Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[OH:8]
Reactant: Oc1ccccc1Br
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(Br)c1O
Reaction time: 1 h
Yield: 34.1 %

Procedure:
51.9 g (0.3 mol) of 2-bromophenol and 300 ml of acetic acid were fed into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer. Thereto was dropwise added 29.7 g (0.33 mol) of 70% nitric acid at a temperature of 15° C. or below, with ice-cooling. The reaction mixture was stirred at a temperature of 10° C. or below for 1 hour and poured into 600 ml of water. The mixture was subjected to extraction with 400 ml of ether. The ether layer was washed with 150 ml of water. The ether layer was subjected to distillation. The residue was transferred into a 1-liter flask provided with a stirrer and a distillation apparatus. Azeotropic distillation was conducted while water was added gradually. The amount of water required for azeotropic distillation was 2,100 ml. The distillate obtained was subjected to extraction two times using 500 ml of ether. The ether layer was dried over anhydrous sodium sulfate and subjected to distillation to remove ether. The resulting crude product was mixed with 10 ml of ethanol. The mixture was heated and then allowed to cool. The formed crystals were collected by filtration and then dried to obtain 22.3 g of 2-bromo-6-nitrophenol (yield: 34.1%, purity: 99.6%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>CS(C)=O.C1COCC1>[C:19]([O:18][C:17]([N:16]1[CH2:24][CH2:25][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)([C:11]#[N:12])[CH2:14][CH2:15]1)=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#CCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2)CC1
Temperature: 0 °C

Procedure:
A suspension of 15.8 g of sodium hydride of a concentration of 60% in oil in 400 ml of DMSO is admixed dropwise at AT under an inert atmosphere with a solution of 30 g of 3-chlorophenylacetonitrile in 200 ml of THF and then with a solution of 45.5 g of tert-butyl bis(2-chloroethyl)carbamate in 200 ml of DMSO and is heated at 60° C. overnight. The reaction mixture is poured into an ice/water mixture and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. This gives 33 g of the expected product.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].[OH-].[Li+]>O1CCCC1.O>[N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([OH:20])=[O:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
Benzyl (1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.4 g) was dissolved in tetrahydrofuran (160 ml) and water (20 ml), and lithium hydroxide (366 mg) was added under ice cooling. After 10 minutes, the mixture was heated to room temperature to continue stirring. After 20 hours, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:10) to obtain the title compound (1.86 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.Cl[Sn]Cl>CCO>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 0.73 h
Yield: 76.2 %

Procedure:
A mixture of [(4-nitro-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (940 mg, 2.57 mmol) and SnCl2.2H2O (2.9 g, 12.9 mmol) in EtOH (˜10 mL) was stirred at 70° C. for 44 min and then concentrated at ambient temperature. The residue was taken up in CH2Cl2 and washed with half saturated aq NaHCO3 (40 mL), H2O (40 mL) and brine (40 mL). The aqueous washes were reextracted once with CH2Cl2, and the combined extracts were dried over K2CO3 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH afforded 657 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][S:14][CH2:15][C:16](OCC)=[O:17].C(OCl)(C)(C)C.Cl>C(Cl)Cl.CCOCC.C(N(CC)CC)C>[CH3:13][S:14][CH:15]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:16]1=[O:17]
Reactant: CCOC(=O)CSC
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Temperature: -50 °C
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 4-amino-benzoate (40.0 g) in DCM (900 ml) at −60° C. there is added, dropwise, ethyl (methylsulphanyl)acetate (34.5 ml) under a nitrogen atmosphere. 29.0 g of tBuOCl are then added, dropwise, to the reaction mixture over 25 minutes, maintaining the temperature between −60° C. and −55° C. After stirring for one hour at −50° C., triethylamine (15.4 ml) is added dropwise. The reaction mixture is brought to 0° C. and then aqueous 3M HCl solution (485 ml) is added dropwise. After stirring for 12 hours at ambient temperature, the phases are separated and the organic phase is washed successively with aq. 2M HCl solution, water and then sat. aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is taken up in ether. The crystals obtained are filtered off, washed with ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1>>[CH3:19][C:20]1[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[C:22]([CH2:31][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:21]=1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 59.6 %

Procedure:
Compound 49 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.O1CCCC1.B>C1COCC1>[OH:29][C@@H:24]1[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-1-tetralone (2.9 g) and (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (2.3 g) in THF (5 ml) was added borane tetrahydrofuran complex (7.1 ml, 1M solution in THF) at −18° C. After being stirred for 30 minutes, the reaction was quenched with 1N HCl solution. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:48]4[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][N:47]=4)[N:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[N:23][N:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:50][O:49][C:45]1[CH:44]=[C:43]2[C:48]([C:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]([NH:31][C:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:21]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[N:22][N:23]=4)=[CH:33][CH:34]=3)=[CH:40][CH:41]=[N:42]2)=[N:47][CH:46]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5nccn5C)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
In a nitrogen purged sealed tube was added 1,4-dioxane (1.35 mL), and the solution was purged with nitrogen for 5 minutes, then sealed. 1-Methyl-2-(tributylstannyl)-1H-imidazole (0.311 g, 0.837 mmol), 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.120 g, 0.279 mmol) were added to the tube, which was then purged with nitrogen and sealed. To the tube was added 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.102 mg, 0.140 mmol), and the tube was purged with nitrogen, sealed, and heated to 100° C., while stirring the reaction for 17 hours. The reaction was cooled to RT, and concentrated. The concentrate was purified using reverse phase chromatography, the product fractions were concentrated, extracted into DCM, washed once with sodium carbonate and once with water, upon which the title compound precipiated. The solids were filtered, washed with water, air dried to yield N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine (0.039 g) as light yellow solid. MS [M+H]=476.0; Calc'd 475.5 for C27H21N7O2.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[CH3:30][C@@H:31]1[C@@H:35]([OH:36])[CH2:34][CH2:33][NH:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@H:35]([OH:36])[C@H:31]3[CH3:30])[CH2:26][CH2:27]2)=[O:21])[CH2:3][CH2:2]1
Reactant: C[C@H]1NCC[C@@H]1O
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@H](O)[C@H]2C)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (2R,3S)-2-methyl-pyrrolidin-3-ol hydrochloride (example 187A) in direct analogy to the general procedure used in example 129. MS: 477.2 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.CC(C)=O.[C:41]([OH:48])(=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45]>CCCCCC>[CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[C:41]([O-:48])(=[O:47])[CH2:42][CH2:43][C:44]([O-:46])=[O:45]
Reactant: O=C(O)CCC(=O)O
Agent: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
Ticagrelor (0.5 g) and acetone (10 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then succinic acid (0.12 g) was added to the above reaction mixture at 25-35° C. and stirred overnight. To the clear solution, n-hexane (50 mL) was added and stirred for about 90 minutes for solid separation. The solid was isolated by filtration, washed with n-hexane (5 mL) and dried to afford the title compound in about 81% yield having chiral HPLC purity of about 99%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (14.1 g, 100 mmol) and 3-aminophenol (11.2 g, 102 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (26.5 g, 191 mmol) and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate-hexane (1:1, 250 mL) and washed with water (250 mL×2) and saturated brine (100 mL), successively. The collected aqueous layer was extracted with ethyl acetate-hexane (1:1, 250 mL). The collected organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad filled with two layers of silica gel and celite, and the filtrate was concentrated. The obtained yellow syrup-like substance was recrystallized from ethyl acetate and hexane to give the title compound (21.8 g, 95%) as yellow crystals.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][NH:20][C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: NC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)NC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine (40.0 mg, 0.148 mmol), 2-cyanoacetic acid (15.0 mg, 0.178 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68.0 mg, 0.178 mmol) in N,N-dimethylformamide (2 mL) were mixed with N,N-diisopropylethylamine (57.0 μL, 0.326 mmol) and stirred at room temperature for 16 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=1/1→2/3 (v/v)) to give the title compound as a colorless solid (11.4 mg, yield 23%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 was added 2-bromo-4-chlorotoluene (10.0 mL, 75.0 mmol) in anhydrous THF (150 mL). The clear sol. was cooled to −78° C. and BuLi (36.6 mL, 82.4 mmol, 2.25 M sol. in hexanes) was added dropwise over 20 min. The resulting light orange sol. was stirred at −78° C. for 1 h, and DMF (30 mL, 375 mmol) was added in a single addition. The resulting mixture was allowed to warm to rt over 4 h. The reaction was quenched by addition of aq. 1M HCl (20 mL), and stirred at rt overnight. The reaction mixture was poured into a 500 mL separatory funnel containing aq. 1M HCl (200 mL). The mixture was extracted with Et2O (3×100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow oil. Purification by short-path distillation under reduced pressure (≈1 mm Hg) yielded the title compound as a light yellow oil (7.99 g, 69%). bp=70-72° C. at 1 mm Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][C:11]#[N:12]>>[N:1]1([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCl
Reactant: C1CCNCC1
Product: N#CCCCN1CCCCC1

Procedure:
Using piperidine and 4-chloro-butanenitrile as substrates. MS (ion spray) m/z 153.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Cl)=[N:4][CH:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:10][CH3:9])=[N:4][CH:3]=1
Reactant: ClCc1ncc(Br)s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ncc(Br)s1
Reaction time: 8 h
Yield: 28.4 %

Procedure:
5-Bromo-2-(chloromethyl)thiazole (177 mg, 0.833 mmol) was stirred in DMF (10 mL) under nitrogen at room temperature and sodium thiomethoxide (117 mg, 1.67 mmol) was added. The mixture was stirred overnight and concentrated. The residue was slurried in ethyl acetate (30 ml), washed with water, dried over sodium sulfate, and concentrated to give a brown oil which was purified by ISCO CombiFlash® chromatography with Heptane:DCM (100:0 to 0:100 over 10 column volume and held for a further 10 CV to give the product as a brown oil (53 mg 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O.C[N:29]([CH:31]=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:5]4[N:8]=[N:29][CH:31]=[CH:3][CH:4]=4)[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C1NC[C@H](c2cccc(Oc3cccnn3)c2)N1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-1-(4-chlorophenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one (210 mg, 0.73 mmol, prepared by using a similar procedure as described in Example 460) and 3-chloropyradazine (167 mg, 1.46 mmol) in DMF (2 mL) is added Cs2CO3 (354 mg, 1.09 mmol). The mixture is stirred at 80° C. for 14 h and is then cooled to room temperature. The reaction mixture is then treated with water (20 mL) and extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, 0%˜10% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.95 (dd, J=4.4, 1.2 Hz, 1H), 7.49 (dd, J=8.8, 4.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.10-7.20 (m, 6H), 5.28 (dd, J=8.0, 4.8 Hz, 1H), 4.70 (br s, 1H), 3.97 (t, J=8.8 Hz, 1H), 3.41 (dd, J=8.8, 6.0 Hz, 1H); HPLC-MS calculated for C19H15ClN4O2 (M+H+) 367.1, found 367.1.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 57 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To a suspension of 82 mg (3.43 mmol) of sodium hydride in 4 mL of benzene was added 315 mg (3.43 mmol) of methyl glycolate and a solution of 384 mg (1.14 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine in 4 ml of benzene. The mixture was heated at 57° C. and monitored by TLC (silica, methylene chloride) for conversion to product. After 2 days, the reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate. The aqueous phase was extracted twice with 7 mL portions of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated 600 mg of solid. The product was purified by flash chromatography (54 g silica, hexane-ethyl acetate gradient 100:0 to 75:25) to provide 211 mg (48%) of [[2-(methylthio)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (300 MHz, CDCl3) δ1.14 (t, 3H), 2.53 (s, 3H), 2.55 (q, 2H), 3.88 (s, 3H), 5.04 (s, 2H), 5.36 (s, 2H), 6.30 (s, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 6.96 (dt, 1H), 7.26 (dt, 1H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[N:36]O)[NH2:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]2[N:35]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])[CH2:12]3)[O:25][N:36]=2)=[CH:31][CH:32]=1
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(Cl)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) of 2-(4-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 62 mg (63% of theory)