Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.C(=[N:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)C1C=CC=CC=1>ClCCl>[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:35][CH2:34]1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: NCC1CCN(C(=O)c2cccnc2Cl)CC1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of 2-chloropyridine-3-carboxylic acid (4.09 g) and 1-methylmorpholine (2.7 ml) in dichloromethane (100 ml) was stirred at -5° C. under nitrogen and ethyl chloroformate (2.4 ml) was added dropwise. After 10 minutes a solution of N-benzylidene-1-(4-piperidyl)methylamine (5.0 g) in dichloromethane (25 ml) was added and stirring continued at -5° C. for 2 hours then at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue stirred with potassium hydrogen sulphate solution (1 M; 250 ml) for 5 hours. The mixture was filtered and the filtrate washed with dichloromethane (2×150 ml), basified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (3×150 ml). The combined extracts were dried over magnesium sulphate and the solvent was evaporated to give 4-(aminomethyl)-1-(2-chloro-3-pyridylcarbonyl)-piperidine (4.81 g) contaminated with some 1-methylmorpholine. This material was used in the next reaction without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2n1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [898746-35-5] (500 mg, 3.08 mmol) in MeOH was added a 2M solution of trimethylsilyldiazomethane in Et2O at 0° C., and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to give the title compound. MS (LC/MS): 177 [M+H]+, 375 [2M+H]+; tR (HPLC conditions k): 2.71
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CC(C(F)(F)F)CC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=CC=1)#N.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[S:69][CH:70]=[CH:71][CH:72]=3)[CH2:63][C:62]=2[OH:73])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]>>[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:62](=[O:73])[CH2:63][CH:64]([C:68]3[S:69][CH:70]=[CH:71][CH:72]=3)[CH2:65][C:66]=2[O:67][CH2:1][CH3:3])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3cccs3)CC2=O)cc1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cccs2)C1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-ethoxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 13), using 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(thiophen-2-yl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 20, 444 mg, 0.87 mmol) as starting material. Yield: 507 mg; ESI mass spectrum [N+H]+=540, Retention time HPLC: 1.29 min (V011_S01).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]2[CH:40]=[CH:39][N:38](C3CCCCO3)[N:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]2[NH:37][N:38]=[CH:39][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCC[C@H]3c3ccn(C4CCCCO4)n3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@@H]2CCC[C@H]2c2ccn[nH]2)cc1F
Yield: 98.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide (287 mg, 0.427 mmol) prepared in Example 151a, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (185 mg, 99%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)C.[C:21]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][C:24]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(CCCCO)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(4-Hydroxy-butyl)-phenyl]-2-methoxy-propionic acid ethyl ester and 4-phenylphenol following the Standard Procedure of coupling-hydrolysis A. 1H-NMR (CDCl3, 200.15 MHz): δ 7.55–7.23 (m, 7H); 7.14 (d, 4H, J=1.1); 6.93 (d, 2H, J=8.4); 4.02–3.96 (m, 3H); 3.37 (s, 3H); 3.11 (dd, 1H, J=14.3, 4.4); 2.97 (dd, 1H, J=14.3, 7.3); 2.66 (t, 2H, J=7.0); 1.83–1.80 (m, 4H). MS (ES) for C26H28O4 [M+NH4]+: 422.2, [M+Na]+: 427.2.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][NH:40][CH2:41]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH:38]2[CH2:44][CH2:43][CH:42]1[CH2:41][N:40]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:22])[CH2:39]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (400 mg, 1.01 mmol) was combined with 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol. 1.1 eq) which yielded 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester after work up and was immediately used in next step without further purification.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].O.[OH-].[Na+].[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CC(C)=O>[CH:14]([NH:17][C:18](=[O:19])[NH:10][C:8](=[NH:9])[O:7][CH3:6])([CH3:16])[CH3:15]
Reactant: CC(C)N=C=O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=N)NC(=O)NC(C)C
Reaction time: 3 h

Procedure:
To 114 parts of 2-methylpseudourea sulfate in 400 parts of water at 0°C is added 106 parts of 50% sodium hydroxide, followed by 400 parts of acetone, and 51 parts of isopropyl isocyanate. The reaction mixture is allowed to come to room temperature in 3 hrs. The organic solvent is then evaporated under vacuum, the aqueous residue saturated with sodium chloride, and the mixture extracted with methylene chloride. The organic extract is dried and the methylene chloride evaporated to yield 78 parts of methyl 4-isopropylallophanimidate, m.p. 64°-67°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21]([CH3:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:20]2[C:21]([CH3:22])=[C:16]([Cl:15])[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A mixture of 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (1.5352 g, 7.06 mmol) and 4,6-dichloro-5-methyl-pyrimidine (11.1512 g, 7.06 mmol) in 15 mL of THF with sodium t-butoxide (1M in THF, 8.3 mL, 8.3 mmol) added dropwise. After 5 min, mixture was concentrated and residue was extracted with CH2Cl2 and H2O. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish solid (2.3469 g, 97%). Exact mass calculated for C15H22ClN3O2S 343.11, found 344.1 (MH+).
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:4]1[CH2:5][CH2:6][CH2:7][S:1][CH2:2][CH2:3]1
Reactant: O=C1CCCSCC1
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCCSCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a flask under argon in an ice-bath, the 4-thiepanone (200 mg, 1.536 mmol) in 6 mL of dried CH2Cl2 was first dried w/4 A sieves and then transferred via a double needle tubing (cannula). TMS-OTf (278 uL, 1.536 mmol) was added dropwise and the reaction was stirred for 10 min. A solution of methyl 5-bromo-1H-indole-7-carboxylate (390 mg, 1.536 mmol) in 7 mL of CH2Cl2 was dried with 4 A sieves and then added into above solution dropwise. Stirring continued for 4 hours and the reaction was warmed to room temperature. The mixture was cooled to 0° C. and triethylsilane (245 uL, 1.536 mmol) was added as one portion. The mixture was stirred overnight then warmed to room temperature. The mixture was quenched water and sat. NaHCO3, then diluted water/AcOEt and washed with H2O and brine. 194 mg of crude product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(Br)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(O)ccc1Br
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CH2Cl2 at −78° C. was added BBr3(4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH2Cl2). After stirring for 3 hours at −78° C. the solution was warmed to 0° C. for 3 hours and then at 25° C. for 1 hour before being quenched with H2O. The mixture was diluted with Et2O and washed with H2O and saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (2.5-10% EtOAc-hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC[C@@H](O)CO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@@H](O)CO)c2n1
Yield: 46 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (R)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (46% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].N[C:14]1[CH:19]=CC=CN=1>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:19]=[CH:14][C:9]=1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: Nc1ccccn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1ccccn1)n1ccnc1
Yield: 133.2 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-aminopyridine (4.75 g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 72 h. The resulting solution was evaporated to a black oil and triturated with hexane. The remaining oily residue was placed under vacuum to provide 13.6 g of crude titled product as a black solid:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:7]=2[CH3:16])[CH2:3][CH2:2]1.C(O)(=O)C>[Fe].O>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:16])=[CH:8][C:9]([NH2:13])=[C:10]([CH3:12])[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC2CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 1.73 g of 1-cyclopropylmethoxy-2,5-dimethyl-4-nitrobenzene, 2.18 g of iron powder, 30 mL of acetic acid and 30 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.84 g of 4-cyclopropylmethoxy-2,5-dimethylphenylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1.[Br:23]N1C(=O)CCC1=O>CC(C)=O>[Br:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1
Reactant: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one is suspended in 30 mL acetone and 2 mg N-bromosuccinimide is added. The reaction mixture is stirred for 3 hours at room temperature, the precipitated product isolated by filtration and washed with acetone. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (0.05% HCOOH). Yield 11.2 mg. LC-MS (ES+) 368 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1ccc(CCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylphenethylamine hydrochloride (1 g) in dichloromethane (20 ml) was added triethylamine (0.94 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (1.29 g) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-(2-[4-acetylphenyl]ethyl)4-methylphenylsulphonamide, 1.58 g, as a yellow crystalline solid: m.p. 124°-126° C.; NMR(d6DMSO) δ 7.84(2H,d), 7.63(3H,m), 7.37(2H,d), 7.29(2H,d), 2.98(2H,q), 2.75(2H,t), 2.55(3H,s), 2.39(3H,s); m/e 318(M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OS(O)(=O)=O>CCOCC>[C:10]1([C:16]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:17])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (10 g, 53.5 mmol) and Mg turnings (1.32 g, 54.3 mg-atom) in 25 mL Et2O was added deoxybenzoin (9.81 g, 50 mmol) in 75 mL Et2O dropwise under reflux. After stirring at reflux 3 h, the mixture was carefully poured onto 1N H2SO4 and ice. The layers were allowed to separate and the aqueous layer was extracted with 25 mL Et2O. The ether layers were combined, washed with H2O (2×80 mL), dried (Na2SO4), and concentrated to give a yellow oil which solidified at room temperature (14.2 g, 93.3% crude yield). Recrystallization from 95% EtOH gave 1,2-diphenyl-1-(4-methoxyphenyl)ethanol as a white powder mp: 111°-112° C. (lit. 112°-113° C.); NMR δ 7.2 (m, 14H, ArH), 3.75 (s, 3H, OCH3), 3.63 (s, 2H, CH2), 2.35 (brs, 1H, OH). The tertiary carbinol (14 g, 46 mmol) and p-TsOH.H2O (1 g, 5.31 mmol) were dissolved in 40 mL dry C6H6, heated to reflux, and stirred 2 h. The red mixture was cooled to room temperature and washed with 5% NaHCO3 (2×75 mL). The combined aqueous layers were extracted with 25 mL C6H6. The organic layers were combined, washed with 100 mL H2O, dried (Na2SO4), and concentrated to give a yellow oil. The (E)- and (Z)-olefin mixture was purified on 60 g flash SiO2 (petroleum ether) and 1,2-Diphenyl-1-(4-methoxyphenyl)ethene was obtained as a clear oil (8 g, 61%); NMR δ 7.15 (m, 10H, ArH), 6.9 (s, 1H, C=CH), 6.8 (AA'BB', c, 4H, MeOC6H 4), 3.71 (d, 3H, (E)- & (Z)-OCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[C:10]([CH3:18])[C:11]=45)=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:42][CH:43]=1
Reactant: O=c1c(-c2ccc(O)c(F)c2)cncn1Cc1ccc(Cl)cc1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cncn(Cc6ccc(Cl)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 137.1 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (13.0 mg, 0.0454 mmol), prepared according to the procedure of Example 43, Step E, 3-(4-chlorobenzyl)-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one (10 mg, 0.0302 mmol) prepared according to the procedure of Example 43, Step D and dissolved in DMF (0.5 mL). A 1M solution of potassium t-butoxide in THF (0.0454 mL, 0.0454 mmol) and potassium carbonate (6.27 mg, 0.0454 mmol) were both added and the resulting mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and the crude mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The organic layer washed with brine, dried over sodium sulfate and evaporated to afford 24.1 mg of brown oil. The crude product was purified by silica gel chromatography (Biotage 12M), loading with chloroform and eluting with 1.5% MeOH in CHCl3 to afford the desired product as an off-white solid (5 mg, 28%). LRMS (APCI pos) m/e 583.2 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2].[OH-].[Na+]>[Cl-].[Na+]>[C:1]([O:4][C@:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C#N)C1CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@@](C)(C#N)C1CC1
Temperature: 10 °C
Reaction time: 118 h
Yield: 15 %

Procedure:
(Warning: Highly toxic hydrogen cyanide is formed in the experiment; use adequate protection). 119.8 g (782 mmol) racemic α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile was emulsified in 7.0 L 0.1 M sodium chloride/3.8 mM sodium phosphate buffer pH 7.0 by stirring. The emulsion was cooled to 10° C. and the hydrolytic reaction started by adding 8.0 g of triacylglycerol lipase from wheat germ (Sigma L-3001) and the pH maintained at 7.0 by the controlled addition of 1.0 N sodium hydroxide solution under vigorous stirring at 10° C. After a consumption of 605.8 mL solution (corresponding to 78% conversion), after 118 h, the reaction was stopped by adding 6 L dichloromethane under vigorous stirring. The emulsion was allowed to stand overnight for phase separation. The organic phase was removed (the turbid part was filtered through silicon-treated Phase Separator (1PS; Whatman) and the filtrate stirred with ca. 1 L of Speedex filter aid). The aqueous phase was extracted again with 2×6 L dichloromethane. The combined organic phases were concentrated in vacuo down to a volume of ca. 40 mL and distilled (final temp. 68-69° C./4 mbar) to give 17.88 g (117 mmol; 15%) of (R)-α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile as a colorless oil. Analysis: purity >99% GC; 98.0% ee (column: BGB-176; 30 m×0.25 mm; 100-140° C. with 2° C./min; H2; 90 kPa; Inj. 200° C.; Det. 210° C.); αD20: +32.92° (c=1.00; EtOH).