Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].O[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH2:13]([O:1][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCCCCCBr
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In a 100 ml four-necked flask, 2.79 g (42.3 mM) of 85 wt % potassium hydroxide was suspended in 30 ml of dimethylformamide, and 10 ml of a dimethylformamide solution containing 5.28 g (43.2 mM) of hydroxybenzaldehyde was added dropwise while maintaining the system at 20° C. or lower, and the resultant was aged at 30° C. for 1 hour. Next, 9.58 g (32.9 mM) of 1-bromopentadecane was added, and the resultant was aged at 70° C. for 21 hours. The reaction mixture was dispersed in water and extracted with toluene. The extract was washed with water and concentrated to give 11.03 g of a slightly colored viscous liquid. Recrystallization from hexane gave 8.91 g of p-pentadecanoxybenzaldehyde (purity: 98.3%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1(C2C3C(=C4C(=CC=3)C(C3C=CC=CC=3)=CC=N4)N=CC=2)C=CC=C[CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC=C)CCC>[CH:16]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[CH2:17]
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [Pd+2]
Agent: C=COCCCC
Agent: CC(=O)[O-]
Product: C=COCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9182.5 %

Procedure:
4.3 g of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, 66 mg of 4,7-diphenyl-1,10-phenanthroline, and 45 mg of palladium acetate were added to 50 mL of butylvinyl ether, followed by stirring at room temperature for 15 minutes, and stirring at 75° C. for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 4.4 g of tert-butyl 4-[(vinyloxy)methyl]piperidine-1-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCNCc1cnccn1
Product: CNC(=O)NCCNCc1cnccn1

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with methyl isocyanate by the procedure of Example 24, then concentrating and separating the residue by column chromatography gives the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Br:19][C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[Cl:34])[C:21]=1[CH2:35]Br>C1COCC1>[Br:19][C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[Cl:34])[C:21]=1[CH2:35][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 1M solution of lithium bis(trimethlsilyl)amide (10.5 mL) at −78° C. was added tert-butyl acetate (1.77 mL, 13.2 mmol) dropwise. To this mixture a solution of 4,6-dibromo-3-(bromomethyl)-2-(2-chloro-4-fluorophenyl)pyridine (4.02 g, 8.77 mmol) (COMPOUND PS) in 9.2 mL of THF was added dropwise over 20 min. After stirring for 30 min at −78° C., the reaction mixture was quenched by the dropwise addition of 3 mL of methanol, then warmed up to rt and partitioned between 30 mL each of saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was extracted with 2×20 mL of ethyl acetate. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with warm Et2O. The mother liquor was purified by flash chromatography on a Biotage 40M column eluting with 97:3 hexanes-ethyl acetate. The two batches were combined to give the tert-butyl 3-[4,6-dibromo-2-(2-chloro-4-fluorophenyl)pyridin-3-yl]propanoate. Mass spectrum (ESI) 492.4 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1OC

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-dimethoxyphenylboronic acid (157 mg, 0.85 mmol) the subtitle compound was obtained (180 mg, 78%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.44(dd, 1H), 7.91(d, 1H), 7.62(d, 1H), 7.57(dd, 1H), 7.25(d, 1H), 7.19–7.14(m, 2H), 6.98(d, 1H), 4.07(s, 3H), 3.97(s, 3H), 3.94(s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1)#[N:37]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[N:39][CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)nc2)CC1
Reaction time: 96 h
Yield: 30.6 %

Procedure:
To a mixture of (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2, 150 mg, 1.0 eq.), anhydrous copper(II) acetate (131 mg, 2 eq.), pyridine (120 microL, 4 eq.) in dichloromethane (3.5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (247 mg, 3 eq.) was added. The reaction mixture was stirred for 4 days and then concentrated in vacuo. The residue was then purified on silica eluting with dichloromethane/methanol 98:2 v:v. One fraction was isolated and dried in vacuo, to yield 57 mg (23%) of the desired product as light yellow oil. MS (m/e): 522.5 (MH+, 100%).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].[H][H].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>O.CN(C)C=O>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[CH:8][CH:9]=2)=[N:18][CH:19]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1.75 h
Yield: 79.5 %

Procedure:
Sodium hydride (3.7g, 0.154 mole) was added in portions to a stirred mixture of dry N,N-dimethylformamide (60 ml) and 4-isopropyloxyphenol (26g, 0.17 mole). After hydrogen evolution had stopped, 2-chloro-5-trifluoromethylpyridine (28.75 g, 0.158 mole) was added and stirring was continued for 1.75 hours at 80°-95° C. Further sodium hydride (0.4 g) was added. After stirring for 1.25 hours at 95° C., the mixture was cooled and poured into water. The water was extracted twice with toluene, the extracts washed with 1M sodium hydrogen carbonate and brine, filtered and evaporated to a brown oily residue which was purified over silica gel with 1:9 ether/hexane as eluant to give the title compound (37.34g).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:25][C@@H:26]([CH3:38])[CH2:27][C@H:28]([CH3:37])[O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.N1(C2C=CN=CC=2)CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:25][C@@H:26]([CH3:38])[CH2:27][C@H:28]([CH3:37])[O:29][C:30]1[CH:35]=[CH:34][C:33]([O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)=[CH:32][CH:31]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.36 g of 4-(4'-n-octyloxyphenyl)benzoic acid, 0.21 g of (S,S)-4-(3'-chloro-1'-methylbutoxy)phenol, 0.02 g of 4-pyrrolidinopyridine, 0.21 g of dicyclohexylcarbodiimide and 10 ml of methylene chloride were stirred together at room temperature for four hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (9:1) as a developing solvent to thereby give the title compound.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]([CH3:19])=[C:8]([CH3:20])[N:7]=1.[OH-].[Na+].O>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: Cc1nc(O)c(Cc2ccccc2)nc1C
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccccc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60° C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].O>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 7.0 g (55.0 mmol) of (R)-3-quinuclidinol were suspended in 100 ml of CH2Cl2. After cooling the suspension to 0° C., a solution of 1,1′-carbonyldiimidazole (10.7 g, 66.0 mmol) in 150 mL of CH2Cl2 was added. The reaction mixture was stirred at 0° C. for 4 hours, then water was added (100 ml). The organic layer was separated, washed with water, dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue oil (13.1 g) was used without further purification.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5]C)=[O:4].[OH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15].[OH-].[Na+].Cl>C(O)CC.C(N(CC)CC)C>[OH:9][CH2:10][CH2:11][N:12]([C:2]([CH3:8])([CH3:7])[C:3]([OH:5])=[O:4])[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)C(C)(C)Br
Reactant: OCCNCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)O)N(CCO)CCO

Procedure:
Methyl 2-bromo-2-methylpropanoate (181.04 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles are added and the mixture stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml., 1.3 moles). Upon cooling, 2-[N,N-bis-(2-hydroxyethyl)-amino]-2-methylpropanoic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.C[O:9][C:10]1[CH2:28][CH2:27][C@H:26]2[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:25]2[CH2:24][CH2:23][C@@:20]2([CH2:21][CH3:22])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH:11]=1.C(O)(=O)C(O)=O>O1CCCC1.O.CO>[C:3]([C@:19]1([OH:29])[CH:18]=[CH:17][C@H:16]2[C@H:15]3[C@H:25]([CH2:24][CH2:23][C@:20]12[CH2:21][CH3:22])[C@@H:26]1[C:27](=[CH:28][C:10](=[O:9])[CH2:11][CH2:12]1)[CH2:13][CH2:14]3)#[CH:4]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Reactant: [Li]CCCC
Agent: C#C
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At 0° C., acetylene is introduced for 15 minutes into a solution of 40 ml of n-butyllithium (15% in hexane) in 100 ml of absolute tetrahydrofuran and then 4.0 g of 3-methoxy-18-methyl-3,5,15-estratrien-17-one in 40 ml of tetrahydrofuran is added dropwise thereto. After 15 minutes, the mixture is combined with 8 ml of water, 40 ml of methanol and 8 g of oxalic acid, stirred for one hour at 60° C., 600 ml of water is added, and the mixture is extracted with ethyl acetate. The organic phase is washed with water and dried. Recrystallization from ethyl acetate yields 2.4 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one. Melting point 197° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 53.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 15; 52.0 mg) was reacted with 1-acetylpiperazine (38.8 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (32.8 mg, 54%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:13][O-:14].[Na+].[OH2:16].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.[Mn]>[C:3]1([CH2:2][C:13]([OH:16])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: ClCc1cccc2ccccc12
Reactant: O
Agent: [Mn]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cccc2ccccc12
Yield: 6.5 %

Procedure:
In the manner described in Example 1, 58 g of alphachloromethylnaphthalene was reacted with CO together with 78 g of a 24 wt-% sodium methylate solution in methanol, 12 g CoCl2.6 H2O, 6 g manganese and 1 g Na2S2O4. The usual processing yielded 35 g naphthyl-(1)-acetic acid methyl ester (yield 53%) and 7 g of alpha-naphthylacetic acid (yield 6.5%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-:6].[Al+3].[Cl-].[Cl-].[Cl:10][CH:11]=[CH:12][Cl:13]>>[Cl:10][CH:11]([C:3]([CH2:2][Cl:1])=[O:4])[CH:12]([Cl:6])[Cl:13]
Reactant: O=C(Cl)CCl
Reactant: ClC=CCl
Reactant: [Cl-]
Agent: [Al+3]
Product: O=C(CCl)C(Cl)C(Cl)Cl

Procedure:
The reaction of chloroacetyl chloride and aluminum chloride with a molar excess of 1,2-dichloroethylene has been reported by Catch et al., J. Chem. Soc. (London) 278 (1948) to afford chloromethyl 1,2,2-trichloroethyl ketone. McLamore et al., J. Org. Chem., 20, 109 (1955) have reported propionyl chloride to react with 1,2-dichloroethylene to provide ethyl 1,2,2-trichloroethyl ketone.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=384 (M+ of free base). α[D]589 =-11.40 (c=0.66, methanol).
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[CH3:36][C:37]1[CH:41]=[CH:40][S:39][C:38]=1S(N)(=O)=O>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31]([NH:7][C:5]([NH:4][S:1]([C:38]3[S:39][CH:40]=[CH:41][C:37]=3[CH3:36])(=[O:3])=[O:2])=[O:6])=[CH:30][CH:29]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: Cc1ccsc1S(N)(=O)=O
Product: Cc1ccsc1S(=O)(=O)NC(=O)Nc1ccc(-n2ccc3cc(N)c(F)cc3c2=O)cc1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 3-methyl-thiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-3-methylthiophene-2-sulfonamide. ES-MS (M+H)+=487.1; 1H-NMR (DMSO-d6) δ (ppm): 8.96-8.92 (bs, 1H), 7.86-7.82 (d, J=5.1 Hz, 1H), 7.66-7.60 (d, J=12.4 Hz, 1H), 7.46-7.40 (m, 2H), 7.32-7.26 (m, 2H), 7.24-7.20 (d, J=7.3 Hz, 1H), 7.03-7.00 (d, J=5.1 Hz, 1H), 6.72-6.68 (d, J=8.8 Hz, 1H), 6.56-6.48 (bs, 1H), 6.50-6.46 (d, J=7.7 Hz, 1H), 2.82-2.78 (bd, J=4.8 Hz, 3H), 2.45-2.43 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(NC(=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CCC(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetophenone (II), MS (m/e) 420, 375, 315, 301, 287 and 283; IR (neat) 1684, 1597, 1581, 1449, 1392, 1369, 1251 and 1164 cm-1 ; NMR (CDCl3) 7.97, 7.56, 7.45, 4.18, 3.39, 2.60, 2.33 and 1.30 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:37].N1C=CC=[CH:40][CH:39]=1.C(B1OB(C=C)OB(C=C)O1)=C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:34])([CH3:36])[CH3:35])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:37][CH:39]=[CH2:40]
Reactant: c1ccncc1
Reactant: CC(C)(C)[S@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O)c1
Agent: [Cu+2]
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=COc1cc([C@@](Cc2ccccc2)(N[S@@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (S)—N—((R)-1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide, prepared as described in Procedure 109, 110, 111, 112, 113, 114, (0.545 g, 1 mmol) in CH2Cl2 (10 mL) was added Cu(OAc)2 (0.182 g, 1 mmol), followed by pyridine (0.79 g, 10 mmol) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (0.159 g, 0.66 mmol). The reaction mixture was stirred overnight under ambient air and filtered through a plug of celite and neutral alumina. The solid was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to yield (S)—N—((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as an off-white foam (0.495 g, 87% yield). LCMS: RT=3.653 min [M+H] 572.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous acetonitrile containing 0.1% trifluoroacetic acid over a 4 minute gradient, monitoring at 220 nM). 1H NMR (CDCl3) ppm 7.2-7.1 (m, 5H), 7.02 (d, J=6.2 Hz, 1H), 6.89 (d, J=6.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.68 (br, 2H), 6.54 (dd, J=6.2 Hz, 13.6 Hz, 1H), 5.84 (t, J=52.7 Hz, 1H), 4.62 (dd, J=2.2 Hz, 13.6 Hz, 1H), 4.40 (dd, J=2.2 Hz, 5.7 Hz, 1H), 4.21 (s, 1H), 3.95 (d, J=12.8 Hz, 1H), 3.55 (d, J=12.7 Hz, 1H), 1.19 (s, 9H).
Reaction SMILES: [C:1]([CH2:6][CH:7]1[CH:11]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][C:8]1=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:21]([OH:24])[CH2:22]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([CH2:6][CH:7]1[O:24][CH:21]2[CH2:22][CH2:8][CH2:9][CH:10]2[CH:11]1/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: OCCO
Reactant: CCCCCCC=CC1CCC(=O)C1CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21

Procedure:
A mixture of 10.142 g. (0.0362 mole) of 2-(carbethoxymethyl)-3-(1-octenyl)cyclopentanone (ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate, Example 213), 3.49 g. (0.0562 mole) of ethylene glycol, 0.344 g. of p-toluenesulfonic acid monohydrate, and 30 ml. of benzene is refluxed for 4.5 hours with azeotropic removal of water. The mixture is cooled, placed onto a column of 130 g. of Florisil in benzene and the ketal is eluted off with benzene. The filtrate is evaporated to yield 9.53 g. of a colorless oil.