Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)#[N:2].C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:32]([O:31][C:29]([C:19]1[N:18]([CH3:20])[N:17]=[C:16]([C:21]#[N:22])[C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: Cn1cc(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)nn1C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Prepare a solution of 4-(2′-cyano-biphenyl-4-yl)-1-methyl-1H-pyrazole-3-carbonitrile (101 mg, 0.355 mmol, prepared in preparation 46) in 3 mL of anhydrous THF and cool to −70° C. Add n-butyl lithium (1.6M in hexanes, 0.2 mL, 0.32 mmol) dropwise, keeping the internal temperature less than −65° C. Stir the orange solution for 30 minutes at −70° C. Next, add ethyl chloroformate (0.1 mL, 1.02 mmol) and allow the reaction to warm to room temperature over one hour. Quench with 2 mL of saturated NH4Cl and dilute with 50 mL of EtOAc. Wash the organic layer with water (1×10 mL) and brine (1×10 mL) and dry over anhydrous Na2SO4. Filter, evaporate and chromatograph over silica gel (100/0-7/3 toluene/EtOAc) to give the title compound, 37 mg (29%) along with 38 mg of recovered starting material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1>C(O)C.C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccncc2)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
1,1-Dimethylethyl 4-(4-pyridinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 1) (11.4 g) was dissolved in ethanol (200 ml) and acetic acid (2.36 ml). Platinum oxide (2 g) was added under a blanket of argon, and the reaction shaken under hydrogen at 50 psi for 18 h. After carefully filtering off the platinum catalyst, the solvent was evaporated and the residue redissolved in ethyl acetate (50 ml) and washed with saturated sodium hydrogen carbonate solution (50 ml). The aqueous phase was extracted into ethyl acetate (2×50 ml) and the combined organics dried (Na2SO4) and evaporated to give the title compound (D2) as white solid (9.4 g).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19]>[B-](F)(F)(F)F.[Ag+].O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 100 ml. of acetone and 65 ml. of water is added 8.0 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride and extracted with half saturated sodium bicarbonate solution. The basic extract is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil with the properties described in Example 27.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26](SC)=[N:27][CH:28]=2)=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:26]2[NH:25][C:24](=[O:31])[C:23]([CH2:22][C:19]3[CH:20]=[N:21][C:16]([CH3:15])=[CH:17][CH:18]=3)=[CH:28][N:27]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (1.30 g), 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.41 g) and pyridine (10 ml) was heated under reflux for 46 hours and evaporated to dryness. The residue was washed with hot water to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone as an oil and this oil was treated with excess of hydrogen chloride in ethanol and evaporated to dryness. The residue was recrystallised from aqueous ethanol containing HCl to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 210°-213°. A sample recrystallised a further time from aqueous ethanol containing HCl had m.p. 224°-227°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20]Cl)[CH3:17]>>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][N:9]=[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])[CH3:17]
Reactant: N=S(=O)(c1ccccc1)c1cccnc1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCN=S(=O)(c1ccccc1)c1cccnc1
Yield: 46 %

Procedure:
In a manner analogous to that described in Example 1, Stage 3, from S-phenyl-S-(3-pyridyl)-sulphoximide and 2-diethylaminoethyl chloride, there is obtained, in a yield of 46% of theory, N-(2-diethylaminoethyl)-S-phenyl-S-(3-pyridyl)-sulphoximide. The corresponding dibenzoyltartrate, after recrystallisation from isoporopanol, melts at 130° C.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12][CH2:13][CH3:14])[N:8]=[C:7]([C:15]([O:17]C)=[O:16])[C:6]=1[Cl:19].O.Cl>C(O)C>[NH2:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12][CH2:13][CH3:14])[N:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]=1[Cl:19]
Reactant: CCOc1nc(C(=O)OC)c(Cl)c(N)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(C(=O)O)c(Cl)c(N)c1Cl
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Lithium hydroxide monohydrate (0.027 g) was added to a room temperature solution of the compound prepared in Example 2 (0.172 g) in ethanol (0.5 mL)-water (0.3 mL). The mixture was stirred for two hours and then brought to pH 3 via the addition of 1 N hydrochloric acid. The precipitated solids were collected by filtration to obtain the title compound (0.110 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:13][CH2:12]2)=[C:7]2[C:3]=1[C:4](=[O:37])[N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:6]2=[O:25].C([O-])(=O)C.[Na+].[CH3:43][S:44]([CH:47]=[CH2:48])(=[O:46])=[O:45]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC(N(C)C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:5]1[C:4](=[O:37])[C:3]2[C:7](=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:2]=2[CH:48]=[CH:47][S:44]([CH3:43])(=[O:46])=[O:45])[C:6]1=[O:25]
Reactant: C=CS(C)(=O)=O
Reactant: COc1ccc(CN2C(=O)c3c(Cl)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)c3c(C=CS(C)(=O)=O)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 150 °C
Yield: 19.4 %

Procedure:
A 10 mL sealed tube was charged with Compound 10 (100.0 mg, 0.19 mmol), sodium acetate (22.0 mg, 0.27 mmol), bis(tri-t-butylphosphine)palladium (0) (13.0 mg, 0.03 mmol), methyl vinylsulfone (0.02 ml, 0.23 mmol), and dimethylacetamide (1.0 mL). The tube was charge with argon and sealed. The mixture was heated at 150° C. for 24 h. The mixture was cooled to room temperature and purified via flash chromatography (230-400 mesh silica gel 60, gradient 90:10-50:50 hexanes:ethyl acetate) to give 21.7 mg (19%) of Compound 62 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=15.6, 1 H), 7.48-7.53 (m, 5 H), 7.01-7.08 (m, 3 H), 6.70-6.90 (m, 3 H), 4.64 (s, 2 H), 4.42 (q, J=6.9 Hz, 1 H), 3.94 (s, 3 H), 3.86 (s, 3 H), 3.33-3.80 (m, 8 H), 3.07 (s, 3 H), and 1.86 (d, J=6.7 Hz, 3 H); MS (ES+) 590 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.CC1C([O:42]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:42])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 80 %

Procedure:
The experiment described in example 2 was repeated using 46.8 g of 5-methoxy-2-[[(4-methoxy-3,5 dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 39.2 g of crystallized Omeprazole are isolated after crystallization and drying (yield 80%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)=[O:26]
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 3 h

Procedure:
Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20ClN3O); MS (ESI): 282 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[C:9]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:20][C:19]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][N:7]=1)=O)[CH3:2]>C1COCC1>[CH2:34]([O:33][C:19]1[CH:20]=[C:21]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:22]([Cl:24])=[CH:23][C:18]=1[C:9]1[O:8][N:7]=[C:6]([CH2:4][NH:3][CH2:1][CH3:2])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCNCc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(Cl)c1
Yield: 68.5 %

Procedure:
To a solution of 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (36 mg, 0.06 mmol) in anhydrous THF under argon was added 1M Borane-THF complex (1 ml) and the solution refluxed overnight. After cooling the solution was poured on to a Isolute® SPE Flash SCX-2 5 g column which was quickly eluted with methanol (2×20 ml). The desired product was then recovered by eluting with a mixture of 10% ammonia in methanol (2×10 ml) which was evaporated in vaccuo to provide 23 mg (65% yield) of a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](F)(F)[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[OH2:64]>CC#N.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](=[O:64])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
(1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg) is dissolve in MeCN (1 mL) and water (1 mL). 1 drop of TFA was added. The mixture was treated with long wavelengh UV light at room temprature for 2 hours. The reaction crude was concentrated down and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL) (3.7 mg).
Reaction SMILES: [CH3:1][C:2]1([C:5](=[O:7])[CH3:6])[CH2:4][CH2:3]1.Br[Mg][C:10]#[CH:11]>O1CCCC1>[CH3:1][C:2]1([C:5]([OH:7])([C:10]#[CH:11])[CH3:6])[CH2:4][CH2:3]1
Reactant: C#C[Mg]Br
Reactant: CC(=O)C1(C)CC1
Solvent: C1CCOC1
Product: C#CC(C)(O)C1(C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. In a 100-mL 3-necked round-bottom flask, a solution of 1-(1-methylcyclopropyl)ethan-1-one (2 g, 20.38 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added into a solution of bromo(ethynyl)magnesium (0.5 M in THF, 53 mL, 1.30 equiv) in tetrahydrofuran (5 mL). The resulting solution was stirred for 8 h at 0° C. in an ice/salt bath. The reaction was then quenched by the addition of 50 mL of sat. aq. NH4Cl. The resulting solution was extracted with 3×150 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 120 mg (5%) of 2-(1-methylcyclopropyl)but-3-yn-2-ol as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][C@H:16]([CH3:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][C@H:16]([OH:15])[CH3:30])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=[N:2]1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:7]([C:6]([C:5]1[O:1][N:2]=[CH:3][CH:4]=1)=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CCc1ccno1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccno2)CC1
Yield: 54.5 %

Procedure:
A mixture of isoxazol-5-ylacetonitrile from Example 48A (3.00 g, 27.8 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (5.53 g, 27.8 mmol) and ammonium acetate (4.28 g, 55.5 mmol) in toluene (50 mL) was heated for 8 h to reflux. Subsequently, the mixture was extracted with water, dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to yield an oil, which precipitated upon treatment with petroleum ether/tert-butyl methyl ether to yield 4.38 g (54.6%) of the title compound as yellowish crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)CCC.O1CCOCC1>CO.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>[O:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[N:39][CH:38]=[CH:37][N:36]=3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4cnccn4)ccnc23)CC1)c1ccccc1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A mixture of compound of Example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl pyrazine (82 mg, 0.22 mmol), Pd(PPh3)4 (88 mg, 0.076 mmol) and dioxane (1 mL) in a sealed tube was heated at 140° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (2.6 mg, 0.0058 mmol, 9%) as a yellow oil.
Reaction SMILES: Cl.N[N:3]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[O:9])[C:4]1=[O:11].C(N(CC)CC)C.[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:35])[CH3:34])[C:26](Cl)=[O:27])(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:35])[CH3:34])[C:26]([N:3]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[O:9])[C:4]1=[O:11])=[O:27])(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: NC(=O)N1CCN(N)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)N2CCN(C(N)=O)C2=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 314.9 %

Procedure:
3-Amino-2-oxo-1-imidazolidinecarboxamide, monohydrochloride (12 g 0.006 mol) was suspended in 300 ml of dichloromethane. The suspension was cooled to 0° C. and 29.2 ml of triethylamine (0.198 mol) was added; the mixture was stirred for another 20 minutes. [3,4-Bis(acetyloxy)benzoyl]chloride (10.5 g) dissolved in 200 ml of dichloromethane was added dropwise with stirring at 0° C. and the mixture was stirred overnight at room temperature, filtered and treated with 50 ml of water. After stirring for 5 minutes, 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide crystallized out (7.2 g) contaminated with some triethylamine hydrochloride. The impurity was removed by treatment with water to yield 6.6 g of 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide, melting point 222°-224° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(I)c1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(-c2ccc(Cl)cc2)c1
Yield: 75.9 %

Procedure:
A solution of 13 g of the product from Example 7 in 105 ml of dimethoxyethane was admixed with 9.9 g of 4-chlorophenylboronic acid, 6.7 g of sodium carbonate, 34 ml of water and 200 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 3 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 9.5 g of product as colorless crystals of m.p. 118-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH3:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[C:16]([Cl:22])[N:15]=1>C1COCC1>[Cl:22][C:16]1[C:17]([CH3:21])=[C:18]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:19]=[C:14]([CH3:13])[N:15]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 2,4,6-trimethylphenol (2.720 g, 20 mmol) in 60 ml of dry THF was treated with NaH (60% in oil, 1.200 g, 30 mmol) at room temperature. After stirring at room temperature for 15 minutes, 2,5-dimethyl-4,6-dichloropyrimidine (3.34 g, 20 mmol) was added and the resulting mixture was heated at reflux for 15 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 5.4528 g of beige solid. The solid was recrystallized from isopropanol to give 5.1345 g of pale yellow solid, mp 86–87° C.; high MS (C15H17CIN20) calc. 276.1025, found 276.10359. 1H NMR (CDCl3) δ 6.87 (s, 2H), 2.37 (s, 6H), 2.28 (s, 3H), 2.01 (s, 6H) ppm.