Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:12]([NH:14][NH:15][C:16]([CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=O)=[O:13])[C:7](=[O:43])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.Cl>ClCCCl.CCOC(C)=O>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:12]2[O:13][C:16]([C@H:18]3[C@@H:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:21][CH2:20][NH:19]3)=[N:15][N:14]=2)[C:7](=[O:43])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(C(=O)NNC(=O)C2C(c3ccccc3)CCCN2C(=O)OC(C)(C)C)c2ccccc2)C(=O)C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCN1CCN(C(c2ccccc2)c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)C(=O)C1=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-({2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazino}carbonyl)-3-phenylpiperidine-1-carboxylate (15.5 mg, 0.026 mmol) in 1,2-dichloroethane (1.5 ml) was added Burgess reagent (21.9 mg, 0.078 mmol). The reaction vessel was sealed and heated to 120° C. for 10 min in an Emry's Optimizer microwave reactor. Additional Burgess reagent (21.9 mg, 0.078 mmol) was added to the solution, and the reaction was sealed and heated again to 120° C. for 10 min in a microwave reactor. The reaction was concentrated in vacuo to yield the cyclodehydration product. A solution of the crude material in EtOAc (5 ml) at 0° C. was saturated with HCl gas and allowed to stir for 2 h. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield 1-butyl-4-(phenyl[5-(cis-3-phenylpiperidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl)piperazine-2,3-dione. HRMS (ES, M+H), cal'd for C28H33N5O3: 488.2656, found: 488.2646. 1H NMR (400 MHz, CD3OD) δ 7.42-7.22 (m, 7H), 7.09 (m, 3H), 6.87 (m, 2H), 5.36 (dd, J=14.6, 5.4 Hz, 1H), 3.88 (t, J=13.2 Hz, 1H), 3.53 (m, 1H), 3.44 (m, 6H), 3.24 (m, 1H), 3.11 (m, 1H), 2.55-2.38 (m, 1H), 2.25 (m, 1H), 2.00 (m, 2H), 1.56 (m, 2H), 1.33 (sext, J=7.4 Hz, 2H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]OS([O-])=O.[K+].[OH2:24]>CO.CCCCC>[CH2:1]([S:8]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11])(=[O:18])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: C=C(CSCc1ccccc1)c1ccccc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CCCCC
Product: C=C(CS(=O)(=O)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
1-Benzylthio-2-phenyl-2-propene (13.2 g, 0.055 moles) is dissolved in methanol (300 cc) and water (300 cc). Oxone (36.9 g, 0.12 moles as HKSO5) is added portionwise and the mixture is stirred at ambient temperature for three hours. The reaction mixture is diluted with water (1,000 cc), pentane (100 cc) is added, and the mixture is stirred vigorously until crystallization takes place. White crystals of 1-benzylsulphonyl-2-phenyl-2-propene (10.7 g, 72%) are obtained by filtration followed by drying. Mp=118° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]I)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CSC.[Cu]Br>[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17][CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](CI)NC(=O)OCc1ccccc1
Reactant: C=CC[Mg]Cl
Agent: [Cu]Br
Solvent: C1CCOC1
Solvent: CSC
Product: C=CCC[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml), then was cooled to −78 degrees C. A solution of allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise, then the solution was stirred for 30 minutes. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled THF (3 ml) was added dropwise, then the reaction was warmed to −40 degrees C. and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat. NH4Cl (4 ml) at −40 degrees C., warmed to RT and the gray reaction mixture turned sky blue. THF was removed in vacuo. Then, Et2O was added and the reaction mixture was filtered to remove precipitated solids. The solids were washed with additional Et2O. The combined organics were extracted with 10% NH4OH (3×), then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 20% EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then the resultant colorless oil was used in the next reaction without further purification (0.8 g, 73%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([F:14])[F:13])[N:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([F:14])[F:13])[N:3]=2)=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCC(F)F
Temperature: 110 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinonitrile (5.01 g, 22.9 mmol), 2-bromo-5-hydroxy-benzaldehyde (3.84 g, 19.1 mmol) and K2CO3 (5.3 g, 38 mmol) in dimethylformamide (30 mL) was heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with H2O (800 mL) and extracted with ethyl acetate (4×800 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to give the title compound as a white solid (6.62 g, 90%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH:9]([CH:22]1[NH:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClCCl.Cl[CH2:43][C:44](Cl)=[O:45]>O>[CH:9]([CH:22]1[N:27]2[C@@H:26]([CH2:28][O:29][CH2:43][C:44]2=[O:45])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N[C@@H](CO)C1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N2C(=O)COC[C@H]2C1
Reaction time: 1 h

Procedure:
Potassium carbonate (81.3 mg) was added to a mixture of [(2R)-6-benzhydryl-4-(2-methoxybenzyl)piperazin-2-yl]methanol dihydrochloride (48.0 mg) in a mixed solvent of dichloromethane and water. Chloroacetyl chloride was. added to the mixture below 5° C. and the whole was stirred for 1 hour. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue was dissolved into tert-butanol (4 ml) and potassium tert-butoxide (22.0 mg) was added to the mixture. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative TLC (15 PLC plate 20×20 cm, silica gel 60 F254, 1 mm, Merck) with a mixture of hexane and ethyl acetate as an eluent to give (9aR)-6-benzhydryl-8-(2-methoxybenzyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-one (30 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:6])[O-:5])[CH3:2].[CH2:7]([Sn+2:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CC>>[CH2:1]([O:3][P:4]([O-:6])[O-:5])[CH2:2][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[CH2:16]([Sn+2:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCO
Reactant: CCOP([O-])[O-]
Agent: CCCC[Sn+2](CCCC)CCCC
Product: CCCCCCCCCCCCOP([O-])[O-]
Temperature: 140 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
In a 500 ml four-neck round-bottom flask equipped with a stirrer, thermometer, standard taper glass stopper, stillhead with condenser, cooled distillate receiver and cold trap, 133 g of tributyltin ethyl phosphite and 68.7 g of lauryl alcohol are heated with stirring for about 5 hours at 140° C, a vacuum of about 30 - 5 mm Hg being applied for 1 hour. Ethanol is initially distilled off and then the excess lauryl alcohol is distilled. 178 g tributyltin lauryl phosphite are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:8][NH:9][CH3:10].[H][H]>[Pd]>[CH3:8][N:9]([CH3:10])[CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CNC
Reactant: [H][H]
Reactant: O=C1CCOCC1
Agent: [Pd]
Product: CN(C)C1CCOCC1
Temperature: 25 °C
Yield: 19 %

Procedure:
Into a reaction device similar to that used in Example 9 were charged 50.0 g (0.5 mol) of tetrahydropyran-4-one, 180.0 g (2.0 mol) of 50% by weight aqueous dimethylamine solution and 20 g (9 mmol in terms of a palladium atom) of 5% by weight Pd/C, and the mixture was reacted at a hydrogen pressure of 0.2 to 0.4 MPa at 50° C. for 7 hours and further at 70° C. for 4 hours. After completion of the reaction, the resulting reaction mixture was cooled to room temperature and the catalyst was filtered off by Celite, and the filtrate was made acidic (pH=1) by adding 60 ml of conc. sulfuric acid and then washed successively with 200 ml of 2-butanol twice and 200 ml of chloroform twice. Then, 130 g of potassium hydroxide was added to the aqueous layer to make the solution basic (pH=11), the aqueous layer was extracted three times with each 300 ml of ethyl acetate and the resulting organic layer was dried over anhydrous magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure, and then, by distillation under reduced pressure (83 to 85° C., 50 mmHg), 12.4 g (yield: 19%) of 4-dimethylaminotetrahydropyrane with a purity of 99% (areal percentage according to gas chromatography) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([CH3:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Cc1ccc(N)cc1C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-benzenesulfonyl chloride (0.51 g) in pyridine (2 mL) were added 3,4-dimethylaniline and dimethylaminopyridine (0.024 g). The reaction mixture was stirred overnight, concentrated under reduced pressure, and diluted with CH2Cl2. The mixture was washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 1:3 EtOAc/Hexane) to give 4-chloro-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[CH:13]=[O:14])=[CH:9][C:2]=12.[BH4-].[Na+].O>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=3)=[CH:9][C:2]=12
Reactant: O=Cc1cccc(-c2cc3nccnc3[nH]2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cccc(-c2cc3nccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A suspension of 3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-benzaldehyde [0.4 g, Example 9(a)] in ethanol (50 mL) was treated with sodium borohydride (200 mg). The mixture was allowed to stir at ambient temperature for 1 hour then treated with water (10 mL) and then evaporated. The residual solid was triturated with water (50 mL) to give a pale yellow solid which was washed with water and then recrystallised from methanol to yield the title compound (0.35 g) as a yellow crystalline solid, m.p. 225-226° C. [Elemental analysis: C, 68.72; H, 4.73; N,18.44%. Calculated for C13H11N3O: C, 69.32; H, 4.92; N, 18.65%].
Reaction SMILES: C1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=2[NH2:11])CC1.C(N([CH:18]([CH3:20])[CH3:19])CC)(C)C.[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:11][C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][CH:18]1[CH2:20][CH2:19]1)=[O:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C2CC2)c1N
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Yield: 516.6 %

Procedure:
To a solution of title compound 381 (0.83 g, 5.84 mmol) and diisopropylethylamine (1.02 mL, 0.74 mmol) in THF (50 mL) was added a solution of 2-chloronicotinoyl chloride (1.03 g, 5.84 mmol) in THF at 0° C. The reaction mixture was stirred over night and concentrated. To the residue was added a saturated solution of bicarbonate (3 mL) and this aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The solid was triturated in DCM (3 mL) and filtered. The filtrate was evaporated and purified by flash chromatography (0% to 80% ethyl acetate in hexanes). The 2 solids were mixed to afford title compound 382 (1.1 g, 65%) as a white solid. MS (m/z): 288.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[F:30][C:31]([F:37])([F:36])[CH2:32][CH2:33]C=O>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:33][CH2:32][C:31]([F:37])([F:36])[F:30])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: O=CCCC(F)(F)F
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(F)(F)F

Procedure:
The product of Example 100 is treated with 4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13]NN(CC)NC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH:30]2[CH2:34][CH2:33][N:32]([C:1]([NH:8][CH2:12][CH2:11][N:10]([CH3:9])[CH3:13])=[O:2])[CH2:31]2)(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(NC)NC
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(S(=O)(=O)c2ccc(Cl)cc2)C1
Yield: 51.4 %

Procedure:
A solution of 5.00 g (0.0309 mole) of 1,1'-carbonyldiimidazole and 2.56 g (0.029 mole) of N,N-dimethylaminoethylamine in 200 ml of tetrahydrofuran was stirred at room temperature for about 1 hr. A solution of 5.99 g (0.0244 mole) of 3-[(4-chlorophenyl)sulfonyl]pyrrolidine (free base) in tetrahydrofuran was added and the solution was refluxed for 16 hr. The solvent was removed in vacuo and the resulting oil was dissolved in a mixture of 200 ml of diethyl ether and 20 ml of methylene chloride. The solution was extracted with one 150 ml portion of water. The ether phase was discarded. On standing at room temperature, the aqueous extract yielded a white precipitate. The precipitate was recrystallized from methylene chloride-diethyl ether to give 4.51 g (51.36%) of white crystals, m.p. 131°-132.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:25](B1OC(C)(C)C(C)(C)O1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO.C1(C)C=CC=CC=1>[CH2:25]([C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)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: Cc1ccccc1
Solvent: CO
Product: N#Cc1cc(Cc2ccccc2)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A 5 ml microwave vial was loaded with 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (125 mg, 0.259 mmol, Example 160A), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.362 mmol) and Pd(Ph3P)4 (15 mg, 0.013 mmol). Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added, the flask flushed with nitrogen, sealed and heat to 110° C. for 4 hours. LCMS after 4 hours showed product and starting material (1:2.5 ratio) (product m/e−=396, consistent with [M−H]−). Additional 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.834 mmol) and Pd(Ph3P)4 (30 mg, 0.026 mmol), Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added. The flask was flushed with nitrogen, sealed and heated to 110° C. for additional 8 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane. The layers were separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica, using a gradient from 100% CH2Cl2 to 50% CH2Cl2+50 EtOAc. Product containing fraction were combined and evaporated to dryness to give 42.3 mg 5-benzyl-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile. (estimated purity 76%). The material was used without further purification. MS (ESI) m/e−=396, m/e+=398 consistent with [M−H]− and [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15].I[CH2:21][CH3:22].[BH4-].[Na+]>C(O)C>[CH2:21]([N:11]1[CH2:10][CH:9]=[C:8]([C:7]2[C:2]([F:1])=[C:3]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1)[CH3:22]
Reactant: CN(C)S(=O)(=O)c1cccc(-c2ccncc2)c1F
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(S(=O)(=O)N(C)C)c2F)CC1

Procedure:
Preparation according to preparation 6: 2-fluoro-N,N-dimethyl-3-pyridin-4-ylbenzene sulfonamide (0.59 g, 2.11 mmol), 1-iodoethane (3 ml), ethanol (40 ml), sodium borohydride (0.4 g, 10.5 mmol). Yield: 0.27 g. MS m/z (rel. intensity, 70 eV) 312 (M+, bp), 311 (33), 297 (93), 146 (36), 110 (32).
Reaction SMILES: C1(N[C:8]2[C:9]3[S:28][CH2:27][CH2:26][C:10]=3N=C(N3CCN(C4C=CC=CC=4)CC3)N=2)CCCCC1.[NH2:29][C:30]([NH2:32])=[O:31].C.[OH-:34].[Na+]>>[N:29]1[C:10]2[CH:26]=[CH:27][S:28][C:9]=2[C:8]([OH:34])=[N:32][C:30]=1[OH:31]
Reactant: c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Reactant: NC(N)=O
Reactant: [OH-]
Agent: [Na+]
Product: Oc1nc(O)c2sccc2n1
Reaction time: 2 h
Yield: 75 %

Procedure:
10.0 g (64.0 mmol) of methylester 3-aminothiophene-2-carboxylate (I) and 19.0 g (31.60 mmol) of urea are mixed and melted for 2 hours at 200° C. After cooling, the reaction mixture is dissolved in 1 molar sodium hydroxide solution and decolorized with activated charcoal. It is filtered and the filtrate is cooled and acidified with 4M hydrochloric acid. The precipitate formed is suction filtered and dried. 8.03 g of product II (75%) is obtained as a powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.[CH3:18]I.O>C1COCC1>[CH3:18][N:15]1[CH:16]=[C:12]([C:11]#[C:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)[N:13]=[C:14]1[CH3:17]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(C)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (76 mg, 55%, 1.57 mmol) was suspended in 2 mL of dry THF. A solution of 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.76 mmol) in 8 mL of dry THF was added and the reaction mixture was stirred at room temperature for 30 min. A solution of methyliodide (142 mg, 1.00 mmol) in 1 mL of dry THF was added and stirring was continued overnight. The reaction mixture was poured into 70 mL of water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient) and a mixture of two regioisomers was obtained. This mixture could be separated by HPLC (chiralpak AD, heptane/ethanol 4/1) and the desired compound was obtained as a white solid (40 mg, 25%), MS: m/e=212.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
139 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) of Example 1a are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 50.1 g. of [3-(dimethylamino)propyl]amine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is removed in vacuo and the residue is suspended in 200 ml. of water. The aqueous mixture is made alkaline with 10% sodium hydroxide solution and extracted three times with 200 ml. portions of ethyl acetate. The organic layer is dried over calcium chloride, evaporated to dryness and crystallized with petroleum ether to obtain 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester, yield: 102 g. (59%); m.p. 20°.