Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
345(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (0.1 mmol) was dissolved in DCM (3 mL), followed by the addition of Et3N (10 mg, 0.1 mmol). The resultant solution was stirred overnight. The solution was then purified using a Gilson to give 2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorobenzoic acid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.S(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([N:2]([CH2:3][CH3:4])[C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:16])[CH3:13]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 8 h

Procedure:
A mixture of 2 g of β-carbolin-3-carboxylic acid, 20 ml of thionyl chloride and 2 ml of dimethylformamide is boiled under reflux for 1 hour. The excess thionyl chloride is removed by distillation under reduced pressure. 20 ml of diethylamine is added under cooling to a suspension of the residue in 20 ml of triethylamine and the mixture is concentrated under reduced pressure. The residue is treated with aqueous ammonia (pH 8.5) and the mixture thus obtained is extracted with chloroform (6×25 ml). The extract is washed with water (2×25 ml), dried (K2CO3), decolorized with a small amount of charcoal and filtered. The filtrate is evaporated to dryness and the residue is kept at 60° C. overnight. The solid (1.56 g; 62%) is recrystallized from toluene to form β-carbolin-3-carboxylic acid diethylamide having a melting point of 170.0° C.
Reaction SMILES: [C:1]([Li])#[C:2][CH3:3].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([C:1]#[C:2][CH3:3])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: [Li]C#CC
Reactant: CCCCC(=O)C/C=C/I
Solvent: C1CCOC1
Product: CC#CC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of propynyllithium at -25° is added a solution of 4-oxo-1-iodo-trans-1-octene in tetrahydrofuran. After the addition, the solution is stirred at -20° to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with toluene to provide the product as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:31])[CH2:30][O:29][CH2:28]1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([C:27]4([OH:31])[CH2:30][O:29][CH2:28]4)=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)COC2)c(F)c1
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.206 mg, 0.66 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.13 g, 1.32 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (0.2 g, 0.66 mmol, 1.0 eq) at RT and stirred for 16 h. The reaction mixture was extracted with DCM (20 mL), washed with water (15 mL), brine (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was purified by CC using EtOAc/PE (7:3) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)urea (0.075 g; 23%) as off white solid (TLC system: EtOAc/PE (1:1); Rf: 0.55).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[C:10]=12)=[O:5])[CH3:2].[Na].[CH3:21][SH:22].O>CN(C)C=O>[CH3:21][S:22][C:11]1[C:10]2[N:9]([N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CS
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn2c1c(SC)nc1ccccc12

Procedure:
2.76 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid ethyl ester are heated with 0.71 g. of the sodium salt of methyl mercaptan in dimethylformamide. After cooling, the reaction mixture is poured into water. The product 4-(methylthio)pyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester is filtered under suction and crystallized from ethanol as white needles, m.p. 97°-98°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=2)[N:20]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 3.5 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 75 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid remains as colorless crystals of m.p. 264-265 C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][CH:13]=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:11]=[C:2]([CH3:1])[C:3]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2ccccc2n(CC=O)c1=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc2ccccc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To 25 mL of a chloroform solution containing 341 mg of (3-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 498 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 80 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 480 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 126 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:21]=[CH:22][C:15]1=2)=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[C:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]4)[C:15]=3[CH:22]=[N:21]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cn1cc(C(F)(F)F)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 65 °C
Yield: 113.7 %

Procedure:
A mixture of 4-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.025 g, 0.085 mmol) and K2CO3 (0.060 g, 0.43 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 65° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.038 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 5.20 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 1-bromo-4-nitrobenzene (404 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 340 mg (90% isolated yield) of the desired product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[CH2:37][CH3:38]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:36][CH2:37][CH3:38])=[CH:41][CH:42]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCCOc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-propoxyphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-propoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=1)[CH3:15]>CCO.Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[C:2]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:14][CH3:15])=[CH:17][C:18]=2[F:23])=[CH:3][C:4]([Cl:13])=[N:5][CH:6]=1)[CH3:12]
Reactant: CCc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(CC)cc1F
Yield: 100 %

Procedure:
Ethyl 4,6-dichloronicotinate (31.62 g, 144.0 mmol) and 4-Ethyl-2-fluoro-phenylamine (20.0 g, 144.0 mmol) were dissolved in EtOH (200 mL), to which was added conc. HCl (6 drops) as for Example 1, alternate Step A to give 6-Chloro-4-(4-ethyl-2-fluoro-phenylamino)-nicotinic acid ethyl ester (46.50 g, 99%). (APCI+) calcd for C16H18ClFIN2O2 322.76 (M−1), found 321.0.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH3:52]>C1COCC1>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[N:31]([CH3:52])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: CI
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)Nc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)N(C)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}carbonyl)cyclohexyl]acetate (500 mg; 0.716 mmol) in anhydrous THF (10 mL) was cooled to 0° C. and treated with sodium hydride (60% in oil; 31.5 mg; 0.788 mmol). The resultant mixture was stirred at 0° C. for 30 min prior to addition of iodomethane (58 μL; 0.931 mmol). The reaction was stirred at room temperature for 14 h and quenched with H2O. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAc/hexanes, and by chiral HPLC (chiralPak IA column, 10% iPrOH/heptane) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methyl)amino]carbonyl}cyclohexyl)acetate as a clear oil. LCMS=713.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.92 (s, 1 H), 7.80 (s, 1 H), 7.73 (s, 1H), 7.29-7.20 (m, 2 H), 7.17-7.15 (m, 1 H), 5.66 (d, J=8.3 Hz, 1 H), 4.95 (d, J=14.8 Hz, 1 H), 4.22 (d, J=16.7 Hz, 1 H), 4.14-4.06 (m, 2 H), 3.897 (d, J=14.7 Hz, 1 H), 3.39 (s, 3 H), 2.70-2.63 (m, 1 H), 2.22-2.18 (m, 1 H), 2.10-2.07 (m, 1 H), 2.00-1.52 (m, 8 H), 1.27-1.19 (m, 3 H), 1.16-1.08 (m, 1 H), 0.76-0.68 (m, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23][N:24]3[C:28](=O)[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:17]=1)C(C1C=CC=CC=1)=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:18]3[C:19]([CH2:35][NH2:36])=[N:20][N:21]=[C:22]3[CH2:23][N:24]=[C:28]([C:27]3[CH:26]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, 5-nitro-2-[3,5-bis-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-nitro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([NH:9][C:10]([NH:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[N:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)C1C=CC=CC=1>Cl>[NH:29]1[CH:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH:22][C:10]([NH:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[NH:9])[N:27]=[CH:28]1
Reactant: O=C(NC(=NCCCSc1ccccn1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCSc1ccccn1)NCCCc1c[nH]cn1

Procedure:
0.84 g (2 mmol) of N-benzoyl-N'[3-(imidazol-4-yl) propyl]-N"-[3-[(pyrid-2-yl)thio]propyl]-guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 6 hours. The reaction product is worked up by a method analogous to that of Example 109. It initially precipitates as a dry, hygroscopic foam but this foam gradually crystallises when triturated with acetone and a few drops of ethanol.
Reaction SMILES: F[C:2]1[N:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH:14]1([NH:20][C:2]2[N:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(F)nc1F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)nc1NC1CCCCC1

Procedure:
In methylene chloride, ethyl 2,6-difluoronicotinate and cyclohexanamine were stirred at 0° C. for 0.5 hour to obtain ethyl 2-(cyclohexylamino)-6-fluoronicotinate (ES: 267). This was stirred in ethanol by adding sodium hydroxide. By concentrating the reaction liquid under a reduced pressure and purifying the resulting residue by silica gel column chromatography, 2-(cyclohexylamino)-6-fluoronicotinic acid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:15][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC(C)C(=O)c1ccc(CBr)cc1
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)C)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 3a using 3-oxopentanoic acid ethyl ester and 1-(4-bromomethylphenyl)-2-methylpropan-1-one.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8]([OH:10])=O)[CH2:3][C:4]([OH:6])=[O:5].N1C(C)=CC=[CH:14][C:13]=1C>O1CCCC1.[Pd]>[CH:8]([CH2:7][C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([O:6][CH2:13][CH3:14])=[O:5])=[O:10]
Reactant: CC(C)(CC(=O)O)CC(=O)O
Reactant: Cc1cccc(C)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)CC=O

Procedure:
40 g of the acid chloride ethyl ester of 3,3-dimethylglutaric acid, prepared in Example 28, are dissolved in 400 ml of tetrahydrofuran. 2 g of 5% palladium-on-charcoal and 22.8 ml of 2,6-lutidine are added and the mixture is hydrogenated at normal pressure and room temperature. When the absorption of hydrogen has ceased, the catalyst is filtered off and the solvent is evaporated off under vacuum. The residue is taken up with water and extracted with ether. The ether phase is washed with a dilute solution of hydrochloric acid in the cold, washed with a solution of sodium bicarbonate in the cold, dried over magnesium sulfate and evaporated under vacuum to give, after distillation of the residue, 18 g of ethyl 4-formyl-3,3-dimethylbutanoate in the form of a liquid with a boiling point b.p.20 of 112°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:20]([C:22]1[C:27](F)=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:21]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:27]1[C:22]([C:20]#[N:21])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ncccc1F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of 2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem. Pharm. Bull, 1985, 33, 565-71) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH2:23]([NH:25][CH:26]([CH3:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:23]([N:25]([CH:26]([CH3:35])[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CCNC(C)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C(C)C(=O)c1ccccc1

Procedure:
tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate (6.5 mmol; 2.03 g) is dissolved in 40 ml of anhydrous dimethylformamide and placed under an inert atmosphere, and 2-(ethylamino)propiophenone hydrochloride (1 eq.; 6.5 mmol; 1.39 g), HBTU (1 eq.; 6.5 mmol; 2.47 g) and N-ethyldiisopropylamine (3.5 eq.; 22.75 mmol; 3.97 ml) are then added.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[C:34]([NH:38][C:39]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 49 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.28 g, 1.9 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 ml). After stirring for 1 hour, t-butylisocyanate (0.21 g, 2 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml) and washed with 0.1 N HCl (20 ml), water (20 ml), brine (20 ml) and dried. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol/isopropyl ether to give 0.36 g (51%) of the product: mp 186–188° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 7.77–7.59 (m, 3H), 6.17 (t, J=6.2 Hz, 1H), 5.86 (s, 1H), 508–5.01 (dd, J=5.4 and 12.4 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.82–2.73 (m, 1H), 2.54–2.40 (m, 2H), 1.98–1.94 (m, 1H), 1.12 (s, 9H); 13C NMR (DMSO-d6) δ 172.33, 169.39, 167.11, 166.59, 156.85, 140.72, 134.20, 132.99, 131.06, 126.54, 121.20, 48.69, 48.37, 37.89, 30.46, 28.88, 21.53; Anal. Calcd. For C19H22N4O5+0.2 water: C, 58.51; H, 5.79; N, 14.37. Found: C, 58.86; H, 6.15; N, 14.24.