Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[K+]>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10](=[O:16])[CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:4]=[CH:5][C:6]=1[O:9][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)CC(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2',3'-dichloro-3,3-dimethyl-4'-hydroxybutyrophenone (15.5 g., 0.059 mole) and potassium carbonate (9.7 g., 0.070 mole) in dimethylformamide (DMF) (60 ml.) is stirred at 65° C. for 1/2 hour. Ethyl bromoacetate (11.7 g., 0.070 mole) is added in one portion and heating and stirring were continued for three hours. A solution of potassium hydroxide (4.6 g., 0.082 mole) in water (80 ml.) is added and the mixture is refluxed for 1/2 hour. The resulting semisolid mass is added to water (750 ml.). The solution is heated to boiling, filtered, cooled and acidified (HCl) to afford 18 g. of [2,3-dichloro-4-(3,3-dimethylbutyryl)phenoxy]acetic acid, m.p. 145°-145.5° C. after recrystallization from benzene.
Reaction SMILES: [Mg].ClC1C=CC(Br)=CC=1.C(C1C(N2C=CN=C2)=NC=CC=1)#N.[Cl-].[NH4+].[Cl:25][C:26]1[CH:44]=[CH:43][C:29]([C:30]([C:32]2[C:33]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[N:34][CH:35]=[CH:36][CH:37]=2)=N)=[CH:28][CH:27]=1.Cl.CC[O:48]CC>C1C=CC=CC=1>[Cl:25][C:26]1[CH:44]=[CH:43][C:29]([C:30]([C:32]2[C:33]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:48])=[CH:28][CH:27]=1
Reactant: N=C(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Reactant: CCOCC
Agent: Cl
Agent: Clc1ccc(Br)cc1
Agent: N#Cc1cccnc1-n1ccnc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A Grignard reagent which is prepared by reacting 1.9 g of magnesium with 15 g of p-chlorobromobenzene in 150 ml of anhydrous ether is added to a suspension of 10.2 g of 3-cyano-2-(1-imidazolyl)pyridine in 200 ml of benzene at 30°-35° C. After the addition is complete, the whole mixture is stirred at room temperature for 1.5 hours. The reaction mixture is treated with an aqueous ammonium chloride solution under ice cooling. To the benzene layer containing the resulting 3-(4-chlorobenzimidoyl)-2-(1-imidazolyl)pyridine is added dilute hydrochloric acid and the mixture is stirred at 35° C. for 10 minutes for dydrolysis. The dilute hydrochloric acid layer is separated and made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer is washed with water, dried and concentrated to give 3-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine as an oil in high yield. This oily product can be used in the next reaction without isolation, but when the oil is treated with toluene, crystallization takes place. Upon recrystallization from toluene the product is obtained as white crystals, melting at 118°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9].[CH2:24]=[C:25]=[O:26]>ClCCl>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9])(=[O:26])[CH3:24]
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Reactant: C=C=O
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2NC(C)=O)n1
Reaction time: 0.25 h

Procedure:
2-Amino-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide (1.0 g) suspended in 25 ml of dichloromethane was treated with ketene for 10 minutes (ca. 0.4 mole/hr). The mixture was allowed to stand and after 15 minutes a light orange solution resulted. Evaporation of the solvent gave an orange glassy oil which was triturated with water and allowed to stand for 16 hours. The white solid thus obtained was removed by filtration and dried in-vacuo to yield 0.24 g of the desired product, m.p. 161°-162°. The product showed absorption peaks by proton NMR at 4.0 (singlet, 3H); 2.5 (singlet, 3H) and 2.1 (singlet, 3H) consistent for the acetylated derivative. The infrared absorption spectrum showed peaks at 1700, 1695, 1610 and 1580 also confirming the desired acylation.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>C(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH:7][S:26]([C:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)CN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 82.9 %

Procedure:
In 50 ml of chloroform were dissolved 2.0 g of 2-acetamidopropylamine and 2.6 g of triethylamine, and to the solution was added dropwise 50 ml of a chloroform solution containing 3.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. Then the mixed solution was stirred at a temperature of 15° C. to 25° C. for two hours, and the reaction solution was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure to give 3.67 g of N-(2-acetamidopropyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(3,4-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1[N+](=O)[O-])c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (580 g, 1.02 mmol) in 4 M HCl in dioxane (15 mL), and water (5 mL) was heated at 100° C. for 8 h and then at room temperature for 10 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product 4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1 H), 8.23 (d, J=2.4 Hz, 1 H), 8.18 (d, J=2.4 Hz, 1 H), 8.14 (dd, J=8.0, 1.4 Hz, 1 H), 8.07 (d, J=2.4 Hz, 1 H), 8.00 (dd, J=8.4, 2.0 Hz, 1 H), 7.80-7.77 (m, 1 H), 7.70-7.66 (m, 2 H), 7.45 (dd, J=8.0, 1.6 Hz, 1 H); Mass spectrum m/z: 520.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-])=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH2:16])[C:8]([O:14][CH3:15])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1N
Yield: 89.2 %

Procedure:
5-tert-Butyl-2-methoxy-1,3-dinitrobenzene (see Example 1, 1.9 g, 0.0075 mol) was added to EtOH (40 mL) under nitrogen purge. To this mixture, ammonium formate (4.9 g, 0.075 mol) was added in a single portion, followed by 10% palladium on carbon (0.75 g, 10 mole %), also in a single portion. This resulted in an immediate exotherm (temperature climbs to 30° C.), along with outgassing. Once the bubbling subsided, the mixture was slowly brought to reflux and maintained at this temperature for 3 h. An aliquot taken at this point showed over 93% conversion to a new, polar material. The mixture was filtered hot through a pad of diatomaceous earth, which was then washed twice with hot EtOH. The filtrate was concentrated under reduce pressure to obtain the title compound as a light grey solid (1.3 g, 90%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[O:34]1[C:38]2[CH:39]=[CH:40][C:41](B(O)O)=[CH:42][C:37]=2[O:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:2]3[S:10][C:9]4[C:8](=[O:11])[N:7]([CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]5)[C:6](=[O:25])[N:5]([CH2:26][C:27]5[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=5)[C:4]=4[CH:3]=3)=[CH:42][C:37]=2[O:36][CH2:35]1
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate 405 mg, compound B99), 1,3-benzodioxol-5-ylboronic acid (368 mg), dichlorobis(tricyclohexylphosphine)palladium (137 mg) and aqueous cesium carbonate solution (1.39 ml, 2.0 M) in dioxane (18 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 80/20 to 50/50 (v/v)] as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[NH:12]1[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[NH2:12][CH2:13][CH2:14][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: C1CN1
Reactant: COC(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCN)cc1

Procedure:
Methyl p-hydroxybenzoate (7.6 g) was dissolved in 50 ml of chloroform with heating, 2.15 g of aziridine was dropped in with stirring, and the mixture was heated to refluxed for 8 hours. The reaction solution was concentrated in vacuo and the residue was purified by a silica gel column chromatography (200 g of silica gel C-200; the eluting solvent used was a 9:1 mixture of chloroform and methanol).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][C@@:11]3([CH3:15])[C@H:7]([CH2:8][N:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C.[O-2].[Ce+4].[O-2].Br([O-])(=O)=O.[Na+]>O.O1CCOCC1>[Cl:1][C:2]1[C:14]2[C:13](=[O:23])[CH2:12][C@@:11]3([CH3:15])[C@H:7]([CH2:8][N:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3CC[C@]2(C)C1
Agent: [Ce+4]
Agent: [Na+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3C(=O)C[C@]2(C)C1
Temperature: 95 °C

Procedure:
cis-Ethyl 6-chloro-3a-methyl-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (5.55 mmol, 1630 mg) was dissolved in water (33 ml), acetic acid (8.25 ml) and 1,4-dioxane (8.25 ml). Cerium(IV) oxide (1.276 mmol, 220 mg) and sodium bromate (5.55 mmol, 837 mg) were added and the reaction mixture was heated to 95° C. for 3 hours. The reaction mixture was cooled to rt, diluted with water (30 ml) and extracted with ether. The organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo to give to give a crude residue that was purified by silica column chromatography (eluting with 0-60% ethyl acetate in heptane) to give cis-ethyl 6-chloro-3a-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (673 mg), m/z=308.7 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(CN2CCNCC2)nc1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCN(C3CCC3)CC2)nc1
Temperature: 62 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
1-(5-Bromopyridin-2-ylmethyl)piperazine (10 g, 39.04 mmol) was dissolved in THF (65 ml), water (0.6 mL), cyclobutanone (4.1 g, 58.6 mmol) and acetic acid (7.5 g, 125 mmol) was mixed. Then 1M NaCNBH3 in THF (3.68 g, 58 mmol) (58 mL) was added. The reaction mixture was then heated and 21eq. water was added in order to solve the rest of material in the mixture. The reaction mixture was heated at 62° C. for 1.5 hours (LC-MS showed full conversion). The reaction mixture was however left overnight at 62° C. The reaction mixture was added DCM (150 mL) and water (100 mL). pH was adjusted to pH=10 with 4N NaOH. The water phase was extracted with DCM (2×25 mL). The combined DCM phase was washed with water (2×25 mL), brine (2×25 mL) finally dried MgSO4, filtered and evaporated in vacuo gave 7.65 g (63%) of a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]([NH:30]C(OCC[Si](C)(C)C)=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:30][C:11]1[C:12]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:14](=[O:15])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2NC(=O)OCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirring solution of tert-butyl 4-(1-(3,4-dichlorophenyl)-6-oxo-3-((2-(trimethylsilyl)ethoxy)carbonylamino)-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (60 mg, 0.10 mmol) in THF (10 ml) at room temperature under argon was added 1M TBAF in THF (1 mL, 1.0 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(3-amino-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (28 mg, white solid, 55%). 1H NMR (400 MHz, CDCl3) δ ppm 1.34-1.55 (m, 9H) 1.65-1.91 (m, 2H) 2.04 (dd, J=12.96, 3.30 Hz, 2H) 3.06-3.39 (m, 2H) 3.59-3.94 (m, 2H) 4.29-4.71 (m, 2H) 6.20 (s, 1H) 7.43-7.50 (m, 1H) 7.54-7.64 (m, 1H) 7.80 (d, J=2.20 Hz, 1H). MS (ESI) 455 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]([OH:27])=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=2)[CH:5]=[C:6]([C:19]([CH3:23])([CH3:20])[CH3:18])[C:1]=1[OH:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 6 h

Procedure:
A portion (10.0 g) of this reaction solution was used in the subsequent process. Phenol (20 g) and sulfuric acid (0.04 g) were added to 10.0 g of reaction solution (1) not only for neutralizing the base in the reaction system but also to render the reaction solution acidic (pH, 1). Thereafter, the following two reactions were performed in one step at 180° C. over a period of 6 hours: a redox reaction in which the unreacted 2,6-di-t-butylphenol and 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone were reacted to produce 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl; and a reaction in which 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl was dealkylated into p,p'-biphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([NH:28][C:29](=O)[O:30]C(C)=C)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:28][C:29]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:30])([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: C=C(C)OC(=O)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(OC)cn1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2cc(F)cc(C(F)(F)F)c2)nc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 62.8 %

Procedure:
To a solution of prop-1-en-2-yl 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2-phenylethylcarbamate (100 mg, 0.210 mmol) in THF (200 μl) was added 2,2,2-trifluoroethanamine (200 μl, 2.1 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 1200 sec then at 150° C. for 1800 sec. The solvent was evaporated under reduced pressure and the residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-100% over 12 min) to give (R)-1-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2 phenylethyl)-3-(2,2,2-trifluoroethyl)urea as white powder (68 mg, 63% yield) LCMS: RT=2.03 min [M+H] 516.2 (LCMS Method 1); HPLC: RT=3.24 min, Purity 98% (HPLC Method 2); NMR: 400 MHz 1H (CD3OD) 8.30 ppm, 1H, s; 7.98 ppm, 1H, dd, J=4.55, 1.26 Hz; 7.46ppm, 1H, s; 7.39 ppm, 2H, m; 7.30 ppm, 1H, m; 7.21 ppm, 1H, m; 7.00 ppm, 3H, m; 6.66 ppm, 2H, m; 4.18 ppm, 2H, m; 3.90 ppm, 1H, m; 3.63 ppm, 4H, m.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C(O)CC>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCCCO
Agent: CCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-butanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extract is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: C(O)(C)(C)C.[Li].[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=43)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2>C1COCC1.N.CO>[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@@H:21]3[CH2:20][CH2:19][C:18](=[O:25])[CH:17]=4)[C@@H:12]1[CH2:11][CH:10]=[CH:9]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Agent: N
Agent: [Li]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@@H]3[C@H]1CC2
Reaction time: 8 h

Procedure:
To estra-1,3,5(10),16-tetraene-3-methyl ether (551.5 mg., 2.055 mmol) in 8.6 ml of anhydrous THF, approximately 30 ml of anhydrous ammonia, and 6.76 g of t-butyl alcohol was added lithium wire (0.24 g, 35 mg-atom) cut in small pieces. The reaction mixture was refluxed 4½ h under argon, after which methanol (2.3 ml) was added and the ammonia was allowed to boil off overnight. The residue was dissolved in 25 Ml of methanol and was acidified to approximately Ph 1 with 5N HCI. After heating in an oil bath between 55 and 70 C for 15 min. the cooed hydrolysis mixture was partitioned between 25 ml of water and 50 ml of ethyl acetate and the aqueous phase was extracted with 25 ml of ethyl acetate. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate and 25 ml of brine, dried over magnesium sulfate, and filtered. Removal of solvent under reduced pressure yielded 0.57 g of oily residue which was purified by flash chromatography on silica gel (eluent: 15% ethyl acetate/hexane) followed by recrystallization from pentane to give crystals (206.1 mg, 39%) homogeneous to TLC, m.p. 67-71 C.
Reaction SMILES: [CH3:1][NH2:2].CO.[S:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.CC(O)=O>>[CH3:1][NH:2][CH2:10][C:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5][CH:9]=1
Reactant: CN
Reactant: O=Cc1csc2ccccc12
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2 M methylamine in methanol (75 mmole, 150 mmole) was added benzo[b]thiophen-3-carboxaldehyde (5.3 g, 33 mmole) and HOAc (4.3 mL, 75 mmole). The reaction was stirred at RT for 1 h, then NaB3CN (2.1 g, 33 mmole) was added portionwise over 5 minutes. The reaction was stirred for an additional 16 h then was concentrated under vacuum. The residue was taken up in Et2O (300 mL) and washed with 1.0 N NaOH (300 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (5% (5% NH4OH/MeOH)/CHCl3) gave the title compound (2.81 g, 48%) as a brownish oil: 1H NMR (400 MHz, CDCl3) δ•7.87 (2d, 2H), 7.40 (m, 2H), 7.32 (s, 1H), 4.02 (s, 2H), 2.56 (s, 3H), 1.5 (br s, 1H).