Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:39][C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][CH:9]=4)=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)=[CH:42][CH:41]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)cc1
Temperature: 95 °C
Yield: 90.7 %

Procedure:
A mixture of Compound 5 (4.5 g, 9.0 mmol), 1-bromo-4-iodobenzene (5.12 g, 18 mmol), Pd(PPh3)4 (0.52 g, 0.45 mmol) and potassium carbonate (4.436 g, 32 mmol) in dioxane/water (150 ml/30 ml) was degassed and heated at 95° C. overnight. After being cooled to RT, the mixture was poured into dichloromethane (300 ml), washed with brine, dried over Na2SO4, then loaded on silica gel, purified by flash column (hexanes to hexanes/ethyl acetate 20:1) to give a light yellow solid (4.30 g, in 90.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1I>>[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(I)c(Cl)c1
Product: CS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 144 step (i) using the product from example 16 step (ii) and the product from example 145 step (ii). Yield 1.08 g.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](=[O:38])(=[O:37])[NH2:36])[CH:30]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]4[O:15][N:39]=[C:28]([C:29]5[CH:30]=[C:31]([S:35]([NH2:36])(=[O:37])=[O:38])[CH:32]=[CH:33][CH:34]=5)[N:27]=4)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) (174 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/MeOH/hexane) as an off-white solid (142 mg, 54%). MS (EI) 526.1 [(M)+]; mp 277° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:27])([F:26])[C:13]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([OH:18])[C:14]([F:17])([F:16])[F:15].O>N1C=CC=CC=1>[F:11][C:12]([F:26])([F:27])[C:13]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:21][CH:20]=1)([OH:18])[C:14]([F:15])([F:17])[F:16]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Temperature: 100 °C

Procedure:
Add 4.22 g (24 mmole) of benzenesulfonyl chloride dropwise to 5.18 g (20 mmole) of 4-(hexafluoro-2-hydroxy-2-propyl)aniline in 25 ml of pyridine and heat to 100° C. for 8 hours. Pour the reaction into H2O and extract with Et2O. Wash with 1N HCl and extract with 1H NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O and hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)-benzenesulfonanilide; m.p. 117°-118° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:21][C:22]([F:26])([F:25])[CH2:23]I.O>CN(C)C=O>[F:21][C:22]([F:26])([F:25])[CH2:23][N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:18]
Reactant: FC(F)(F)CI
Reactant: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 5.13 g of 4-phenyl-6-chloro-2(1H)-quinazolinone in 60 ml of dimethylformamide was added 0.85 g 62% sodium hydride, and the resulting mixture was stirred at 100° C. for 30 minutes. Thereafter, 10.0 g of 2,2,2-trifluoroethyl iodide was added and the mixture was stirred at 140° C. for 8 hours. After cooling, the reaction mixture was poured into 300 ml of water and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was absorbed on a silica gel column, eluted with chloroform to obtain 3.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone which was recrystallized from ethanol to give pale yellow leaflets melting at 185.0°-186.0° C., and 2.0 g of 2-(2,2,2-trifluoroethoxy)-4-phenyl-6-chloroquinazoline which was recrystallized from ethanol to give pale yellow needles melting at 113.0°-114.0° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:32].[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:30])([CH3:31])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[C:6]([F:32])[CH:7]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-acetic acid methyl ester (Intermediate 83, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with a 2 M solution of lithium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-8% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.041 g, 35%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2c(Nc3ccccc3)cn(-c3ccccn3)c2C1
Yield: 43.4 %

Procedure:
A suspension of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (50 mg, 0.16mmol), aniline (17 μL, 0.19 mmol), sodium tert-butoxide (18 mg, 0.19 mmol) tris(dibenzylideneacetone)dipalladium (7.2 mg, 0.008mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1-binaphthyl (9.8 mg, 0.016 mmol) in toluene (3 mL) was heated at reflux for 3 h. The toluene was evaporated and the residue chromatographed on silica gel, eluting with isohexane: EtOAc (9:1→4:1). The title compound (23 mg, 43%) was isolated as a yellow solid. mp 135-138° C. Found: C, 73.98; H, 6.10; N, 12.33%. C21H21N3O0.0.45(H2O): C,74.29; H, 6.50; N, 12.38%. 1H NMR (360 MHz, d6-DMSO) δ 1.07 (6H,s), 2.37 (2H,s), 3.03 (2H,s), 6.81 (1H,t, J=7.4 Hz), 7.08 (2H,d, J=7.7 Hz), 7.25-7.29 (2H,m), 7.41 (1H,dd, J=7.2 and and 4.9Hz), 7.72 (1H,d, J=8.1 Hz), 8.01 (1H,d of t, J=7.6 and 1.8 Hz), 8.16 (1H,s), 8.57-8.60 (1H,m). MS (ES+) 332 (M+1).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.34 g, 4.27 mmol), trifluoroacetic anhydride (15 mL) and dichloromethane (20 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (20 mL) and ethanol (20 mL) were added to the residue and the mixture was stirred at room temperature for 1 hr. 8N Aqueous sodium hydroxide solution (4 mL) was further added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.10 g, 68%) as a white solid. To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.10 g, 2.92 mmol) thus-obtained and triethylamine (1.21 mL, 8.76 mmol) in tetrahydrofuran (15 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (345 μL, 3.80 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=70/30→40/100) and recrystallized from ethyl acetate-hexane to give the title compound (863 mg, 60%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1([O:7][CH3:8])[CH2:5][NH:4][C:3]1=[O:6].[C:9]1([CH2:15][C:16](O)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[C:9]1([CH2:15][C:16]([NH:1][C:2]2([O:7][CH3:8])[CH2:5][NH:4][C:3]2=[O:6])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC1(N)CNC1=O
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC1(NC(=O)Cc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 61 mg of 3-amino-3-methoxy-2-oxoazetidine in 2 ml of THF are added 72 mg of phenylacetic acid, 71.3 mg of 1-hydroxybenzotriazole and 130 mg of dicyclohexylcarbodiimide, and the mixture is stirred at room temperature for 3 hours. The dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is chromatographed on a column of silica gel [eluted with n-hexane-ethyl acetate (1:2)] to obtain 86 mg of 3-phenylacetamido-3-methoxy-2-oxoazetidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](O)(=[O:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=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>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), terephthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid (21.5 mg, 37.6%). HRMS (ES+) m/z Calcd for C30H26Cl2F2N2O3+H [(M+H): 571.1362; Found: 571.1363.
Reaction SMILES: [NH2:1][CH:2]([PH:10](=[O:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCOCC1.O>[C:4]1([CH2:3][CH:2]([PH:10](=[O:11])[OH:12])[NH:1][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Temperature: 20 °C
Yield: 83.7 %

Procedure:
To a solution of 7 g (37.8 mmol) of (1-amino-2-phenylethyl)phosphinic acid in 86 ml of a mixture of dioxane and water, in the presence of one equivalent of sodium hydroxide (1.51 g), are added dropwise, at 0° C and simultaneously, a solution of 7.55 g (44.26 mmol) of benzyl chloroformate in 21 ml of dioxane and, in order to keep the pH of the reaction at about 9, a solution of 2.42 g of sodium hydroxide in 21 ml of water. At the end of the addition, the mixture is maintained at a temperature in the region of 20° C. for 2 hours. The aqueous phase is then washed with 3 times 20 ml of diethyl ether. The aqueous phase is acidified, at 0° C., with vigorous stirring, using 27 ml of 6N hydrochloric acid solution. The abundant white precipitate formed is filtered off, washed with water and dried. 12.08 g of product are recovered (yield=83.7%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:31])([CH3:30])[CH2:27][NH:28][CH3:29])[CH2:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].CC1C=CC(S([O-])(=O)=O)=CC=1>ClCCl.C(N(CC)CC)C>[CH3:29][N:28]([CH2:27][C:26]([CH3:31])([CH:23]1[CH2:24][CH2:25][N:20]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH3:30])[C:5](=[O:7])[CH3:6]
Reactant: CCCCCCCCCCCCN1CCC(C(C)(C)CNC)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCN1CCC(C(C)(C)CN(C)C(C)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.2 %

Procedure:
3.4 ml (3.6×10-2 mole) of acetic anhydride was added to a solution of 8 g (2.4×10-2 mole) of 1-dodecyl-N,β,β-trimethyl-4-piperidineethanamine in 100 ml of dichloromethane and 16.8 ml of N,N-diethylethanamine. The reaction mixture was stirred for 12 hours at room temperature. The solution was poured into a 1N sodium hydroxide solution and extracted with trichloromethane. The organic phase was washed with water, dried and filtered and the solvents were evaporated off under reduced pressure. 8.7 g of N-methyl-N-[2-methyl-2-[(1-dodecyl)-4-piperidinyl]propyl]acetamide (yield: 97%) was obtained, from which the 4-methylbenzene sulphonate was prepared and recrystallised from ethyl acetate. M Pt=102°-103° C.
Reaction SMILES: [Br-:1].[K+].C1OCCOCCOCCOCCOCCOC1.ClC1C=C(C=CC=1)C(OO)=O.[CH:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])([CH3:34])[CH3:33]>C(Cl)Cl>[Br:1][C:39]1[CH:38]=[CH:37][C:36]([O:41][CH3:42])=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:40]=1
Reactant: COc1ccccc1C(C)C
Reactant: [Br-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a suspension of potassium bromide (18.8 g, 157.7 mmol) in 400 mL of methylene chloride at 0° C. were added 18-Crown-6 (2.08 g, 7.88 mmol), 3-chloroperoxy benzoic acid (27.2 g, 157.7 mmol) and 2-isopropylanisole (12.0 g, 78.8 mmol). After stirring for 3 hours at 0° C., the reaction mixture was poured into ice water (500 mL), and stirred for 30 minutes. The organic layer was separated, washed with saturated NaHCO3 solution (400 mL), followed by water (300 mL), and dried (MgSO4). The solvent was evaporated to give an oil, which was purified by flash column chromatography (silica gel, 98:2 hexane/ethylacetate) to give 13 g (56.7 mmol, 72%) of 4-bromo-2-isopropylanisole (3) as an oil; 1HNMR (CDCl3) δ 1.2 (d, 6H), 3.3 (heptet, 1H), 6.7 (d, 1H), 6.84 (d, 1H), 7.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2](=[CH2:18])[CH2:3][C:4]1([CH3:17])[CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([OH:13])[CH:10]=2)[C:5]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28]>CN(C=O)C>[O:16]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH2:26][C:27]([OH:29])=[O:28])=[C:8]([Cl:14])[C:7]=2[Cl:15])[CH2:12][C:4]1([CH2:3][C:2]([Cl:1])=[CH2:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: C=C(Cl)CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
[1-Oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid is prepared following substantially the same procedure described in Example 4, Step D, using the following reagents: 2-(2-chloroallyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.8 g., 0.0157 mole), potassium carbonate (6.0 g.), ethyl bromoacetate (4.5 ml.) and DMF (55 ml.). The above procedure gives 2.7 g. (48%) of [1-oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which after recrystallization from butyl chloride melts at 160°-162° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.CO>[CH3:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:14][CH:13]=1)[OH:17]
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While cooling well, a solution of 2.5 g of sodium borohydride in 10 ml of water is added dropwise to a solution of 20.2 g of para-cyclohexyl-acetophenone in 250 ml of methanol. The mixture is stirred at room temperature for 1 hour and the pH then adjusted to 2 with semi-concentrated hydrochloric acid. The batch is evaporated completely and the residue extracted several times with ether. The solution is dried and the ether evaporated to obtain methyl-(para-cyclohexylphenyl)-carbinol in the form of colorless crystals melting at 81°-83°C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:18])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CC(C)=O.O>[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH2:27][CH:26]=[CH2:25])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1coc2c(C(=O)c3cccs3)ccc(O)c12
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12

Procedure:
To a solution of compound 3 (0.50 g, 1.92 mmol) in acetone (10 mL) was added sequentially potassium carbonate (0.53 g, 3.84 mmol) and allyl bromide (0.47 g, 3.84 mmol). The mixture was heated to reflux for two hours, cooled, diluted with water (50 mL), and acidified with 2N HCl. The aqueous mixture was extracted with methylene chloride (3×25 mL) and the combined extracts dried (Na2SO4) and concentrated to an oil. The crude 3-methyl-4-allyloxy-7-(2-thienoyl)benzofuran thus obtained was sufficiently pure for further synthesis. 1H NMR d 2.44 (3H, d, J=2 Hz), 4.74 (2H, d, J=4 Hz), 5.44 (2H, m), 6.12 (1H, m), 6.71 (1H, d, J=8 Hz), 7.15 (1H, m), 7.36 (1H, d, J=2 Hz), 7.68 (3H, m).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][OH:19])=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[O:23]>>[OH:19][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:24][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])=[CH:3][CH:4]=2)[N:9]=[C:8]([CH3:12])[CH:7]=1
Reactant: Cc1cc(N2CCC[C@H]2CO)c2ccc(I)cc2n1
Reactant: CC(C)(C)C(N)=O
Product: Cc1cc(N2CCC[C@H]2CO)c2ccc(NC(=O)C(C)(C)C)cc2n1

Procedure:
In analogy to example 47, on reaction of (S)-[1-(7-iodo-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol with trimethylacetamide there was obtained (S)-N-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yl]-2,2-dimethyl-propionamide as amorphous white yellow solid. ISP mass spectrum, m/e: 342.3 (M+1 calculated for C20H27N3O2: 342).