Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:19][C:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:20]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A suspension of 13.8 g of 3-nitroaniline and 20 mL of triethylamine in 200 mL methylene chloride was cooled to 0° C. under a nitrogen atmosphere atmosphere and treated with 10.2 g of acetyl chloride, added in a dropwise manner. The reaction mixture was allowed by warm to room temperature overnight. Removal of the volatiles in vacuo gave a crude yellow solid which was washed with 5% aqueous hydrochloric acid, water and was then dried. The yield of 3-nitroacetanilide was 17.4 g as a light yellow solid, m.p. 147°-149° C.; NMR (CDCl3 /DMSO-d6): δ 2.1 (3H, br s), 7.5 (1H, t, J=9 Hz), 8.0 (2H, br t), 8.6 (1H, br s) 10.1 (1H, br s); IR(KBr): 1675, 1550, 1525, 1350 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:14]1([CH:17]=O)[CH2:16][CH2:15]1.C(O)(=O)C.B.N1[CH:29]=[CH:28][CH:27]=[CH:26]C=1C>CO>[CH:14]1([CH2:17][N:1]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:2]2[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:15]1
Reactant: O=CC1CC1
Reactant: CCOC(=O)c1cc(N)ccc1Cl
Reactant: Cc1ccccn1
Agent: B
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc(N(CC2CC2)CC2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of ethyl 5-amino-2-chlorobenzoate, cyclopropanecarboxaldehyde (458 μl) and acetic acid (1.43 ml) dissolved in methanol (20 ml), α-picoline borane (804 mg) was added at ice cool temperature, and was stirred under nitrogen atmosphere overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, sodium hydrogencarbonate aqueous solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and ethyl 2-chloro-5-(cyclopropylmethylamino)benzoate (881 mg) and ethyl 5-[bis(cyclopropylmethyl)amino]-2-chlorobenzoate (423 mg) were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:33]1[N:34]([C:38]2[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=2[C:40](O)=[O:41])[N:35]=[CH:36][CH:37]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:40]([C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[N:34]4[N:35]=[CH:36][CH:37]=[N:33]4)=[O:41])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid and DCM in place of DMF. DCM was used in place of DMF. MS (ESI) mass calcd. For O21H23N7O, 389.46; m/z found 390.1 [M+H]+. 1H NMR (CDCl3): 8.03-7.91 (m, 1H), 7.81-7.64 (m, 2H), 7.54-7.20 (m, 3H), 6.99-6.87 (m, 1H), 4.87-3.93 (m, 4H), 3.78-3.48 (m, 2H), 3.29-2.75 (m, 2H), 2.39-2.29 (m, 4H), 2.06-2.02 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:28]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:29])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(-c2cncc(CNC(=O)N3CCOCC3)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) are added morpholine-4-carbonyl chloride (0.026 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol) and the reaction is stirred at room temperature overnight. The mixture is then washed with water and extracted with dichloromethane twice. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford morpholine-4-carboxylic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.41-3.47 (m, 4H), 3.66-3.72 (m, 4H), 3.84 (s, 3H), 4.55 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). MS (ESI) m/z 410.00 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:5]1[NH:6][C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1COCC[Si](C)(C)C)C(=O)C(F)CS2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c([nH]1)C(=O)C(F)CS2
Yield: 92.7 %

Procedure:
305 mg of the product of Stage B and 1.75 ml of trifluoroacetic acid were heated at 40° C. for 12 hours in 6.1 ml of dichloromethane. The mixture was poured into water, sodium bicarbonate was added until a pH of 6-7 was obtained. Extraction was carried out with methylene chloride and the solvent was eliminated under reduced pressure to obtain 180 mg of the expected product.
Reaction SMILES: [Cl-].[CH:2]([NH:5][P:6]([CH2:9][CH2:10][Cl:11])(=[O:8])[OH:7])([CH3:4])[CH3:3].ClCCP(Cl)(Cl)=[O:16].[CH:19](N)([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH:2]([NH-:5])([CH3:4])[CH3:3].[CH:19]([O:16][P:6]([CH2:9][CH2:10][Cl:11])(=[O:8])[OH:7])([CH3:21])[CH3:20]
Reactant: CC(C)NP(=O)(O)CCCl
Reactant: CC(C)N
Reactant: O=P(Cl)(Cl)CCCl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)OP(=O)(O)CCCl
Product: CC(C)[NH-]

Procedure:
The 2-chloroethane-phosphonic acid N-mono-isopropylamide chloride used as starting product was prepared from 2-chloroethane-phosphonic acid dichloride and iso-propylamine in toluene at 0° C. Yield: 91% of the theory, nD28 = 1.4854.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.Cl.Cl.[NH2:28][CH2:29][CH2:30][SH:31]>>[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][S:31][CH2:30][CH2:29][NH2:28])[N:7]=1
Reactant: NCCS
Reactant: Nc1nc(CO)c[nH]1
Agent: Cl
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the picrate salt with hydrochloric acid) with cysteamine hydrochloride by the procedure of Example 1 gives 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
0.33 g of sodium ethanethiolate was added to a mixture of 0.45 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. Water was poured to the reaction mixture cooled to room temperature, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 0.42 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[ClH:12].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].[CH2:18]=O>>[ClH:12].[CH2:13]([N:15]([CH2:18][CH:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[CH2:16][CH3:17])[CH3:14]
Reactant: O=C1CCCc2ccccc21
Reactant: CCNCC
Reactant: C=O
Agent: Cl
Product: CCN(CC)CC1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
α-Tetralone (292 g), diethylamine hydrochloride (240 g) and 37% aqueous formaldehyde (220 g) are combined and heated on a steam bath with stirring for 1 hour. The reaction mixture is cooled to 25° C and washed with three 120 ml portions of ether. The aqueous layer is made alkaline with concentrated ammonium chloride and extracted with chloroform. The chloroform is removed under vacuum and the residue taken up in ether. The resulting solution is treated with excess ethereal hydrogen chloride, producing an insoluble gum. The ether is decanted and the gum repeatedly scratched against the walls of the beaker to initiate a slow crystallization. The mass is allowed to stand overnight during which period crystallization is completed. The resulting solid mass is pulverized and washed with a minimal amount of ethanol. The mixture is filtered and the filter cake is stirred slowly in ether. The solid material is filtered off and dried for 4 hours at 25° C (0.1 mm of mercury) to yield 200 g of the title compound that melts beginning anywhere from 127° C to 135° C, depending on the rate of heating.
Reaction SMILES: CS[C:3](=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[CH:4]([CH3:6])[CH3:5].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17][CH:16]=1>CN(C)C=O>[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:3]([CH:4]([CH3:6])[CH3:5])=[N:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: CSC(=Nc1ccccc1F)C(C)C
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 120 °C
Reaction time: 59 h
Yield: 67.6 %

Procedure:
N-(2-Fluorophenyl)-2-methylthiopropionimidate methyl ester (7.84 g) prepared in the Reference Example 1 and biphenyl-4-carboxylic acid hydrazide (5.25 g) were dissolved in N,N-dimethylformamide (50 ml), followed by addition of p-toluenesulfonic acid·monohydrate (941 mg), and stirred at 120° C. for 59 hours. After the reaction solution was cooled to ambient temperature, the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-chloroform/methanol=100/1 to 50/1 to 20/1), to afford 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole as pale yellow solid (5.98g, 68%). A part of the product was recrystallized from ethyl acetate, to afford the entitled compound as pale yellow crystal. The physico-chemical values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.69-3.73 (m, 4H), 3.98 (s, 4H), 4.16 (s, 3H), 6.54-6.55 (m, 1H), 7.28-7.49 (m, 1H), 7.63-7.75 (m, 2H), 8.33 (d, J=4.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](COCOC)=[C:7]([C:14]([CH2:18][CH3:19])=[CH:15][CH2:16][OH:17])[CH:6]=[C:5]([Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=1.C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:29])C.C(OO)(C)(C)C>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@:14]1([C:7]2[CH:6]=[C:5]([Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[O:29][C@@H:15]1[CH2:16][OH:17])[CH3:19]
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Reactant: CCC(=CCO)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)(C)OO
Solvent: ClCCl
Product: CC[C@]1(c2cc(OC)nc([Si](C)(C)C)c2)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5a (937 mg, 2.76 mmol) and activated 4 Å molecular sieves (280 mg) in CH2Cl2 (26 mL) at −20° C. was added diethyl-L(+)-tartrate (568 mg, 2.75 mmol), and Ti(OiPr)4 (629 mg, 2.2 mmol). After stirring for 1 h, tBuOOH (1.1 mL, 5.0-6.0 M in decane, predried over 4 Å molecular sieves for 1 h) was added with a syringe. The reaction mixture was kept in the freezer at −20° C. for 60 h. The solution was removed from the freezer, diluted with Et2O (5.2 mL) and quenched with a saturated Na2SO4 solution (2.6 mL). The resulting heterogeneous mixture was stirred and allowed to warm to room temperature for 2 h. Then it was filtered through a celite pad (washing with hot EtOAc several times). The combined filtrates were concentrated under vacuum. The residue was dissolved in Et2O (13 mL) at 0° C. and a 1N NaOH solution saturated with NaCl was added (8 mL). The two-phase mixture was vigorously stirred at 0° C. for 1 h and then transfered to a separatory funnel. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 651 mg (66% yield) of the crude product 6a as a clear oil with 92% ee and sufficiently pure for the subsequent reaction. Epoxide 6a was analyzed for enantiomeric purity using a Chiralcel OD-H column with 98.5:1.5 hexane:iPrOH as the eluent, using the racemate as the standard. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 0.9 (t, J=7.5 Hz, 3H), 1.79 (m, 1H), 1.97 (m, 1H), 3.23 (t, J=5.8 Hz, 1H), 3.45 (s, 3H), 3.9 (m, 2H), 3.99 (s, 3H), 4.64-4.72 (m, 4H), 7.09 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−1.93, 9.18, 25.63, 29.66, 53.42, 55.59, 60.64, 61.21, 63.46, 64.63, 96.44, 115.45, 121.32, 148.36, 161.89, 165.16; IR (film, NaCl, cm−1) 3463, 2945, 1562, 1451, 1345, 1041, 840; LRMS (70 eV, EI) m/z (rel int %) 355 (M+), 340, 324, 310, 294, 280, 262, 250, 89, 73, 57. HRMS m/z calcd for C17H29NO5Si (M+) 355.1815, found 355.1812, [α]23D=+28(c=0.25, CH2Cl2).
Reaction SMILES: [CH:1]12[CH2:7]C(C[CH2:6]1)[CH2:3][CH2:2]2.[CH3:8][CH:9]=[CH:10][CH3:11].[CH:12]1[CH2:16]C=[CH:14][CH:13]=1>>[CH2:8]=[C:9]1[CH:2]([CH3:3])[CH:1]2[CH2:7][CH:10]1[CH2:11][CH2:6]2.[CH3:8][C:9]1[CH:12]2[CH2:16][CH:11]([C:10]=1[CH3:1])[CH2:14][CH2:13]2
Reactant: C1CC2CCC1C2
Reactant: C1=CCC=C1
Reactant: CC=CC
Product: C=C1C2CCC(C2)C1C
Product: CC1=C(C)C2CCC1C2

Procedure:
The method of the invention to give the bicyclo[2.2.1]heptane derivatives in one step comprises reacting 2-butene with cyclopentadiene in the presence of an isomerization catalyst for simultaneous isomerization to give 2-methylene-3-methylbicyclo[2.2.1]heptane and/or 2,3-dimethylbicyclo[2.2.1]hept-2-ene.
Reaction SMILES: [C:1]([CH:4]([CH:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(O)C.[BrH:22].[NH:23]([C:25]1[NH:26][CH2:27][CH2:28][N:29]=1)[NH2:24]>C(O)(=O)C>[BrH:22].[C:11]([C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]([CH3:2])[N:24]([NH:23][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)[C:16]=1[CH3:17])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C(C)=O)C(C(C)=O)C(=O)OCC
Reactant: NNC1=NCCN1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)OCC)c(C)n(NC2=NCCN2)c1C

Procedure:
To a solution of 15 g. (0.0581 mole) of diethyl 2,3-diacetylsuccinate in 150 ml. of absolute ethanol, 1.2 ml. of glacial acetic acid is added. The mixture is gently refluxed for 5 minutes then 8.13 g. (0.0467 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide is added. The mixture is refluxed for 20 hours, then the solvent is evaporated off. The obtained residue is recrystallized several times from isopropanol, and 6.3 g. of the title compound are recovered. M.p. 172°-4°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[C:26](O)(=[O:35])[C:27]1[C:28]([O:33][CH3:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:12]2[NH:11][N:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:35])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:7][CH:6]=3)[C:13]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:21]=1
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Reactant: COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Nc1ccc(Nc2n[nH]c(NCc3ccc(O)cc3)c2C(N)=O)cc1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in 8.0 mL of DMF and TEA (183 μL, 3.0 eq.) was then added to the reaction vessel. Reaction was then stirred on an ice bath for 15 min and o-Anisic acid (67 mg, 1.00 eq.) dissolved in DMF (2.0 mL) was slowly added into the reaction. The reaction continued stirring for 18 hrs and allowed to reach room temperature. The reaction was tracked via HPLC, once completed and no traces of starting material is present, the solvent was then removed via vacuo and column chromatography was used to purify the compound. A gradient of 0 to 20% MeOH in dichloromethane was used and the desired fractions were combined, evaporated and triturated with diisoproyl ether then filtered to yield product as an off white powder (0.025 g, 12.0% yield).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]1([CH3:56])[C:45]([CH3:47])([CH3:46])[O:44][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH:51]=O)[O:42]1.O>C1COCC1>[CH3:46][C:45]1([CH3:47])[C:41]([CH3:40])([CH3:56])[O:42][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)/[CH:51]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[O:44]1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A solution of (4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (2.9 g, 6 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.4 g, 6 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (E)-methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)benzoate (0.9 g, 41%) as a colorless oil. LC-MS: 365 [M+H]+, tR=1.98 min.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:3]1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH:4]2[CH2:5][N:2]([CH3:19])[CH2:3]2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)ccc1NC1CNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a mixture of azetidin-3-yl-(4-bromo-2-nitro-phenyl)-amine, hydrochloride (27.7 mmol, 8.54 g) in acetonitrile (100 mL) and 37% aqueous formaldehyde (83.0 mmol, 6.28 mL, 3.00 equiv.) at 0° C. add sodium triacetoxyborohydride (88.6 mmol, 18.8 g) slowly. Stir at room temperature under nitrogen overnight. Remove volatiles under reduced pressure. Dilute with ethyl acetate, wash with 10% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 8.5 g of an orange solid. Purify on a 120 g silica column eluting with 5% methanol in dichloromethane to obtain the title compound (5.92 g, 75%). LC-MS m/z (79Br/81Br) 286.0/288.0 [M+H]+.
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:41]=O)=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[CH3:43][C:44]1[O:45][CH:46]=[N:47][N:48]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:41][C:46]3[O:45][C:44]([CH3:43])=[N:48][N:47]=3)=[C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:34]=2)[CH:31]=1
Reactant: O=Cc1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: Cc1nnco1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nnc(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)o1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.25 (d, J=1.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.61 (d, J=9.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.22 (dd, J=9.5, 1.8 Hz, 1H), 4.58 (s, 2H), 2.52 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15].[C:24]([O:30][CH2:31][CH:32]=[CH2:33])(=[O:29])[CH2:25][C:26]([CH3:28])=O>CC(O)C>[CH2:31]([O:30][C:24]([C:25]1[CH:20]([C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[NH:1][C:26]=1[CH3:28])=[O:29])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=CCOC(=O)C1=C(C)Nc2ncnn2C1c1ccc(C#N)cc1
Temperature: 90 °C

Procedure:
3-amino-1,2,4-triazole (1.28 mg, 15.24 mmol) and triethylamine (2.2 ml, 15.25 mmol) were heated in IPA (30 ml) at 90° C. until most of the solid had dissolved. 4-Cyanobenzaldehyde (2.0 g, 15.27 mmol) and allyl acetoacetate (2.17 g, 15.28 mmol) were added and the reaction was heated at 90° C. overnight. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. Some solid material was filtered off and the ethyl acetate layer was separated, washed with brine, dried (Na2SO4) and the volume reduced. The solid which precipitated was filtered, washed with ethyl acetate and combined with the solid obtained earlier. The pale yellow product was dried in vacuo at 40° C.