Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C[Mg]Br.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])SC2C=CC=CN=2)=[CH:15][CH:14]=1)#[N:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([C:3]1[NH:4][C:5]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=2)=[O:27])=[CH:6][CH:7]=1)[CH3:2]
Reactant: N#Cc1ccc(C(=O)Sc2ccccn2)cc1
Reactant: CCc1ccc[nH]1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1ccc(C(=O)c2ccc(C#N)cc2)[nH]1
Reaction time: 0.67 h

Procedure:
To a solution of 2-ethyl-1H-pyrrole in toluene (120 mL) was added dropwise 1M methylmagnesium bromide in tetrahydrofuran (170 mL) in a dry ice-acetone bath below −60° C. over 30 minutes. Then the mixture was stirred in an ice-water bath for 40 minutes. To this reaction mixture was added S-(2-pyridinyl) 4-cyanobenzenecarbothioate (15.2 g) portionwise over 10 minutes in a dryice-acetone bath. After 1.5 hours stirring, saturated ammonium chloride (100 mL) was added therein and the reaction mixture was allowed to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N sodium hydroxide (100 mL) twice, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with isopropyl ether to give 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (12.7 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(Cc3cccnc3)CC2)n1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield via the procedure outlined for Example 5 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and 3-chloromethyl pyridine hydrochloride to give an off-white glass: 1H NMR (CDCl3, 400 MHz) δ 8.49-8.44 (m, 2H), 7.63 (d, 1H, J=7.6), 7.22 (t, 1H, J=4.8), 7.19-7.13 (m, 2H), 7.12-7.01 (m, 2H), 6.94 (d, 2H, J=8.0), 6.63 (d, 2H, J=8.0), 3.85-3.60 (m, 4H), 3.60-3.45 (m, 6H), 2.98 (s, 3H), 2.70 (t, 2H, J=6.4), 0.51 (m, 2H), 2.35 (m, 4H), 1.79(m, 2H); low resolution MS (ES+) m/e 574 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1): Rf=0.43; Anal. calcd. for C31H37N8OCl: C, 64.96; H, 6.51; N, 19.55. Found: C, 64.72; H, 6.58; N, 19.46.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:12]#[N:13])[CH2:8][CH2:9][CH3:10]>CCOCC>[C:20]1([C:11]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][NH2:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC(CN)(Cn1cncn1)c1ccccc1
Yield: 68.1 %

Procedure:
To a 5 liter flask stirring under nitrogen, fitted with a mechanical stirrer, was charged 21 g (0.55 mole) of lithium aluminum hydride. To the lithium aluminum hydride was charged 127 g (0.50 mole) alpha-butyl-alpha-phenyl-1H-1,2,4-triazole-1-propanenitrile in 2500 mL of dry ether over 2.5 hours. The reaction was stirred for an additional 5 hours after which GLC indicated the reaction was complete. The reaction was quenched with sodium sulfate, filtered and the organic phase separated. The aqueous phase was extracted with 1000 mL of ether. The organics were combined, washed with 3×1.5 liters of ice water, dried, filtered and concentrated without external heating and gave 88 g (69.2% yield) of a pale green oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.I[CH3:18]>>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[N:9]=[C:8]([S:12][CH3:18])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CI
Product: CSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 89 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with iodomethane to give the title compound in 89% yield.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH:19]1[CH2:24][CH2:23][N:22](C(=O)C)[CH2:21][CH2:20]1)[CH2:8][P:9]([O:15]C(C)C)([O:11]C(C)C)=[O:10])C>Cl>[NH2:28][CH:5]([CH:6]=[C:7]([CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)[CH2:8][P:9]([OH:11])([OH:15])=[O:10])[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Agent: Cl
Product: NC(C=C(CP(=O)(O)O)C1CCNCC1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g (2.17 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated under reflux in 20 ml of 6N hydrochloric acid for 8 hours. After concentration by evaporation, the residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are then added, the mixture is stirred for 2 hours at room temperature and for one hour with ice cooling, and then the suspension that has formed is filtered off with suction. 2-amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid having a melting point of 212° (decomp.) is obtained.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][NH:18][CH:19]([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CNC(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C(C)C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3 g, 12.57 mmol) in DMSO (20 ml) was added methyl(propan-2-yl)amine (1.3 g, 17.77 mmol), and DIEA (3.2 g, 24.76 mmol). The resulting solution was stirred overnight at 70° C. The product was precipitated by the addition of ice/water and collected by filtration to afford methyl 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (2.5 g, 72%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH:6]2[CH:8]([OH:9])[CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(OCC)(=O)C>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][CH:2]2[CH2:7][CH:6]3[CH:8]([OH:9])[CH:3]2[CH2:4][CH2:5]3)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: NC1CC2CCC1C2O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CC2CCC1C2O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2-aminobicyclo[2.2.1]heptan-7-ol (prepared according to U.S. Pat. No. 5,583,221) (1.29 g, 10.1 mmol) and triethylamine (1.67 mL, 12 mmol) in 75 mL tetrahydrofuran was added 4-chlorobenzenesulfonyl chloride (2.53 g, 12 mmol). The reaction was stirred at room temperature for 2 h, then diluted into 150 mL ethyl acetate and washed with brine (100 mL). The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 10 to 50% ethyl acetate in hexane over 25 min to give 2-(4-chlorophenylsulfonamido)bicyclo[2.2.1]heptan-7-ol (2.12 g, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79-7.81 (1H, m), 7.77-7.79 (1H, m), 7.46-7.48 (1H, m), 7.44-7.46 (1H, m), 5.61 (1H, d, J=10.32 Hz), 4.00 (1H, s), 3.34-3.48 (1H, m), 2.00-2.04 (1H, m), 1.86 (1H, d, J=3.78 Hz), 1.83 (1H, br. s.), 1.68-1.76 (1H, m), 1.59-1.66 (1H, m), 1.37-1.54 (2H, m), 0.97-1.09 (2H, m). LC/MS R.T.=1.98 min; [M+H]+=302.16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=2)[C:13](=[O:16])[CH2:14]Cl)=[C:4]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:3]=1.[CH3:35][NH:36][CH3:37]>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=2)[C:13](=[O:16])[CH2:14][N:36]([CH3:37])[CH3:35])=[C:4]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Reactant: CNC
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CN(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product from step (i) (0.1 g) was dissolved in MeOH and dimethylamine (2M in MeOH, 0.61 ml) was added. The reaction mixture was stirred for 72 h at rt, the solvents were evaporated and the residue purified by RPHPLC to give the title compound 24 mg.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]([CH:12]([CH3:29])[C:13]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)=[O:14])[C:4](=[O:30])[CH:3]=1.BrBr.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([C:43]#[N:44])=[C:38](B(O)O)[CH:39]=1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]([C:2]2[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][N:5]([CH:12]([CH3:29])[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:27][CH:28]=3)=[O:14])[C:4](=[O:30])[CH:3]=2)[CH:35]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CC(C)Oc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1I
Agent: BrBr
Product: CC(C)Oc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
100 mg of a mixture (3:1) of tert-butyl 4-({2-[4-iodo-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) and the analogous bromine compound and 41 mg (0.23 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 31 mg (29% of theory)
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([CH2:19][O:20][CH3:21])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][C:5]1[C:6]([CH2:19][O:20][CH3:21])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2
Reactant: [H][H]
Reactant: COCc1c([N+](=O)[O-])ccc2c1CN1CC(=O)NC1=N2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCc1c(N)ccc2c1CN1CC(=O)NC1=N2

Procedure:
To a suspension of 9.18 g. (3.4 × 10-2 mole) of 7-Nitro-6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one hydrochloride in 95% ethanol (300 ml.) is added 10 ml. of concentrated hydrochloric acid and 0.45 g. of 10% Pd/C catalyst. The mixture is placed on a Paar hydrogenator, shaken until theoretical hydrogen is absorbed, removed and water (150 ml.) added to effect dissolution of the precipitate. The mixture is filtered under suction, the catalyst washed with 95% ethanol and the mixture evaporated to dryness yielding the title product as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCOC(C)=O.C(Cl)Cl.[NH3:52]>CO>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([NH2:52])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)C1CC[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCC(C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 80 %

Procedure:
In a sealed tube a solution of Methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (diastereoisomer 1) (Intermediate 7, 6 mg, 9.94 μmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day and then it was left still for 2 days. The solvent was evaporated to dryness and the crude was purified by silica cartridges twice (1st time: from 1:0 to 95:5 DCM/MeOH; 2nd time: EtOAc and then 97.5:2.5 DCM/0.5M NH3 in MeOH) to give the title compound (4.7 mg, 7.99 μmol, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95-8.03 (m, 1H) 7.63-7.73 (m, 2H) 7.29-7.37 (m, 1H) 7.12-7.20 (m, 1H) 7.00-7.06 (m, 1H) 6.86-6.92 (m, 1H) 6.71-6.79 (m, 1H) 5.27-5.38 (m, 1H) 4.34-4.43 (m, 1H) 3.54-3.64 (m, 1H) 3.16-3.25 (m, 1H) 3.03-3.14 (m, 1H) 2.67-2.84 (m, 3H) 2.30-2.41 (m, 3H) 1.96-2.08 (m, 1H) 1.62-1.80 (m, 2 H) 1.38-1.58 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:12].C([O-])(O)=O.[Na+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>C1COCC1.C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH2:12])=[N:4][C:5]=3[CH:10]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cn1c(N)nc2cc(N)ccc21
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(N)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 1-Methyl-1H-benzoimidazole-2,5-diamine (0.63 g, 3.89 mmol) in THF (4 ml) and ethanol (12 ml) was added NaHCO3 (0.98 g, 11.67 mmol) and 2,4-dichloropyrimidine (1.45 g, 9.7 mmol) and the reaction was heated to 80° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-Chloro-pyrimidin-4-yl)-1-methyl-1H-benzoimidazole-2,5-diamine as an red solid. MS (ESI) m/z=275 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)#[N:2].S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:31][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)#[N:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc(Cc2ccccc2C=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N#Cc1cccc(Cc2ccccc2C=NC(c2ccccc2)c2ccccc2)c1
Temperature: 4 °C

Procedure:
To a stirred suspension of 3.58 g of 2-(3-cyanobenzyl)benzaldehyde and 10.4 g of anhydrous magnesium sulfate was added 3.6 ml of diphenylmethanamine, and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give an oil that crystallised on addition of diethyl ether and cooling to 4° C. to give 4.11 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine, melting at 113-115° C. A stirred solution of 1.0 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine in 15 ml of tetrahydrofuran was cooled to −78° C. and 6.7 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 20 min then 0.9 ml of propargyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction mixture was diluted with 25 ml of saturated aqueous ammonium chloride and extracted into dichloromethane. The combined organic extracts were dried over sodium sulfate the evaporated to give crude N-(diphenylmethylidene)-2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine which was not characterised due to instability. The crude product was dissolved in 20 ml of acetone and 5 ml of 1 M hydrochloric acid added. The solution was stirred at room temperature for 3 h then cooled to 4° C. overnight. The acetone was removed by evaporation and the crude product redissolved in 20 ml of dichloromethane. The solution was extracted with two 20 ml portions of 2N hydrochloric acid. The combined acid extracts were washed with 10 ml of dichloromethane and then basified with 4N sodium hydroxide solution. The basic extracts were combined and reextracted with three 20 ml portions of dichloromethane, the combined organic extracts were dried over sodium sulfate and evaporated to give 120 mg of product. The product was dissolved in 1 ml of methanol and 57 mg of fumaric acid was added. The product was crystallised by trituation with ether and cooling to 4° C. to yield 120 mg of 2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine (E)-butenedioate, melting at 182-184° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:20])/[CH:17]=N/O)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:22]>>[C:11]([C:9]1[CH:8]=[C:7]2[C:6](=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[NH:15][C:16](=[O:20])[C:17]2=[O:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1ccc(NC(=O)/C=N/O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)NC(=O)C2=O
Temperature: 0 °C
Yield: 42 %

Procedure:
N-(2,4-Di-tert-butyl-phenyl)-2-[(E)-hydroxyimino]-acetamide (500 mg, 1.7 mmol) in concentrated sulfuric acid (3.8 mL) was heated at 90° C. for 2 h. This solution was cooled at 0° C. and slowly added to ice-water (15 mL), the brown precipitate was filtered off and purified by chromathography on silica gel with a gradient of 0% to 25% of ethyl acetate in heptane to afford 200 mg (42%) of an orange powder. MS: m/z=259 (M).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[Br:11][C:12]1[CH:13]=[N:14][C:15](Br)=[N:16][CH:17]=1>O1CCCC1>[Br:11][C:12]1[CH:13]=[N:14][C:15]([CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:16][CH:17]=1
Reactant: CCOC(=O)CC#N
Reactant: Brc1cnc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a chilled stirred suspension of sodium hydride (60% in oil, 34.55 mmol) in tetrahydrofuran (20 mL) was added 1.17 g of ethyl cyanoacetate (10.34 mmol) portionwise over 10 minutes. After effervescence has ceased, the yellow cloudy mixture was left to warm up to room temperature whilst stirring. 2.00 g of 5-bromo,2-bromo-pyrimidine (10.34 mmol) in 30 mL of tetrahydrofuran was added. And the mixture was left to stir at room temperature for six hours. The resultant brown mixture was concentrated under reduced pressure to give a bright brown precipitate to which water (200 mL) was added. After extraction with heptane (200 mL), the aqueous phase was acidified by the addition of HCl 1M and the resultant precipitate was collected by filtration to give on drying ethyl (5-bromopyrimidin-2-yl)(cyano)acetate as a bright brown powder (0.67 g, yield=24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C

Procedure:
A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction mixture is concentrated and the residue triturated with ether to give 2-(4-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester as a yellow solid, 5.8 g (70%). LC-MS: 278 (M+1)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)[CH3:19].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.ClCCl.CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:20]([CH2:18][CH3:19])[CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:38])([F:36])[F:37])[C:39]([F:40])([F:41])[F:42])=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CCNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 53.3 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.781 mmol, 183 mg), 2-(4-((4-(ethylamino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.781 mmol, 300 mg) and triethylamine (1.873 mmol, 0.261 mL, 190 mg) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.937 mmol, 180 mg). The reaction was stirred for 24 hours. Chromatography on silica eluting with dichloromethane to dichloromethane/methanol (10%) gave the title compound (250 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[N:8][OH:9])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:7](=[N:8][O:9][C:17](=[O:18])[NH:16][CH3:15])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccccc2OC1=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1Oc2ccccc2OC1(C)C
Reaction time: 16 h

Procedure:
To a solution of 17.9 g of 3,3-dimethyl-2-oximinobenzodioxane and 5 drops of triethylamine was added 18.0 ml of methyl isocyanate. The reaction mixture was then left at ambient temperature for 16 hours. The reaction mixture was concentrated and filtered to yield 3,3-dimethyl-2-[O-(methylcarbamoyl)oximino]benzodioxane, m.p. 174°-176° C.