Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:26][CH2:27][CH2:28][CH2:29][CH3:30])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:33])[C@:7]1([CH3:32])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:31])[CH:9]=[CH:8]1)(=O)C>CO.O1CCCC1>[CH2:27]([S:26][C:19]1([S:23][CH2:24][CH3:25])[CH2:18][CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:33])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:32])[C:12](=[CH:11][C:10](=[O:31])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Solvent: CO
Solvent: C1CCOC1
Product: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 102.8 %

Procedure:
11β-Acetyloxy-17-(butylthio)-17-(ethylthio)-9-fluoroandrosta-1,4-diene-3-one (925 mg) is dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml). The solution is stirred, purged with nitrogen and 3.0 M sodium hydroxide (3.0 ml) is added. After 2 hours a slight excess of acetic acid is added and the mixture is then concentrated in vacuo. It is diluted with water (150 ml) and extracted with chloroform. The chloroform extract is washed with water, dried (MgSO4 anh.) and evaporated to afford the title compound (870 mg). Examinations of the nmr spectrum and tlc behavior of this compound show the presence of some 17-(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4,16-triene-3-one and two 17-stereoisomers of the title compound. The material is applied on four 2.0 mm Merck silica gel plates and the plates are developed twice with chloroform-ethyl acetate (7:3). The products from the upper 1/3 and lower 2/3 of the broad band are isolated separately by extraction with chloroform-methanol (3:1 ) to afford respectively 340 and 527 mg of solids. One crystallization of the 340 mg of solid from ethyl acetate-hexane (1:1) and drying (100° C., 0.3 mm of Hg, 20 hours) gives the analytical specimen of the title compound (281 mg) melting point 118°-125° C. with consistent spectral data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(=O)([O-])[O-].[Na+].[Na+].[C:36]([CH2:39][C:40]1C=CC(B(O)O)=[CH:42][CH:41]=1)(O)=O.[C:49]([O:52][CH2:53]C)(=[O:51])[CH3:50]>C1(C)C=CC=CC=1.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>[CH3:53][O:52][C:49]([C:50]1[CH:42]=[CH:41][C:40]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:39][CH:36]=1)=[O:51]
Reactant: O=C(O)Cc1ccc(B(O)O)cc1
Reactant: CCOC(C)=O
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
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
Product: COC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1

Procedure:
Dissolve trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl ester (5 g, 10.54 mmol) in 50 mL toluene, add aqueous 2 M sodium carbonate and evacuate/purge with nitrogen 3 times. Add p-carboxymethylphenylboronic acid (2.85 g, 15.81 mmol), degas again, then add Pd(PPh3)4 (1.22 g, 1.05 mmol). Degass/purge one more time then reflux overnight. Separate layers, wash the organic layer with water twice, then wash with brine. Dry over sodium sulfate, filter and concentrate under vacuum to yield a brown foam. Add ethyl acetate to get a tan solid and filter to get 3.8 g product. Concentrate the filtrate to recover 0.4 g more product after purification via silica gel chromatography using 25% ethyl acetate: MS (m/z): 460 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@H:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:19][C:20]([C:22]2[N:23]([CH3:31])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[O:12])[C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CN1CCOCC1>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:8]([C@@H:7]([NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:19][C:20]([C:22]1[N:23]([CH3:31])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:12])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:33][CH:32]=1)#[N:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(N)cc2)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(NS(C)(=O)=O)cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To 62 mg (0.14 mmol) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-(4-amino-benzyl)cyano-methyl]-carbamoyl}cyclohexyl)-amide dissolved in 1 mL DMF was added 16 mg (0.14 mmol) of methanesulfonyl chloride, 2 mg (0.014 mmol) of 4-dimethylaminopyridine, and 0.031 mL (0.28 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate, and concentrated. Reverse phase column chromatography was employed to separate the pure title compound from the unreacted starting material, and provided 10 mg of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-methanesulfonylamino-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide. HPLC: 100% pure, yield: 14%, MS: 522 (M+H+).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].I[CH3:14].Cl>CN(C=O)C.O.CCOC(C)=O>[CH3:14][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10]
Reactant: OCc1ccccc1CO
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccccc1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2-benzenedimethanol (1.38 g, 10 mmol) in DMF (10 mL) cooled in an ice bath is added NaH (400 mg, 60% in mineral oil, 10 mmol) in portions. The mixture is stirred at 0° C. for 15 min then at RT for 30 min. To this is added iodomethane (1.45 g, 10.2 mmol) dropwise and the mixture is stirred at RT for 1 h. Ice, EtOAc and water is added and the mixture is acidified with 1N HCl. The organic phase is washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13]O)[O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[C:41]1([C@H:47]([NH2:49])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClC(Cl)C.O>[ClH:21].[Cl:21][C:22]1[S:26][C:25]([S:27]([N:2]([CH3:1])[C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:49][C@@H:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH3:48])[O:10]3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CNc1ccc2c(c1)OC(CO)CC2
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: O
Product: C[C@@H](NCC1CCc2ccc(N(C)S(=O)(=O)c3ccc(Cl)s3)cc2O1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A solution of [7-(methylamino)-3,4-dihydro-2H-chromen-2-yl]methanol (386 mg; 2.00 mmol) and pyridine (0.8 mL; 10 mmol) in dichloroethane is treated with 5-chlorothiophene-2-sulfonyl chloride (477 mg, 2.2 mmol), stirred at ambient temperature for 1 h, treated with pyridine (0.8 mL; 10 mmol) and benzenesulfonyl chloride (1.0 mL; 8 mmol), heated at 60° C. with stirring for 2 h, poured into water and extracted with ethyl ether. The combined extracts are washed successively with dilute aqueous HCl and saturated aqueous solution of sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The resultant residue is treated with (1R)-1-phenyl-1-ethanamine (2.6 mL; 20 mmol) at 100° C. with stirring for 2 h, cooled to ambient temperature, poured into water and extracted with ethyl ether. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by column chromatography (silica gel, 1% methanol in methylene chloride) to afford the free base of the title product as a clear oil (525 mg, 55% yield). Treatment with an ethereal solution of HCl gives the title product as a white crystalline powder, mp 236° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]Cl)([O-:14])=[O:13]>C(OCC)C>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: N#Cc1ccc2cc[nH]c2c1
Solvent: CCOCC
Product: N#Cc1ccc2c(Sc3ccccc3[N+](=O)[O-])c[nH]c2c1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 1H-indole-6-carbonitrile (1.00 g, 7.04 mmol) in diethyl ether (50 mL) was added at rt 2-nitrobenzenesulfenyl chloride (1.34 g, 7.04 mmol) and the reaction mixture was stirred for 18 hrs. The mixture was concentrated and the crude product was purified using column chromatography (ethyl acetate/heptane 1:4→4:1) to give 3-(2-Nitro-phenylsulfanyl)-1H-indole-6-carbonitrile (1.62 g, 5.49 mmol, 78%).
Reaction SMILES: [I:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=O.[F:9][C:10]([F:21])([F:20])[CH:11]([F:19])[C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14].[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>ClCCl>[F:21][C:10]([F:9])([F:20])[CH:11]([F:19])[C:12]([F:17])([F:18])[S:13]([O-:16])(=[O:14])=[O:15].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([I+:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=Ic1ccccc1
Reactant: CC(C)(C)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc([I+]c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Temperature: 0 °C

Procedure:
4.4 g (20 mmol) of iodosylbenzene was suspended in 100 ml of dry dichloromethane. The suspension was cooled to 0° C. with stirring. 4.65 g (20 mmol) of 3,3,3,2,1,1-hexafluoropropane sulfonic acid (optionally distilled) was added at the same temperature thereto under exclusion of moisture. The mixture was stirred at room temperature for 3 hours. The temperature of the mixture was returned to 0° C., and 2.68 g (20 mmol) of 4-t-butylbenzene was added thereto at that temperature. The temperature of the mixture was returned to room temperature, followed by stirring for 6 hours. Thereafter, the insolubles were removed by filtration. The solvent was removed from the filtrate. The oily residue was purified by recrystallization (twice) from diethyl ether. The structure was confirmed by 1H-NMR (CDCl3): δ=0.81 (s, 9H), 4.98-5.22 (m[d], 1H), 7.18-7.23 (d, 2H), 7.58-7.65 ppm (m, 7H).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][C:13]1[C:18]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1.ICCCCCCI>O.C(COC)OC>[Cl:12][C:13]1[C:18]([C:19]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Reactant: CCCCCC
Agent: ICCCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cccnc2Cl)CCCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.62 ml, 0.966 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (146 mg, 0.483 mmol) obtained in Example 98. At −78° C., the resulting mixture was stirred for 20 minutes, followed by the addition of 1,6-diiodohexane (0.095 ml, 0.580 mmol). The temperature of the reaction mixture was gradually raised to room temperature, at which stirring was performed for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to yield the title compound (60 mg, 32%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1cccc(F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
6-Fluoro-2-pyridinecarboxylic acid (available from Asymchem Laboratories, 570 mg, 4.0 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1531 mg, 4.0 mmol) were dissolved in DMF (15 ml) and treated with DIPEA (2.11 ml). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (500 mg, 2.0 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The mixture was concentrated in vacuo to give an orange oil. DCM (5 ml) was added and the resultant precipitate was collected by filtration to give the title compound (235 mg) as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])(=O)=O.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:6][CH2:7][N:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)N(C)CCOS(C)(=O)=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: CCOC(=O)N(C)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 0.23 g of 2-(N-ethoxycarbonyl-N-methylamino)ethyl methanesulfonate (prepared as described in Preparation 34') and 0.26 g of 4-diphenylmethylpiperazine was stirred at 80° C. for 5 hours. At the end of this time, the mixture was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 0.25 g (yield 64%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.C[O:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18](OC)OC.S(=O)(=O)(O)O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:18]=[C:17]2[CH2:16][C:15]([OH:23])=[O:14]
Reactant: COC(=O)CCC(OC)OC
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 1.6 %

Procedure:
A mixture of 4-trifluoromethylphenylhydrazine (5 g), 4,4-dimethoxybutyric acid methyl ester (6 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 90° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained residue, and the mixture was heated to reflux for one hour. Water was added to the reaction mixture which was then rendered acidic with concentrated aqueous hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane, methanol, and acetic acid to obtain 0.11 g of the title compound as a colorless powder (1.5% yield).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[BH3-]C#N.[Na+].[CH3:23][C:24](O)=O>CC#N.O>[CH2:23]([N:4]([CH2:1][CH3:2])[C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:7]([CH:6]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:24]
Reactant: CC=O
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Acetaldehyde (1.07 ml, 0.8 g, 19.12 mmol, 8 eq) was added to a stirred solution of dimethyl 5-aminoisophthalate (0.500 g, 2.39 mmol, 1 eq) in CH3CN (15 ml) and water (0.5 ml) at 0° C. After 10 min NaBH3CN (0.395 g, 5.98 mmol, 2.5 eq) was added. The reaction was adjusted to pH {tilde over ( )} 7 with HOAc. After 1.5 h the reaction was adjusted to pH {tilde over ( )} 7 with HOAc a second time. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.575 g (2.17 mmol, 91% yield) of the product.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:15])[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 4.48 g. diethylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was diluted with petroleum ether (b.p. 40° - 60°C.), causing the deposition of an oil which gradually solidified. The solid product was collected and recrystallized from a mixture of ether and petroleum ether (b.p. 40° - 60°C.) to give 1-diethylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50.5° - 51.5°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])[N:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=O)[nH]n1
Reactant: CC(Br)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C=O)nn1C(C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a mixture of 5-formylpyrazole-3-carboxylic acid ethyl ester (5.42 g) and anhydrous dimethyl formamide (80 ml), 1.41 g of 60% sodium hydride oil suspension were added at 0° C. After 30 minutes, 6.30 g of 2-(1-bromoethyl)pyridine were added at 0° C. The mixture was stirred overnight at room temperature and 120 ml of water was added thereto. The mixture was extracted with ethyl acetate (3×300 ml). The combined organic solution was dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 2/1) to afford 4.0 g of 3-formyl-1-(1-(2-pyridinyl)ethyl)pyrazole-5-carboxylic acid ethyl ester as a viscous oil. NMR: 1.33 (t, 3H), 2.01 (d, 3H), 4.29 (m, 2H), 6.73 (q, 1H), 7.40 (s, 1H, 4-pyrazolyl H) 7.06, 7.19, 7.63, 8.57 (4 m, 4H, pyridyl H's), 10.04 (s, 1H, CHO). Also obtained was 535 mg of 5-formyl-1-(1-(2-pyridyl)ethyl)pyrazole-3-carboxylic acid ethyl ester as a viscous oil. NMR: 1.41 (t, 3H), 2.05 (d, 3H), 4.42 (q, 2H), 5.51 (q, 1H), 7.46 (s, 1H, 4-pyrazolyl H), 7.07, 7.17, 7.61, 8.54 (4 m, 4H, pyridyl H's), 9.88 (s, 1H, CHO).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20]>C1C(O)=CC=CC=1C>[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=1)=[NH:20]
Reactant: CN(C)C#N
Reactant: CSc1cccc(-c2ccccc2N)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CSc1cccc(-c2ccccc2NC(=N)N(C)C)c1

Procedure:
A mixture of 2-amino-3'-methylthiobiphenyl hydrochloride (3.3 g), N,N-dimethylcyanamide (1.55 ml) and m-cresol (10 ml) was heated at 90°-95° C. for 14 hours to give N,N-dimethyl-N'-(3'-methylthio-2-biphenylyl)guanidine (m.p. 94°-95° C.) which was recrystallised from hexane.
Reaction SMILES: C([N:3](CC)[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6]N)C.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][CH2:6][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][NH2:3])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using tert-butylamine LC/MS (M+H)+: 283. HPLC ret. time (Condition B): 2.202 min.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[N:7]3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CCOC(=O)c1c(C)nc2cccc(Cl)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2cccc(NCCc3ccc(N)cc3)n12
Yield: 75.5 %

Procedure:
A mixture of 4.07 g (17.1 mmol) of 5-chloro-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine, 3.48 g (25.6 mmol) of 2-(4-aminophenyl)ethylamine and 4.41 g (34.1 mmol) of N,N-diisopropylethylamine in 60 ml of acetonitrile was heated for 64 hours under reflux with stirring. After cooling, the solvent was distilled off. To the residue was added chloroform. The residue was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=30:1) and recrystallized from ethyl acetate-n-hexane to give 4.37 g of the desired compound (75.7%, pale brown crystals).