Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5]1([C:11]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(OCC)(=O)C>[C:15]1([C:13]([C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=C(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 78 %

Procedure:
While the temperature is maintained at from 2° C. to 25° C., 16 g of the composition prepared as in Example 8 are added in small fractions over a period of 15 minutes to 35 ml of dimethyl sulfoxide containing 4.8 g of benzoin. After 2 hours, agitation at ambient temperature, the medium is poured into 200 ml of water and 60 ml of ethyl acetate. The precipitate formed is eliminated and the organic phase is concentrated under vacuum. The solid residue is recrystallised from 20 ml of ethanol. Benzil is obtained with a yield of 78%.
Reaction SMILES: S(=O)(=O)(O)O.O.[O:7]=[C:8]1[CH:17]([NH:18]C(=O)C)[CH2:16][C:15]2[C:10](=[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:12]=[CH:13][CH:14]=2)[N:9]1[CH2:28][C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.[OH-].[Na+]>C(OCC)(=O)C>[NH2:18][CH:17]1[CH2:16][C:15]2[C:10](=[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[C:8]1=[O:7]
Reactant: CC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 86 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Sulfuric acid (470.6 mL) was added to water (5.65 L) at room temperature, and N-(2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (561.5 g) was added thereto at an internal temperature of 41-43° C. The mixture was heated at an internal temperature of 80 to 92° C. for four hours while being stirred. Under cooling on ice, 25% sodium hydroxide (2,715 g) was added dropwise to the reaction mixture at an internal temperature of 50° C. or lower, to thereby adjust the pH of the mixture to 7. Ethyl acetate (1.0 L) was added to the resultant mixture while being stirred, and 25% sodium hydroxide (300 g) was added thereto at an internal temperature of 50° C. or lower, to thereby adjust the pH of the mixture to 10. An additional ethyl acetate (1.83 L) was added to the mixture, and stirring was performed for five minutes, to thereby partition the mixture. Ethyl acetate (2.83 L) was added to the aqueous layer at an internal temperature of 30° C. or lower, and stirring was performed for five minutes, to thereby partition the mixture. An additional ethyl acetate (2.83 L) was added to the aqueous layer, and the above-described extraction procedure was repeated. The ethyl acetate layers were combined, and the combined ethyl acetate layer was concentrated under reduced pressure, to thereby evaporate ethyl acetate (6.8 L). The reaction mixture was left to stand overnight in a refrigerator, and the crystals that precipitated were recovered through filtration. The thus-recovered crystals were washed with ethyl acetate (566 mL). The thus-obtained solid was dried in air overnight and then at 60° C. under reduced pressure, whereby the title compound (389.2 g) was yielded as pale yellow crystals.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[N:7]#[C:8][NH2:9]>>[O:5]=[C:4]([CH2:3][N:1]([C:8](=[NH:7])[NH2:9])[CH3:2])[OH:6].[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:8](=[NH:7])[NH2:9])[CH3:2])[OH:6]
Reactant: CNCC(=O)O
Reactant: N#CN
Product: CN(CC(=O)O)C(=N)N
Product: O

Procedure:
DE 199 20 962 A1 concerns the adjustment of the pH of a sarcosine-containing solution by bipolar electrodialysis. In this process the solution that is prepared is preferably adjusted to a pH of 9 to 10 and can subsequently be reacted with cyanamide to form creatine or creatine monohydrate.
Reaction SMILES: C([O:5][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[CH2:7][C@H:8]([NH:11][C:12](=[O:33])[C@H:13]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:14][C:15](=[O:28])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH:9]=[O:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]1([NH:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[OH:5])=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.4 %

Procedure:
To a solution of (3S)-3-[N-((1-naphthylamino)acetyl)leucinyl]amino-4-oxobutanoic acid tert-butyl ester semicarbazone (0.201 g, 0.38 mmol) in CH2Cl2(2.0 mL)-anisole(0.5 mL) at room temperature under nitrogen was added trifluoroacetic acid (2.0 mL). The resulting solution was stirred at room temperature for 5 hrs, evaporated to dryness and chased with CH2Cl2 and toluene-CH2Cl2 (1:1). The resulting solid was triturated with CH2Cl2—Et2O to give the title compound (0.176 g, 98%) as a pale gray solid. TLC(EtOAc-pyridine-AcOH—H2O; 60:20:5:10) Rf=0.45.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Br)(=O)C([Br:49])=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:10]1[Br:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
2,3,4,6-Tetra-O-benzyl-D-glucopyranose (1.0 g, 1.9 mmol) was dissolved in anhydrous DCM (6 mL) and anhydrous DMF (0.4 mL) under argon. The resulting solution was stirred at 0° C. Oxalyl bromide (4 mL, 2M in DCM, 24 mmol) was added dropwise over a 5 min period . The reaction was stirred at RT. After a 40 min period, t.l.c. (petrol:ethyl acetate, 2:1) indicated the formation of a major product (Rf 0.7). The reaction was cooled to 0° C. and quenched with ice cold water (30 mL) added over a 5 min period. The reaction was partitioned between DCM (20 mL) and water. The aqueous layer was re-extracted with DCM (3×20 mL), the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title product (1.10 g, 95%) as a crude yellow oil; δH (400 MHz, CDCl3), 3.57 (1H, dd, J1,2 3.5 Hz, J2,3 9.1 Hz, H-2), 3.68 (1H, dd, J5,6 2.1 Hz, J6,6′ 11.0 Hz, H-6), 3.79-3.84 (2H, m, H-4, H-6′), 4.07 (1H, at, J9.1 Hz, H-3), 4.07-4.11 (1H, m, H-5), 4.47-4.62 (3H, m, PhCH2), 4.74 (s, 2H, PhCH2), 4.84-4.89 (2H, m, PhCH2), 5.10 (1H, d, J11.1 Hz, PhCH2), 6.46 (1H, d, H-1), 7.15-7.41 (20H, m, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:3]=12>C(O)(C(F)(F)F)=O.ClCCl>[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=2)=[CH:25][CH:24]=1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CCC(n3nc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 10.8 %

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-amine (850 mg, 1.93 mmol), tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate (1.25 equiv., 812 mg, 2.41 mmol), tetrakis-(triphenylphosphine)palladium (135 mg) and sodium carbonate (2.5 equiv., 511 mg, 4.83 mmol) in degassed water (10 mL) and DME (30 mL) was heated and stirred at 85° C. for 16 h. The solvent was removed under reduced pressure to give a brown foam which was purified by column chromatography over silica gel using 10% methanol and 1% ammonium hydroxide in dichloromethane as the eluent. Trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)carbamate was formed as an off white foam (800 mg, 80%). A solution of tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)carbamate (800 mg) in TFA (4 mL) and dichloromethane (4 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the oily residue was basified with saturated aqueous sodium hydrogen carbonate solution and the aqueous layer washed with dichloromethane (3×20 mL). The aqueous layer was concentrated and DMF added (20 mL). The salts were removed by filtration and the DMF was removed in vacuo. The residue was purified by column chromatography over silica gel using 10% methanol in dichloromethane as the eluent to afford 3-[4-(aminomethyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (70 mg, 11%). m-Tolyl isocyanate (1.1 equiv., 13.7 mg, 0.1 mmol) was added to a solution of 3-[4-(aminomethyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (35 mg, 0.083 mmol) in pyridine (0.5 mL) and then stirred for 2 days. The reaction mixture was purified using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5 μm, 100×21.2 mm column; 0-100% acetonitrile and 0.05M ammonium acetate, buffered to pH 4.5, over 12.5 min at 25 mL/min) to give trans-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzyl)-N′-(3-methylphenyl)urea (17 mg, 37%); 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (2H, m), 2.05 (4H, m), 2.18 (2H, m), 2.25 (3H, s), 2.33 (4H, m), 2.45-2.53 (8H, m), 4.38 (2H, br d), 4.65 (1H, m), 6.52 (1H, t), 6.66 (1H, d), 7.10 (1H, t), 7.19 (1H, brd), 7.26(1H, br s), 7.46(2H, d), 7.63 (2H, d), 8.23 (1H, s) and 8.51 (1H, s) and m/z (MH+) 554.2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[C:36]([N+]([O-])=O)[CH:35]=[CH:34][N:33]=1>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:36]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[CH:37]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (973.5 mg, 0.002699 mol) in DMF (8.00 mL, 0.103 mol) was added NaH (202 mg, 0.00504 mol) (60% in oil). After stirring the mixture for 10 minutes, 2-chloro-4-nitro-pyridine (400.0 mg, 0.00252 mol) was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with (3×50 ml EtOAc). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain the title compound (0.9859 g, 83%) as a clear oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:37])[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)c1ccc(O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)cc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 63% purity by HPLC. MS (ESI+): m/z=474.4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][CH3:35])=[O:38])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution containing the product from Example 23Q (0.442 g, 0.95 mmol) in THF (10 mL) was treated with the product from Example 1F (0.20 g, 1.06 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.88 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-75% ethyl acetate/dichloromethane to give the title compound (0.34 g, 56% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH:23]1[C:33]2[CH:32]=[CH:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH:31]=[CH:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2,4-bis(1,1-dimethylethoxy)pyrimidine (50 g) in dry tetrahydrofuran (11) at -78° C. was added n-butyllithium (69 ml of a 2.5M solution in hexanes) dropwise. After 0.5 hours, a solution of 5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) was added. The reaction mixture was stirred at -78° C. for three hours and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (400 ml) was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give the crude 5-(2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol which was used directly.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:13])[N:7]([NH2:12])[C:8]([SH:11])=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14]I>[OH-].[Na+].CO>[C:1]([C:5]1[C:6](=[O:13])[N:7]([NH2:12])[C:8]([S:11][CH3:14])=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 20 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
4 parts by weight of 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one are dissolved in a mixture of 11 parts by weight of 2-normal sodium hydroxide and 4 parts by weight of methanol and the solution is treated at 0° C with 3.2 parts by weight of methyl iodide. The reaction mixture is then stirred for a further 4 hours at 20° C. The reaction product crystallizes out and is filtered off, dried and recrystallized from benzene. 3.52 parts by weight of 6-tert.-butyl-3-methylthio-4-amino-1,2,4-triazin-5(4H)-one of melting point 126°-127° C are obtained Yield: 82% of theory.
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[C:13]1([CH2:19][CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)[CH:28]=[O:29]>CCCCCC.O1CCCC1>[C:13]1([CH2:19][CH2:20][N:21]2[C:25]([CH:28]=[O:29])=[N:24][CH:23]=[N:22]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CCn2cncn2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1ncnn1CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexane (119 ml) was added dropwise at -70° C. under nitrogen to a solution of N-(1-methylethyl)-2-propanamine (26.7 ml) in tetrahydrofuran (280 ml) and the mixture was stirred for 30 minutes. 1-(2-phenylethyl)-1,2,4-triazole (0.173 mol) in tetrahydrofuran (20 ml) was added and the mixture was stirred at -70° C. for 1 hour. N,N-dimethylformamide (17.4 ml) was added dropwise and the mixture was stirred at -70° C. for 1 hour and then at room temperarure for 2 hours. The mixture was poured into ice water and extracted with 1,1'-oxybisethane. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (11.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 99/1/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 7g (40%) of 2-(2-phenylethyl)-2H-1,2,4-triazole-3-carboxaldehyde (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH:10]3[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[N:22]=[C:23]2[C:29]([N:30]=[C:31]=[O:32])=[C:28]([C:33](OCC)=[O:34])[S:27][C:24]2=[N:25][CH:26]=1>>[ClH:20].[ClH:20].[CH3:1][O:2][C:3]1[C:8]2[N:9]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[C:33](=[O:34])[C:28]5[S:27][C:24]6[N:25]=[CH:26][C:21]([Cl:20])=[N:22][C:23]=6[C:29]=5[NH:30][C:31]4=[O:32])[CH2:13][CH:10]3[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1N1CCN(CCN)CC1CO2
Reactant: CCOC(=O)c1sc2ncc(Cl)nc2c1N=C=O
Product: COc1cccc2c1N1CCN(CCn3c(=O)[nH]c4c(sc5ncc(Cl)nc54)c3=O)CC1CO2
Product: Cl

Procedure:
The product from Example 13A and the product from Example 8D were processed as described in Example 1L to provide the title compound. mp 280-282° C.; [α]23D−20.9° (c 1.15,DMSO); 1H NMR (300 MHz, DMSO-d6) δ2.95-3.80 (m, 7H), 3.80 (s, 3H), 3.86-4.75 (m,6H), 6.44-6.95 (m, 3H), 9.03 (s, 1H), 10.80 (bs, 1H), 13.03 (s, 1H); MS (DCI/NH3) m/e 501 (M+H)+; Anal. calcd for C22H21N6O4SCl.2.4 HCl: C, 44.90; H, 4.01; N, 14.28. Found: C, 44.91; H, 3.70; N, 14.16.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 84.3 %

Procedure:
To a solution of (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (51.8 g, 213 mmol) in acetonitrile (400 mL) was added ethyl 2-bromoacetate (38.2 mL, 345 mmol) and triethylamine (70 mL, 506 mmol). The mixture was heated at reflux for 5 h, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (52.7 g, 85% yield). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=8.5, 5.5 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.16-3.27 (m, 1H), 3.03 (d, J=11.5 Hz, 2H), 2.43 (td, J=11.2, 3.3 Hz, 2H), 1.81-2.09 (m, 4H), 1.51-1.73 (m, 2H), 1.30 (t, J=7.3 Hz, 3H). MS m/z 294.4 (M+1), retention time=1.94 min.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C[CH2:19][N:20](CC)CC.C(OCC)(OCC)OCC.C(N)C(C)C>C1COCC1>[NH2:15][C:14]1[N:20]([CH2:6][CH:1]([CH3:2])[CH3:11])[CH:19]=[N:12][C:13]=1[C:16]#[N:17]
Reactant: CCN(CC)CC
Reactant: N#CC(N)C#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CN
Solvent: CCOC(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)Cn1cnc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a suspension of aminomalononitrile p-toluenesulfonate (1 g, 4.0 mmol, 1 equiv) in THF (30 mL) at 25° C. was added NEt3 (0.65 mL, 4.8 mmol, 1.2 equiv) in one portion. The mixture was stirred for 30 min to afford a homogeneous solution. To this solution was added triethyl orthoformate (0.80 mL, 4.8 mmol, 1.2 equiv) and the solution was heated at reflux for 3 h. TLC indicated the presence of starting material and additional triethyl orthoformate (0.4 mL, 2.4 mmol, 0.6 equiv) was added. The solution was heated at reflux for another 2 h then cooled to 25° C. NEt3 (0.65 mL, 4.8 mmol, 1.2 equiv) and isobutylamine (350 mg, 4.8 mmol, 1.2 equiv) were added sequentially and the reaction was stirred at 25° C. for 15 h. The reaction was concentrated in vacuo and the crude residue was redissolved in CH2Cl2 (100 mL) and washed with saturated Na2CO3 solution (25 mL) The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic fractions were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound (426 mg, 65%) as a light yellow solid: 1H NMR (CDCl3, 600 Hz) δ 0.96 (d, J=6.6 Hz, 6H), 2.01-2.07 (m, 1H), 3.57 (d, J=7.8 Hz, 2H), 3.94 (br s, 2H), 7.05 (s, 1H); 13C NMR (CDCl3, 150 Hz) δ 19.8, 28.9, 51.6, 115.7, 116.5, 133.5, 144.8; MS (ESI+): calcd C8H13N4 [M+H]+ 165.1. found 165.1.