Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:27][CH2:28][O:29]C1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:27][CH2:28][OH:29])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCOC1CCCCO1
Reactant: Cc1c(C(=O)Nc2cccc(O)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(C(=O)Nc2cccc(OCCO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-(3-hydroxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 31) (0.1 g, 0.29 mmol) in acetonitrile (10 mL) and a couple of drops of DMF, were added 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (0.09 μl, 2 eq) and potassium carbonate (0.08 g, 2 eq). The reaction was heated at 40° C. for 1 week. After evaporation, the residue was dissolved in DCM, washed with water and dried over sodium sulphate. After purification by flash chromatography eluting with DCM/MeOH, 98/2, the crude compound was dissolved in MeOH and some drops of a concentrated HCl solution in AcOEt were added and the solution was stirred at room temperature for 3 hours. After evaporation, the compound was recrystallised (twice) from methanol and washed with a mixture of ether and pentane. The title compound was obtained as a green solid (45 mg, 36%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0804, Rt: 2.87 min. MP: 144.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:4].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]2
Reactant: COC(=O)CC1CCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1CCc2cc(Br)ccc2N1
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution of 2-methoxycarbonylmethyltetrahydroquinoline (31.5 g, 0.153 mol) in DMF (750 mL) was added dropwise a solution of N-bromosuccinimide (27.41 g, 0.154 mol) in DMF (550 mL) at 0° C. The mixture was stirred for 2 h at the same temperature, poured into water (2 L), and extracted with a mixture of toluene and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 44.72 g of the title compound (quant).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O[CH:8]=[N:9][C:10]1[S:18][C:17]2[CH2:16][CH2:15][N:14]([CH2:19][CH3:20])[CH2:13][C:12]=2[C:11]=1[C:21](OCC)=[O:22])C>C(O)C>[OH:2][CH2:1][CH2:3][N:4]1[C:21](=[O:22])[C:11]2[C:12]3[CH2:13][N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][C:17]=3[S:18][C:10]=2[N:9]=[CH:8]1
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Reactant: NCCO
Solvent: CCO
Product: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Yield: 68.3 %

Procedure:
5.0 ml (81 mmol) of ethanolamine were added to 17.0 g (55 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 130 ml of ethanol, and the mixture was boiled at reflux for 2 h. The mixture was then evaporated down to a volume of approx. 50 ml and this was thoroughly stirred in an ice bath. The fine solids which precipitated out were filtered off with suction and then washed with cold ethyl acetate. 10.5 g (63%) of a pale brown product were isolated.
Reaction SMILES: [CH3:1][CH:2]1[CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:1][CH:2]1[CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CCC(C)NC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC1CCn2c(cc3ccc(C(=O)O)cc32)C(=O)N1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
To a solution of ethyl 3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (120 mg, 0.42 mmol) in ethanol (10 mL) is added 1M NaOH solution (1.0 mL, 1.0 mmol). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (3 mL) is and water (60 mL) are added and the mixture is concentrated. The residue is purified by preparative HPLC to afford the title compound (63 mg, 58%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20].CCOCC>CCCCCC.CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To sodium hydride (1.35 g, 56.2 mmol), prewashed in hexane, in 30 ml of DMF is added 4-nitrophenol in 5 ml of DMF at 15°. After anion formation is complete, ethyl N-chloroethylcarbamate (7.12 g, 47.0 mmol) is slowly added. The slurry is heated to 85° and stirred for 17 hours, after which the reaction is cooled to RT, poured into ice water and ether, and extracted with ether. The combined organic layers are washed with 10% sodium hydroxide, with water and with brine, dried and filtered and the solvent is removed by rotoevaporation to give ethyl N-[2-(4-nitrophenoxy)ethyl]carbamate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.ClS([N:19]=[C:20]=O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:28](I)[CH3:29]>CN(C=O)C>[CH2:28]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:12]=2)[C:8]([C:20]#[N:19])=[CH:9]1)[CH3:29]
Reactant: CCI
Reactant: FC(F)(F)Oc1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C#N)c2ccc(OC(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) in dry DMF (10 mL) at 0° C., is added chlorosulfonylisocyanate (2.35 g, 1.44 mL, 16.6 mmol). The mixture is then brought to room temperature slowly and stirred for 1 h. The mixture is poured into ice (100 mL) and stirred for 1 h. The precipitate is collected by filtration and washed thoroughly with water and dried in vacuo, which is then dissolved in DMF (15 mL). To the solution is added K2CO3 and EtI (2.59 g, 1.34 mL, 16.6 mmol), and the mixture is stirred at 50° C. overnight. It is then poured into ice-water (200 mL). The precipitate is collected by filtration and washed with water, dried in air and purified by chromatography (silica gel, DCM) to furnish 1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (2.90 g, 86%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=O.Cl.[NH2:25]N.O.CCOC(C)=O>C(O)C>[NH:25]1[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC(c2ccn[nH]2)C1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of (E)-benzyl 3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate (19 g, 54.05 mmol, 1.00 equiv, 90%) in ethanol (100 mL). To this was added conc.HCl (3 mL, 36%) drop wise and allowed to stir for 10 minutes. Then, to the resulting mixture was added NH2NH2.H2O (60 mL, 80%) and refluxed overnight. The progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the resulting mixture was concentrated on a rotary evaporator and diluted with H2O (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). Combined organic layers were dried over anhydrous magnesium sulfate, filtered off and concentrated on a rotary evaporator affording a residue that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (2:3) to give benzyl 3-(1H-pyrazol-5-yl)piperidine-1-carboxylate as colorless oil (13 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41].CCCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)c2cc(O)ccc2O)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (1.5 mL) was added a mixture of gentisic acid (150 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added IPE/heptane at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.44 g).
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].[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43](O)=[O:44].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([C:35]3[NH:34][C:42]4[C:37]([CH:36]=3)=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5[nH]4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in DMF (30 mL). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.3 g, 2.4 mmol) and indole-2-carboxylic acid (0.4 g, 2.2 mmol) were added. The reaction was initiated by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.0 mmol) and stirred at room temperature overnight. The mixture was poured into cold water (120 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc solution was washed with water (3×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid residue was slurried with hot acetone (20 mL) to give 1H-indole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 70%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.08-2.11 (m, 1H), 2.56-2.65 (m, 2H), 2.85-2.98 (m, 1H), 4.99 (d, J=5.5 Hz, 2H), 5.15-5.22 (dd, J=5.4 and 12.7 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 7.16-7.22 (m, 3H), 7.42 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.75-7.83 (m, 3H), 9.15 (t, J=5.4 Hz, 1H), 11.15 (s, 1H), 11.64 (s, 1H); 13C NMR (DMSO-d6) δ 22.00, 30.34, 37.92, 48.89, 102.95, 112.31, 119.78, 121.54, 121.92, 123.45, 127.04, 127.14, 131.18, 131.57, 133.06, 134.33, 136.54, 139.29, 161.52, 166.97, 167.55, 169.83, 172.75; Anal. calcd. for C23H18N4O5+0.24H2O: C, 63.54; H, 4.28; N, 12.89. Found: C, 63.39; H, 4.38; N, 12.80.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]([CH3:36])=[CH:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:17][C:18]([CH3:36])=[CH:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CC(C)=CCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CC(C)=CCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
137 mg of compound 12 was obtained in a similar manner to those described in the Examples 1 and 2 using 332 mg of ethyl 4-(2-aminophenoxy)butyrate and 200 mg of 3-[1-(3-methyl-2-butenyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([N:12]([CH3:35])[C@H:13]([C:17]([NH:19][C@H:20]([C:32]([NH2:34])=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N:29]([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl.C(NCC)C>[NH2:1][C@H:2]([C:10]([N:12]([CH3:35])[C@H:13]([C:17]([NH:19][C@H:20]([C:32]([NH2:34])=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N:29]([CH3:30])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(N(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(N(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of Fmoc-Phe-N-Me-Val-Tyr(3-NMe2)—NH2 (163 mg, 0.227 mmol) in methylene chloride (1.5 ml), diethylamine (1 ml) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=10:1:0.1) to give the titled compound (91.2 mg, 81%).
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:1][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C=CCCCC
Reactant: C1=CCCC=CCC1
Product: C=CCCC=CCCC=CCCCC

Procedure:
disproportionating 1,5-cyclooctadiene and 1-hexene in the presence of a disproportionation catalyst under disproportionation conditions suitable to give 1,5,9-tetradecatriene,
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(Cc2ccccc2)nc1C#N
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCN(CC)c1nc(C#N)c(C#N)nc1Cc1ccccc1
Yield: 75.5 %

Procedure:
2,3-Dicyano-5-chloro-6-benzylpyrazine (1.27 g; 0.005 mole) was dissolved in 30 ml of benzene, and the solution was cooled to 5° to 10° C. With stirring, the mixture was worked up in the same way as in Example 13 using 0.80 g (0.01 mole) of diethylamine. Recrystallization from ethanol afforded 1.10 g (yield 75%) of 2,3-dicyano-5-diethylamino-6-benzylpyrazine.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:25][CH:26]=3)=[O:15])=[C:9]([C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:37]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C[NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([O:76]C(C)(C)C)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:30]=[C:28]([NH:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])[CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:20][CH2:19][C:18]2[CH:31]=[CH:32][CH:33]=[C:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][C:9]=3[C:34](=[O:51])[NH:35][C:36]3[CH:40]=[CH:39][N:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[N:37]=3)[CH:17]=2)[CH:22]=1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCOCCOCCOCCNC(=O)Cc1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
Into a round bottom flask was placed a solution of 2-(3-((3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzyl)thio)-phenyl)acetic acid 23 (0.119 mmol, 1 equiv) in acetonitrile (0.5 mL), and DIPEA (78.9 mg, 0.612 mmol, 4 equiv). To this was added a solution of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (33.08 mg, 0.127 mmol, 1.1 equiv) in acetonitrile (0.5 mL), followed by HATU (57.9 mg, 0.153 mmol, 1.2 equiv). The mixture was stirred at room temperature. The reaction progress was monitored by LCMS. After 1 h, more 8b (15 mg) was added to the solution, and the solution was stirred another 30 min. The solvent was removed by evaporation at reduced pressure. The residue was dissolved in DCM (1 mL). To this was added TFA (0.5 mL). The solution was stirred for 1 h and then the solvent was evaporated at reduced pressure. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. Lyophilization gave 37 mg of product. 1H NMR (400 MHz, dmso) δ 11.55 (s, 1H), 11.46 (s, 1H), 8.65 (d, J=2.6 Hz, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.05 (t, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.78-7.67 (m, 3H), 7.61 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.4 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.22 (s, 1H), 7.17 (d, J=4.9 Hz, 3H), 7.01 (s, 3H), 4.30 (s, 3H), 3.54 (t, J=6.4 Hz, 4H), 3.43 (s, 14H), 3.41-3.16 (m, 15H), 3.16-3.09 (m, 3H), 2.39 (t, J=6.4 Hz, 3H), 1.76-1.66 (m, 4H), 1.61-1.52 (m, 2H). MS (ES, m/z) 917 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:22][N:23]([CH2:34][CH:39]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH:33][C:17](=[O:19])[CH:16]=[CH:15][C:12]3[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)C=Cc4ccc(C(F)(F)F)cc4)ccc3o2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.3 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of 3-(4-trifluoromethyl-phenyl)-acrylic acid (0.249 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 3-(4-trifluoromethyl-phenyl)-acryloyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.06 mL) in CH2Cl2 (5.0 mL). Shake the reaction mixture overnight at room temperature. Filter the reaction mixture and wash the product with CH2Cl2. Dry the product on high vacuum to yield the desired product as an off-white solid (0.321 g, 91%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CD3OD): δ 8.93-8.89 (m, 1H), 8.71 (dt, J=8.0, 1.8 Hz, 1H), 8.17-8.13 (m, 1H), 7.85-7.72 (m, 4H), 7.55 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 1.8 Hz, 1H), 6.94 (d, J=15.8 Hz, 1H), 4.57-4.47 (m, 1H), 3.75-3.67 (m, 2H), 3.36-3.29 (m, 2H), 3.28 (s, 3H), 2.96 (s, 3H), 2.41-2.28 (m, 2H), 2.27-2.18 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][NH:13][N:14]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:23][CH2:24][F:25])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1nn[nH]n1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nnn(CCF)n1
Reaction time: 0.25 h

Procedure:
To a solution of [2-(2H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester 0.45 g, 2.11 mmol) in dry DMF (14 ml) was suspended Cs2CO3 (0.825 g, 2.53 mmol) and the reaction mixture stirred for 15 minutes. 1-Bromo-2-fluoroethane (0.63 ml, 8.44 mmol) was added and the reaction mixture stirred at ambient temperature for 5 hours. The reaction mixture was filtered and the DMF evaporated to afford the crude product as a brown oil. The crude material was absorbed onto silica and purified by silica chromatography eluting with a gradient of 3:1 to 2:1 Ethylacetate:hexane to afford the titled product as a colorless oil.
Reaction SMILES: O.[O:2]=[CH:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:14][C:15]1[CH:20]=CC(S(O)(=O)=O)=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH2:17]([O:2][CH:3]([O:13][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]([Cl:7])([Cl:6])[Cl:5])[CH2:16][CH:15]([CH3:20])[CH3:14]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CCO
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCOC(OCCC(C)C)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral-hydrate, 10 g of isoamyl-alcohol, 0.1 g of 4-methyl-benzene-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. After a reaction time of 9 hours the benzene is washed with a sodium-hydrogen-carbonate solution and water, dried on magnesium sulfate, then vacuum distilled.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](SC)=[N:7][C:8]#[N:9]>C(#N)C>[C:8]([N:7]=[C:6]([N:2]([CH3:1])[NH2:3])[S:5][CH3:4])#[N:9]
Reactant: CNN
Reactant: CSC(=NC#N)SC
Solvent: CC#N
Product: CSC(=NC#N)N(C)N
Reaction time: 16 h

Procedure:
A mixture of methyl hydrazine (0.48 ml) and cyanocarbonimidodithioic acid dimethyl ester (1.3 g) in acetonitrile was stirred at 25° for 16 hours. The resulting solution was evaporated to a gum which was crystallized from acetonitrile/ether to give the title compound as colourless granules (210 mg) m.p. 69°-71°.