Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8](=[CH2:10])[CH3:9].Cl>O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: C=C(C)C
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Yield: 96.5 %

Procedure:
To 97.5 ml. (1 mole) of anhydrous chloral 0.5 g. of ferric chloride hexahydrate is added. To the obtained yellow clear solution 58-59 g. of isobutylene are introduced so that the temperature does not exceed 15°-20° C. To the reaction mixture a mixture of 35 ml. of water and 15 ml. of concentrated hydrochloric acid is added and the layers are separated. The organic layer is washed with water, diluted with benzene and water is removed from the mixture in a vacuo of 100 Hgmm. 194.6 g. (96.5%) of 1,1,1-trichloro-4-methyl-4-pentene-2-ol are obtained. Active ingredient content: 98.2%. The product can be further purified by vacuum distillation.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][C:10]1=[O:21])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-:22].[Na+]>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:11][C:10]=1[O:21][C:6](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)CC2(CCCCC2)CC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC2(CCCCC2)CC1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(1-allyloxyaminopropylidene)spirobicyclohexane-3,5-dione (1.5 g) in acetone (30 ml), sodium hydroxide (0.2 g) in water (1 ml) was added at room temperature and then benzoylochloride (0.7 g) was added. After stirring for 5 hr, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and oily substance (0.8 g) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:29]1[S:30][CH:31]=[C:32]([C:34]([OH:36])=O)[N:33]=1)[CH2:26][CH2:27][CH3:28].[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:52][CH2:53][C:54]2([O:59][CH2:58][CH2:57][N:56]([C:34]([C:32]3[N:33]=[C:29]([CH2:25][CH2:26][CH2:27][CH3:28])[S:30][CH:31]=3)=[O:36])[CH2:55]2)[CH2:60][CH2:61]1)([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38]
Reactant: CCCCc1nc(C(=O)O)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of 2-butylthiazole-4-carboxylic acid (example 78, step g) (0.193 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.4 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.35 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][CH2:6][CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([OH:1])=[C:10]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[CH2:5][CH2:6]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc2c(cc1C(F)(F)F)NCC2
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(O)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of indoline (D4, 2.84 g, 14 mmol) and acetic anhydride (1.32 ml, 14 mmol) in dry dichloromethane (50 ml) was stirred at room temperature for 3 h, then evaporated. The residue was treated cautiously with saturated sodium bicarbonate solution, then the solid product was filtered off, washed with water and dried to give the title compound (3.28 g, 96%), m.p. 244-7° C.
Reaction SMILES: O=[C:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8].CC1C(C2(C3C(C)=C(Br)C(O)=C(C(C)C)C=3)OS(=O)(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1Br.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:58]([NH:65][CH:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(=O)CC)P(=O)(OCC)OCC
Agent: Cc1c(C2(c3cc(C(C)C)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(C(C)C)c(O)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(OCC)C(CC(CC)NCc1ccccc1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
To a stirred solution of tetraethyl 3-oxopentane-1,1-bisphosphonate (0.50 g, 1.4 mmol) in methanol (5 ml) was added a small amount of bromothymol blue and benzylamine (0.75 g, 7.0 mmol). Acetic acid was added dropwise until the solution turned yellow (pH=6), and NaCNBH3 (57 mg, 0.9 mmol) was added. The resulting yellow solution was stirred at room temperature for 2 days, at which time more NaCNBH3 (20 mg) was added. After stirring a total of 4 days, the reaction was quenched by adding concentrated HCl until the pH was less than 1, and the solvents were removed in vacuo. The residue was taken up in water (10 ml) and washed with diethyl ether (2×20 ml). The aqueous layer was made basic (pH greater than 10) by the addition of solid KOH, saturated with NaCl, and extracted with dichloromethane (5×25 ml). The combined extracts were dried (Na2SO4) and concentrated to give tetraethyl 3-benzylaminopentane-1,1-bisphosphonate. This material was hydrolyzed by heating at reflux in concentrated HCl (6 ml) for 20 hours. The volatiles were removed under vacuum, the residue dissolved in water (10 ml) and concentrated under vacuum to give 0.49 g of Compound No. 159 as a hygroscopic foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1.Br[CH:14]([CH2:24][CH2:25]Cl)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16]>CC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:14]2([N:10]3[CH:11]=[N:12][C:8]([Cl:7])=[N:9]3)[CH2:25][CH2:24]2)=[O:16])=[CH:18][CH:19]=1
Reactant: Clc1nc[nH]n1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 45 %

Procedure:
34 g (246 mmol) of potassium carbonate and 35 g (338 mmol) of 3-chloro-1,2,4-triazole are initially introduced into 130 ml of acetone under reflux and 50 g (169 mol) of 2-bromo-4-chloro-1-(4-chlorophenyl)-butan-1-one in 60 ml of acetone are added dropwise. The mixture is boiled under reflux for 8 hours, the solution is filtered off with suction from the residue and the solvent is stripped off in vacuo. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulphate, and the solvent is evaporated. Chromatography on silica gel (eluent: dichloromethane) gives 42.9 g of the title compound (90% of theory) of m.p. 85° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[CH:24]2)=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(OCC)(=O)C>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[CH:24]2)=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: CCCc1ncn(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1ncn(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogen carbonate (1.12 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.58 g, 83%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][OH:16].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>CCCCCC.CN(C)C=O>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][O:16][CH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccncc1CO
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1ccncc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (89.1 mg, 2.04 mmol, 1.1 eq) was washed twice with n-hexane under argon and suspended in 1 ml dimethyl formamide. (4-o-Tolyl-pyridin-3-yl)-methanol (370 mg, 1.86 mmol), dissolved in 4 ml dimethyl formamide, was added dropwise and the mixture was stirred lh at room temperature. 3,5-Bis(trifluoromethyl)benzyl bromide (627 mg, 2.04 mmol, 1 eq), dissolved in 2 ml dimethyl formamide, was added and the mixture was stirred 2.5 h at room temperature.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.O>CCOCC>[OH:8][C@@H:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (˜14.2° C.) and left overnight. LC-MS (16 min) showed 9:1 ratio of the R to S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120 g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc(CCl)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-5-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (138 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14](O)=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:38][C@@H:37]([CH2:39][CH2:40][NH2:41])[CH2:36][O:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:41][CH2:40][CH2:39][C@H:37]([OH:38])[CH2:36][OH:35])=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N(CC(=O)NCC[C@H](O)CO)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.9 %

Procedure:
A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The reaction mixture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was dissolved into tetrahydrofuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N—((S)-3,4-dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS (ES+) m/z Calcd for C28H33Cl2F2N3O3+H [(M+H)+]: 568.1940; Found: 568.1943.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
The photoinitiator dibenzoyl biphenyl was prepared by placing 200 mL nitrobenzene, 38.5 g (0.25 mole) biphenyl, and 140.6 g (1.00 mole) benzoyl chloride into a 1 liter 3-necked flask equipped with a water condenser. While stirring, 160 g (1.2 mole) aluminum trichloride was added slowly over a period of about 30 minutes. During the reaction, the temperature increased from 30° C. to 55° C. The color changed from yellowish to light brown, then reddish. The flask was kept in a water bath at a temperature of 55° C. to 60° C. for 3 hours while stirring. The reaction mixture was then cooled to 35° C. The reaction mixture was poured into 1.2 L of 8% HCl solution with vigorous stirring. The organic layer was separated and poured into a blender and 500 mL n-hexane was added. The mixture was vigorously stirred for 5 minutes and then filtered. The solid was washed with n-hexane. The thus-produced dibenzoyl biphenyl was dried and recrystalized twice in chloroform.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:18])C=CC=CC=1.C([N:30]([CH2:33]C)CC)C>C1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:30]=[C:33]=[O:18]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CC2CCC1C2
Solvent: c1ccccc1
Product: O=C=NC1CC2CCC1C2

Procedure:
The reaction of 2-norbornanecarboxlic acid and diphenylphosphoryl azide in a solution of triethylamine and benzene provided a solution comprising 2-norbornyl isocyanate (I.R.: 2270 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-(2-norbornyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:28][CH2:29][OH:30])[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=2)[CH2:10][CH2:9]1.[OH:31]O>C(O)(=O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N:11]3[CH2:10][CH2:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])([CH2:28][CH2:29][OH:30])[O:13][C:12]3=[O:14])[N+:16]=2[O-:31])=[CH:26][CH:25]=1
Reactant: O=C1OC(CCO)(c2ccccc2F)CCN1c1cccc(-c2ccc(F)cc2)n1
Reactant: OO
Solvent: CC(=O)O
Product: O=C1OC(CCO)(c2ccccc2F)CCN1c1cccc(-c2ccc(F)cc2)[n+]1[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
6-(2-fluorophenyl)-3-(6-(4-fluorophenyl)pyridin-2-yl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (680 mg, 1.66 mmol) was added to acetic acid (20 mL), 30% aq hydrogen peroxide (50 mL) was added at rt and the reaction mixture was stirred for about 5 h at 80° C. The mixture was extracted with CH2Cl2 and the organic phase washed with Na2SO3 solution, then dried over Na2SO4. Removal of the solvent gave the crude product, which was purified by HPLC and give 2-(4-fluorophenyl)-6-(6-(2-fluorophenyl)-6-(2-hydroxyethyl)-2-oxo-1,3-oxazinan-3-yl)pyridine 1-oxide (80 mg, 11%). LC-MS Method 2, tR=1.704 min, m/z=427.1. 1H NMR (CD3OD) 2.33-2.50 (m, 2H), 2.60-2.77 (m, 2H), 3.08-3.20 (m, 1H), 3.32-3.40 (m, 1H), 3.40-3.52 (m, 1H), 3.70-3.85 (m, 1H), 7.08-7.37 (m, 5H), 7.40-7.69 (m, 4H), 7.70-7.86 (m, 2H). 1H NMR (400 MHz, CDCl3): δ=2.5 (s, 2H), 2.6 (m, 2H), 3.05 (m, 1H), 3.3 (m, 1H), 3.35-3.6 (m, 1H), 3.75 (m, 1H), 7.0-7.8 (m, 11H).
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O>ClC1C=CC=CC=1Cl>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCCCC(=O)O
Yield: 17.7 %

Procedure:
A solution is formed by mixing 81.6 grams of trimellitic acid anhydride and 130.0 grams of p,p' diphenyl methane diisocyanate and 222.6 grams of o-dichlorobenzene by heating the mixture. At approximately 160°C. a clear, homogeneous solution is obtained. Once clarity is obtained 11.0 grams of adipic acid are added slowly. The temperature of the mixture is raised to approximately 180°C. and slow reflux is maintained. After approximately 40 minutes, a yellow viscous resin is obtained and 296.8 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 2200 cps, utilizing a Brookfield viscometer and a resin solution of approximately 30% weight resin.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:14]([CH3:13])[CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(Cl)noc2c1
Reactant: CNCCN1CCOCC1
Product: COc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Temperature: 140 °C
Yield: 49.4 %

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (6.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (13.8 g). The reaction was heated to 140° C. over 48 hours and then cooled to room temperature. The residue was partitioned between ethyl acetate (EtOAc) and water, extracted again with EtOAc, and the organic phase was dried over magnesium sulfate (MgSO4) and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1% methanol/dichloromethane (MeOH/DCM) provided the product (4.7 g), m.p. 43°-44° C.