bottom flask was added 3-methylthieno[2,3-c]furan-6-(4H)-one (130 mg, 0.843 mmol, 1.0 eq) and chloroform (5 mL). To above solution was added bromine (86 μL, 1.08 mmol, 2.0 eq) in chloroform. The reaction was heat to reflux for 3 hr, cooled down, diluted with dichloromethane, washed with water, diluted sodium thiosulfate. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 5.16 (2H, s), 2.19 (3H, s);
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:5]([Cl:14])[N:4]=1.[CH3:15][O-:16].[Na+]>CO>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:5]([O:16][CH3:15])[N:4]=1.[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:16][CH3:15])[C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:5]([Cl:14])[N:4]=1
Reactant: C[O-]
Reactant: CCCCc1c(Cl)cc(CO)nc1Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1c(Cl)cc(CO)nc1OC
Product: CCCCc1c(OC)cc(CO)nc1Cl

Procedure:
A solution of 103 g (0.44 mol) of 2-hydroxymethyl-4,6dichloro-5-n-butyl-pyridine in 100 ml of methanol is added dropwise over the course of 15 minutes, whilst stirring, to a solution of 59.4 g (1.1 mol) of sodium methylate in 500 ml of methanol. After completion of the addition, the reaction mixture is heated for 56 hours under reflux. It is then evaporated to dryness and the residue is suspended in ether. After filtration, the ether filtrate is dried by means of sodium sulphate, filtered and evaporated. Fractional distillation of the residue in a high vacuum yields 2-hydroxymethyl-4-chloro-5-n-butyl-6-methoxy-pyridine of the formula ##STR10## of boiling point 95°-98° (0.06 mm Hg) and 2-hydroxymethyl-4-methoxy-5-n-butyl-6-chloro-pyridine of the formula ##STR11## of boiling point 130°-134° (0.03 mm Hg).
Reaction SMILES: C(O)CCO.I.[C]=O.[CH:9]([OH:13])([OH:12])[CH2:10][CH3:11].OCCCI.[C:19]1(=[O:24])[O:23]CC[CH2:20]1>O>[C:19]([OH:24])(=[O:23])[CH2:20][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: CCC(O)O
Reactant: O=C1CCCO1
Agent: I
Agent: OCCCI
Agent: [C]=O
Solvent: OCCCO
Solvent: O
Product: O=C(O)CCCC(=O)O
Temperature: 175 °C
Reaction time: 6 h

Procedure:
A solution containing 2 mls 1,3-propanediol, 15 mls water, 3 mls of 57% hydriodic acid and 0.1 g RhCl3.XH2O were placed in an autoclave, pressurized with 1200 psi of carbon monoxide, and heated with shaking at 175° C. for 6 hours. Analysis indicated the presence of 7.8 millimoles of gamma-butyrolactones (28.2% conversion based on the propanediol introduced). Unreacted propanediol and 3-hydroxypropyliodide were also present. The solution was returned to the autoclave, pressurized with 1100 psi of carbon monoxide and heated with shaking at 175° C. for 6 hours more. The product now contained 15.1 millimoles of gamma-butyrolactone (54.4% conversion), but some 3-hydroxypropyliodide was also present. No glutaric acid was formed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:22])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Yield: 77 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and N-bromosuccinimide (489 mg, 2.75 mmol) were combined in chloroform and heated at reflux for 12 hours. The cooled reaction mixture was concentrated and the product was isolated by column chromatography to yield 6-amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (752 mg, 77% yield): mp 173-175° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.24 (dd, 1H), 5.73 (br s, 2H), 4.03 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:21]1([C:27](C2C=CC=CC=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1CC2C3C(=CC=CC=3)C(=O)CC=2CC1>>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]2[CH:29]=[CH:27][C:21]3[C:26]([C:2]=2[C:3]=1[OH:5])=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: O=C(O)C(F)(F)F
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1CCC2=C(C1)c1ccccc1C(=O)C2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2ccc3ccccc3c2c1O

Procedure:
In a 500 ml 3-neck flask equipped with magnetic stirrer and reflux condenser with nitrogen inlet, 66 ml of trifluoroacetic acid and 88 ml of trifluoroacetic anhydride were mixed together cautiously. The mixture was stirred under nitrogen and 54.6 g (0.21 mole) of 97% triphenylmethanol was added in increments over a 30 minute period giving an intense yellow-green solution. Heat was liberated. The reaction mixture was refluxed for one hour, cooled and 22.0 g (0.105 mole) of 3-methyl-1,2,3,4-tetrahydrophenanthrone as prepared above was added all at once, followed by refluxing under nitrogen for 21 hours. The amber mixture was cooled in an ice water bath and filtered to remove the solids. The filtrate was poured on crushed ice and the light tan precipitate was collected, washed with water and air-dried overnight. The solids were extracted with several portions of hexanes at room temperature to take up the 4-phenanthrol trifluoroacetate. The hexanes were concentrated to 400 ml, cooled in a freezer, then filtered. The filtrate was concentrated under vacuum to an oil. 40 ml of degassed 10% aqueous sodium hydroxide (containing a trace amount of sodium hydrosulfite) was added to the oil, followed by 110 ml of methanol. Nitrogen was passed through the mixture with stirring for one hour at room temperature. The mixture was filtered, and while cooling in an ice water bath, the filtrate was acidified with dilute hydrochloric acid to give a light tan precipitate. The precipitate was collected by filtration, washed with water and dried under vacuum to give 17.9 g (79.13% by weight) of 3-methyl-4-phenanthrol as a tan solid. M/e 208; M.P. 88°-92° C.; λmax 275 (16,200) methanol.
Reaction SMILES: [CH2:1]([N:8]([C:23](=[O:26])[CH2:24]Cl)[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:28]>CC#N>[CH2:1]([N:8]([C:23](=[O:26])[CH2:24][I:28])[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2)C(=O)CCl)[C@H](O)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2)C(=O)CI)[C@H](O)C1

Procedure:
To a solution of trans-tert-butyl 4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate (144 g, 376 mmol) in CH3CN (2 L) was added NaI (56.4 g, 376 mmol) in one portion. The mixture was stirred at reflux for 1 h and then concentrated. The residue was dissolved in DCM (1 L) and filtered. The filtrate was concentrated under reduced pressure to afford trans-tert-butyl 4-[benzyl(iodoacetyl)amino]-3-hydroxypiperidine-1-carboxylate, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[C:40](=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (2-methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine (40 mg, 0.13 mmol) in 4 mL of methylenechloride cooled at 0° C. was added triethylamine (50 uL, 0.36 mmol), few crystals of dimethylaminopyridine and acetic anhydride (50 uL, 0.53 mmol). The reaction mixture was stirred for 1 h at 0° C., warmed to room temperature, and stirred overnight. The reaction mixture was diluted with 25 mL of ethyl acetate and washed with 25 mL of saturated sodium bicarbonate. The organic layer was dried over anhydrous NaSO4, filtered and concentrated. The residue was purified by chromatography (40% ethyl acetate/hexane) to give the title compound (39 mg, 0.11 mmol, 85%). 1H NMR (CDCl3): 7.65-7.69 (m, 1H), 7.52 (ddd, J=8.4, 6.6, 1.8, 1H), 6.93-7.12 (m, 4H), 6.72 (m, 2H), 3.56 (s, 3H), 3.01 (s, 6H), 2.52 (s, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12j and 5-methylthiazole
Reaction SMILES: [OH:1][C@H:2]([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([C:16]#[N:17])=[N:5]1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][C@H:2]([OH:1])[CH3:18])[N:5]=[C:6]2[C:16]#[N:17]
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A solution of (R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (0.76 g, 2.93 mmol) in EtOH (10 ml) was added to a suspension of iron (powder) (1.310 g, 23.46 mmol) and ammonium chloride (1.569 g, 29.3 mmol) in water (10 ml). The reaction mixture was heated in a microwave reactor at 80° C. for 15 min. The reaction vial was cooled to room temperature and the reaction mixture was filtered through celite, rinsing with EtOH, water, EtOH again, and then EtOAc. The filtrates were combined and diluted with EtOAc. The organic layer was washed with saturated aq. NaHCO3 solution, water, then brine, then dried over MgSO4, filtered, and evaporated to dryness. (R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (470 mg) was obtained as a pale yellow solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CC(O)=O>CO.C(Cl)(Cl)Cl>[Br:8][C:21]1[S:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccsc1-c1ccc(S(C)(=O)=O)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(Br)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (209 mg, 1.18 mmol) was added in small portions to a stirred solution of Intermediate Y (365 mg, 1.18 mmol) in a mixture of MeOH (10 ml) and chloroform (5 ml) at 0° C. AcOH (0.250 ml) was added and the reaction was stirred at 0° C. for 1 hour then at r.t. for 3 hours. More NBS (35 mg, 0.20 mmol) was added at 0° C. and the reaction was stirred at r.t. over night. A new reaction was also started. NBS (342 mg, 1.92 mmol) was added in small portions to a stirred solution of Intermediate Y (519 mg, 1.67 mmol) in a mixture of MeOH (15 ml) and chloroform (7 ml) at 0° C. AcOH (0.50 ml) was added and the reaction was stirred at r.t. over night.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2[CH:18]=1.[CH3:23]CN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:19][C@H:17]2[CH2:18][CH2:13][C@H:14]([CH3:23])[CH2:15][CH2:16]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1cccc(Cl)c1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)CCc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To solution of 4-trans-methyl-cyclohexylamine hydrochloride (500 mg, 3.3 mmol) and 3-(3-chlorophenyl)propionic acid (609 mg, 3.30 mmol) in DCM (25 mL) was added HOBt (445 mg, 3.3 mmol) and EDAC (633 mg, 3.3 mmol). The mixture was stirred for 10 min at room temperature before the addition of DIPEA (1.13 mL, 6.6 mmol) and the resulting solution was stirred for a further 16 h at room temperature. DCM (25 mL) was added and the organics were washed with water (2×15 mL), 1N NaOH (10 mL), dried (MgSO4), filtered and concentrated in vacuo to yield 900 mg of 3-(3-Chloro-phenyl)-N-(trans-4-methyl-cyclohexyl)-propionamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:35][CH:34]=[CH2:33])=[O:22])[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a −78 □C solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (5.02 g, 16.4 mmol) in THF (90 mL) was added lithium hexamethyldisilazide (1.0 M in THF, 18.1 mL, 18.1 mmol). After 1 h allyl bromide (2.19 g, 18.1 mmol) was added, the reaction stirred at this temperature for 0.5 h, then warmed to 25 □C. After 3 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 60% EtOAc:hexanes to give the title compound (4.08 g). MS: m/z=346.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:50][O:51][C:52]1[CH:60]=[CH:59][C:55]([CH:56]([OH:58])[CH3:57])=[CH:54][CH:53]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:58][CH:56]([C:55]1[CH:59]=[CH:60][C:52]([O:51][CH3:50])=[CH:53][CH:54]=1)[CH3:57]
Reactant: COc1ccc(C(C)O)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(C)OC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2Cl)cc1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (66 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (88 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methoxy-α-methylbenzyl alcohol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 53%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[C:20]([C:21]#[N:22])=[C:16]3[NH:15][C:14]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:37]>OP(O)(O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][CH:28]=4)[C:20]([C:21]([NH2:22])=[O:37])=[C:16]3[NH:15][C:14]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Reactant: O
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Yield: 58 %

Procedure:
A solution of 1′-benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile (200 mg, 0.42 mmol) in H3PO4 (15 mL) was heated to 120° C. for 2 hr. The solution was poured to water (10 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (120 mg, 58.0%) as an off-white solid. MS (ESI, m/e) [M+1]+ 493.9.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([CH:10](O)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].S(Cl)([Cl:41])=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([CH:10]([Cl:41])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]glycolate (2.136 g) in anhydrous methylene chloride (20 ml) are added thionyl chloride (0.90 ml) and pyridine (0.33 ml) with stirring at 0° C. After stirring for 1 hour at 0° C., the mixture is poured into ice water, and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the crude product of a mixture of epimers at position α.