Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:36])[NH:21][C@@H:22]([C:30]1[O:34][N:33]=[C:32]([CH3:35])[N:31]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:30]1[O:34][N:33]=[C:32]([CH3:35])[N:31]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:36]
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reaction time: 3 h

Procedure:
{(1R)-1-{(1R)-1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (4.5 g, 8.99 mmol) was suspended in ethyl acetate (50 ml) and a saturated mixture of hydrogen chloride in ethyl acetate (45 ml) was added. After 3 h at 20° C., the reaction mixture was filtered to give 3.17 g of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:7]1)C.[OH-].[K+].O>CO>[CH:6]1([CH2:5][C:4]([OH:18])=[O:3])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:7]1
Reactant: CCOC(=O)CC1Cc2cccc3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1Cc2cccc3cccc1c23

Procedure:
The ester obtained in Step C (1.9 g, 7.91.10−3 mol) is heated at reflux in the presence of potassium hydroxide (2.34 g, 4.17.10−2 mol, 5.3 eq.), water (16 ml) and methanol (16 ml) for one night. After evaporating off the solvent, the residue is taken up in water and extracted twice with ether. The basic aqueous phase is acidified using concentrated HCl in the cold state. The acid is extracted with ethyl acetate and dried over MgSO4. After evaporating off the solvent under reduced pressure, the title compound is obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:37])([C:7]1([O:32][Si](C)(C)C)[C:19]2[N:18](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]3[C:12](=[CH:13][C:14]([C:30]#[N:31])=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1)[C:3]([F:6])([F:5])[F:4].[OH-].[K+]>C1COCC1.O>[OH:32][C:7]1([C:2]([F:37])([F:1])[C:3]([F:4])([F:5])[F:6])[C:19]2[NH:18][C:17]3[C:12](=[CH:13][C:14]([C:30]#[N:31])=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3(O[Si](C)(C)C)C(F)(F)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3(O)C(F)(F)C(F)(F)F
Yield: 40.4 %

Procedure:
To a solution of 1-(perfluoroethyl)-9-tosyl-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (180 mg, 0.3 mmol) in THF (5 mL), KOH (90 mg, 1.6 mmol) in H2O (1 mL) was added. The reaction mixture was refluxed for 20 h, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:19) as eluant] to afford the title compound as a white solid (40 mg, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.5 (bs, 1H), 7.9 (s, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 2.90-2.86 (m, 1H), 2.74-2.56 (m, 1H), 2.56 (s, 1H), 2.33-2.29 (m, 1H), 2.20-2.12 (m, 2H), 2.04-2.03 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:34]4[CH:33]=[C:32]([F:31])[C:37]([F:38])=[C:36]([F:39])[CH:35]=4)=[CH:3][C:4]([C:27]([F:28])([F:30])[F:29])=[CH:5][C:6]=3[N:10]=2)[C@H:12]([CH3:26])[CH2:13]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Bromo-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (152 mg, 0.3 mmol, Example 151) and 4,5,6-trifluorophenylboronic acid (106 mg, 0.6 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 556 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:14].CO>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([C:10]([F:12])([F:13])[F:11])[C:2]([NH2:1])=[C:3]([I:14])[CH:4]=1
Reactant: N#Cc1cc(I)c(N)c(C(F)(F)F)c1
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(I)c(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 3.4 %

Procedure:
4-Amino-3-iodo-5-trifluoromethylbenzonitrile (1805.2 mg, 5.19 mmol) was dissolved in THF at 0° C. After Borane-THF complex (3 eq, 17.36 mmol, 17.36 ml) was slowly added into the reaction mixture, A reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hr. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-trifluoromethylphenylamine (55.1 mg).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:25]=[N+]=[N-])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([NH2:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(N)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 18 h

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-azido-methyl}-benzonitrile (1.77 g, 4.02 mmol), triphenylphosphine (1.16 g, 4.42 mmol), water (0.5 mL) and tetrahydrofuran (25 mL) is stirred 18 hr. The mixture is concentrated, diluted with water (100 mL) and extracted to ethyl acetate (3×50 mL). The combined extracts are dried over sodium sulfate, filtered, and concentrated to a bright yellow residue. The compound is used without further purification. LCMS M−1 413.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1.[CH3:40][C:41](O)=[O:42]>>[C:41]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:9]([C:13]([N:15]2[CH2:24][CH:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])[CH2:10]1)(=[O:42])[CH3:40]
Reactant: CC(=O)O
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CC(=O)N1C[C@@H](C(=O)N2CC(N(C(=O)C(C)(C)C)C3CCC(C)(C)CC3)C[C@H]2C(=O)N(C)C)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the procedure described in Step F of Example A1 using (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolineamide (84 mg, 0.15 mmol) prepared in Example E1-1 and AcOH via amide coupling reaction.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][C:10]=1[CH3:30])(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][CH2:32]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[C:10]([CH3:30])[CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: C1=CCNC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CC=CC1

Procedure:
Prepared analogously to Example 5d from 110 mg (0.25 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate and 1.92 mL (25 mmol) 2,5-dihydro-1H-pyrrole.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18](O)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH3:33].Cl.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC[C@H](N)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 60 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeuOBz hydrobromide salt (3.02 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocDPhe-LeuOBz in 54% yield. Debenzylation of BocDPhe-LeuOBz (2.25 g.) by hydrogenation with palladium catalyst gave BocDPhe-LeuOH in 87% yield. Condensation of BocDPhe-LeuOH (1.50 g.) and HNleNH2 hydrochloride salt (0.667 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocDPhe-Leu-NleNH2 in 60% yield. De-t-butoxycarbonylation of BocDPhe-Leu-NleNH2 (1.00 g.) using hydrogen chloride in acetic acid gave HDPhe-Leu-NleNH2 hydrochloride salt in 79% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[F:22])([CH3:12])[N:3]=1>C(O)C.C(N(CC)CC)C.[Pd]>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:22])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1N
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of (S)-2-amino-6-(2-fluoro-5-nitro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.55 g) in ethanol (25 ml) and triethylamine (0.25 ml) was added Pd/C (10%, 80 mg) and the mixture was hydrogenated at atmospheric pressure for 3 h. The mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica using ethyl acetate/MeOH (1:1) to give (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.49 g) as a pale yellow amorphous solid. MS (ESI): m/z=297.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:16]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1ccc(-c2ccccc2)cc1
Yield: 78.9 %

Procedure:
4-Phenylphenol 64 (25.5 g, 0.15 mol), allyl bromide (20.0g, 0.165mol) and K2CO3 (41.5 g, 0.15 mol) in 75 ml of dry DMF were stirred at room temperature overnight. The reaction mixture was diluted with 500 ml of diethyl ether and washed with water. The ether layer was washed with brine, dried and concentrated to give a lightly brown solid that was recrystallized from hexane to give 24.9 g of 4-allyloxy-biphenyl 65.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c(Cl)cc1Cl
Yield: 46.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,4-di-chloro-5-methoxyaniline (125 mg, 0.65 mmol) to provide 201 (77 mg, 56% yield) as a white solid. LC-MS (M+H=386, obsd.=386).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:5][CH2:4]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>C1COCC1>[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:4][CH2:5]1
Reactant: Fc1cccc(CBr)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cccc(F)c4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 50 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 1-Bromomethyl-3-fluorobenzene (150 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-water and extracted with DCM. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by crystallization with DCM/hexane to give the title compound (49 mg) as a white solid.
Reaction SMILES: Cl.O=[C:3]1[NH:22]C2=NC=C(C3C=CC(C(=N)OCC)=CC=3)N=C2[N:4]1CCN1CCCCC1.[O:31]=[C:32]1[NH:48][C:35]2=[N:36][CH:37]=[C:38]([C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)[N:39]=[C:34]2[N:33]1[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.Cl>C(O)C>[N:4]1[N:45]=[C:44]([C:43]2[CH:42]=[CH:41][C:40]([C:38]3[N:39]=[C:34]4[N:33]([CH2:49][CH2:50][N:51]5[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]5)[C:32](=[O:31])[NH:48][C:35]4=[N:36][CH:37]=3)=[CH:47][CH:46]=2)[NH:22][CH:3]=1
Reactant: N#Cc1ccc(-c2cnc3[nH]c(=O)n(CCN4CCCCC4)c3n2)cc1
Reactant: CCOC(=N)c1ccc(-c2cnc3[nH]c(=O)n(CCN4CCCCC4)c3n2)cc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ncc(-c3ccc(-c4nnc[nH]4)cc3)nc2n1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
Ethyl 4-(2-oxo-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate hydrochloride. 4-(2-Oxo-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (0.5 g., 1.43 mmol) was placed in anhydrous ethanol (5 mL) and cooled on an ice bath. The mixture was charged with hydrogen chloride gas for 15 min, capped and allowed to stir overnight while warming to rt. The solvent was removed and the residue treated with ether, filtered and dried under high vacuum to yield the title compound (0.4 g., 64.6% yield). MS (ESI) m/z 395.6[M+1]+
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C#N)cc1F
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1.00 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-methoxybenzonitrile (0.683 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (926 mg, 69% yield) as a solid after drying. MS: MS m/z 300.1 (M++1).
Reaction SMILES: C(OC([N:8]([CH:38]([CH3:40])[CH3:39])[C@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:12]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:12]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:11][CH2:10]1)([CH3:39])[CH3:40]
Reactant: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Step 1 product (120 mg) in CH2Cl2 is treated with CF3COOH (7 ml) and stirred at room temperature for 2 hours. The solution was evaporated and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 90 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.12 (s, 1 H), 8.02 (d, J=7.8 Hz, 1 H), 7.76 (d, J=7.8 Hz, 1 H), 7.57 (t, J=7.8 Hz, 1 H), 7.35 (bt, 1 H), 6.96 (bd, 1 H), 4.93 (m, 1 H), 4.51 (m, 1 H), 4.12 (d, J=4.8 Hz, 2 H), 3.03 (m, 1 H), 2.77 (m, 1 H), 2.61 (m, 1 H), 2.31 (bs, 1 H), 2.04 (m, 2 H), 1.80-1.30 (m, 4 H), 1.17 (m, 6 H), 1.08 (d, J=6.2 Hz, 6 H). MS found: (M+H)+=472.36.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>C1C=CC=CC=1>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[F:11][C:12]1[CH:13]=[CH:14][C:15]([OH:32])=[C:16]([CH:31]=1)[O:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>C(#N)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH:8]([CH3:10])[CH3:9])=[C:16]([CH:31]=1)[O:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cc(F)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
7.71 g of potassium carbonate (56 mmol) and 7 ml of 2-iodopropane (70 mmol) are added to a solution of 14 g of 2-[2-(5-fluoro-2-hydroxyphenoxy)ethyl]isoindole-1,3-dione (6) (47 mmol) in 250 ml of acetonitrile. The mixture is stirred for 16 hours at 80° C. and the solvent is then evaporated off under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with normal aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. It is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by chromatography on a column of silica (eluent: 82/18 cyclohexane/ethyl acetate). 12.2 g of a white solid are isolated.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][O:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:18]1[N:17]([CH2:16][O:15][CH3:14])[CH:21]=[CH:20][N:19]=1)[OH:39])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccccc1C(=O)c1ccccc1
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccccc1)c1ccccc1C(C)(C)C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere and at -60° C., 38 ml. (0.08 mol) of a butyllithium solution (20% in n-hexane) were added drop-wise over the course of 45 minutes to a mixture of 9.6 g. (0.08 mol) of N,N,N',N'-tetramethylethylenediamine and 7 g. (0.06 mol) of 1-(methoxymethyl)imidazole in 100 ml. of anhydrous tetrahydrofuran. The mixture was stirred for another two hours under the same conditions and then 16 g (0.0675 mol) of o-tert.-butylbenzophenone in 100 ml. of anhydrous tetrahydrofuran were added dropwise. After the addition was completed, the mixture was stirred for 2 hours at -60° C., and one hour at room temperature. The mixture was decomposed with 5 ml. of water, the precipitate was filtered off and the filtrate was dried over sodium sulphate and concentrated. The solid residue was crystallised from isopropyl alcohol. α-(o-tert.-Butylphenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol was obtained. Melting point 149°-150° C.
Reaction SMILES: [Mg].BrCCBr.[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:10])[CH3:7].[Br:19][C:20]([CH2:22]Br)=[CH2:21]>C1COCC1>[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][C:20]([Br:19])=[CH2:21])[CH3:10])[CH3:7]
Reactant: CCOC(C)OCCCCCCBr
Reactant: C=C(Br)CBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(Br)CCCCCCCOC(C)OCC
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
A slurry of 5.6 g of magnesium turnings (230 mmol) in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. 1-(1-Ethoxyethoxy)-6-bromohexane (38.5 g, 152 mmol) was fed slowly to the reaction mixture, maintaining the temperature at 40-50° C. At the end of the addition the reaction mixture was held 20 minutes, then transferred by cannula to solution of 33.4 g (167 mmol) of 2,3-dibromopropene in 25 ml of THF at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, then stirred at room temperature for 15 minutes, then quenched with water. The reaction mixture was transferred into a separatory funnel. A small amount of 1 N HCl was added, the phases were separated, the ether phase was washed with water and brine, then dried over magnesium sulfate, filtered, and stripped to give 33.63 g of a yellow liquid which was used without further purification.