Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:8][C:9](=[O:24])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:23])[C@H:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[C:19]([S:18][CH2:17][C@@H:16]([CH3:22])[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([OH:32])=[O:5])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
1-[(2S)-3-(Acetylthio)-2-methyl-1-oxopropyl]-L-prolyl-L-phenylalanine tert-butyl ester (1.19 g, 0.025 Mol) was dissolved in a solution of trifluoroacetic acid:CH2Cl2 (1:2, 30 ml) and the reaction was stirred at room temperature for 1 hour. Then it was evaporated under reduced pressure affording 1-[(2S)-3-(acetylthio)-2-methyl-1-oxopropyl]-L-prolyl-L-phenylalanine as a clear oil (1.00 g, 100%) that was used in the subsequent reaction without any further purification.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].Cl>O1CCCC1>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C#N)c1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(CN)c1C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A solution of borane-tetrahydrofuran complex (94.6 g, 1.1 mole) in tetrahydrofuran (1100 mL) was added dropwise to a stirred solution of 2,3-dimethyl-6-nitrobenzonitrile (96 g, 0.55 mole) in dry tetrahydrofuran (650 mL) maintained under an atmosphere of argon. After stirring overnight, 10% hydrochloric acid solution (1300 mL) was added dropwise and the mixture heated to reflux. After 30 minutes, the tetrahydrofuran was distilled off, the residue filtered to remove insoluble material and the filtrate made basic with concentrated ammonium hydroxide solution (350 mL). The mixture was extracted with diethyl ether (2×500 mL), the combined extracts washed with water (2×400 mL), dried over potassium carbonate and concentrated to afford 2,3-dimethyl-6-nitrobenzyl amine (93.85 g, 95%) as an oil used without further purification as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O-:3])=[O:2].[C:17]1([N:27]=[C:28]=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([NH:27][C:28]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: NCCCCCOc1cccc([N+](=O)[O-])c1
Reactant: S=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OCCCCCNC(=S)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of 5-(3-nitro-phenoxy)-pentylamine (867 mg, 3.87 mmol) in dichloromethane (5 mL) was added 1-naphthyl isothiocyanate (788 mg, 4.26 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by silica gel column chromatography to give 1-naphthalen-1-yl-3-[5-(3-nitro-phenoxy)-pentyl]-thiourea (1.3 g, 3.18 mmol, 82%) as a yellow gel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)([O-:3])=[O:2].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>FC(F)(F)CO>[N+:1]([C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCNCC1
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1cccc2c3c([nH]c12)CCNC3
Temperature: 105 °C
Yield: 55.4 %

Procedure:
2-Nitrophenylhydrazine (3.7 g, 24.2 mmol) and 4-piperidone monohydrate hydrochloride (3.7 g, 24.2 mmol) were suspended in 2,2,2-trifluoroethanol (25 mL). The resultant mixture was heated at reflux for 2 h and then concentrated. Conc. HCl (35 mL) was added in one portion. The resultant mixture was then heated at 105° C. for 15 h, and allowed to cool to rt, after which it was poured onto ice. While vigorously stirring, a 50% NaOH solution was added portionwise over 10 min until pH 12, maintaining the internal temperature at <20° C. The solid was collected via filtration and dried at room temperature under vacuum for 18 h to afford 6-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.91 g, 55%). 1H NMR (300 MHz, DMSO) δ 11.65-11.60 (br s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 3.86 (s, 2H), 2.99 (br s, 2H), 2.72 (br s, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[NH4+:24].[OH-]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15](=[O:17])[NH2:24])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(N)=O)C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
In a 100 mL round bottomed flask cis-3-(tertbutoxycarbonylamino)-cyclohexanecarboxylic acid (2.26 g, 9.29 mmol) was suspended in THF (15 mL). The suspension was cooled to −10° C. in an acetone-dry ice bath. To the cooled suspension was added slowly TEA (2.6 mL, 18.7 mmol) and subsequently ethyl chloroformate (1.03 mL, 10.7 mmol) so that the temperature is maintained. The cooling bath was removed upon addition and the reaction was stirred at room temperature for 3 h. The reaction mixture was cooled to −10° C. and NH4OH (2.17 mL, 55.7 mmol) was added slowly. After stirring at room temperature for 18 h, the precipitate was collected by filtration. The precipitate was washed with water and dried in vacuo at 50° C. to afford 1.67 g (74%) of (cis-3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.19 (br. s., 1H), 6.76 (d, J=7.9 Hz, 1H), 6.65 (br. s., 1H), 3.04-3.30 (m, 1H), 1.98-2.21 (m, 1H), 1.50-1.84 (m, 4H), 1.37 (s, 9H), 0.90-1.29 (m, 4H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][CH2:36][CH2:37][OH:38]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:35]([CH2:36][CH2:37][OH:38])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: OCCNCc1ccccn1
Product: CN(C)c1cccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:24]([C:20]1[CH:21]=[C:22]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc(C#N)c(C#N)c2)cc(C(C)(C)C)c1O
Reaction time: 72 h

Procedure:
To a stirred solution of 4-nitrophthalonitrile (8 g, 0.05 mol) was added 2,6 di-tert-butylphenol (11.44 g, 0.06 mol), potassium carbonate (9 g, 0.07 mol) and DMF (50 ml), producing a deep red colour. The reaction mixture was stirred under a nitrogen atmosphere for 72 h. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml), the organic layer was further washed with water (3×75 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded the crude product. Recrystallisation from ethanol yielded the pure product 4-(3,5-di-tert-butyl-4-hydroxyphenyl)phthlonitrile (1) as colourless, prismatic crystals (18.70 g, 81.70%), m.p. 209-210° C.; IR (KBr) 3416 (OH), 2231 (CN) cm- 1; (Found C, 79.55%; H, 7.50%; N, 8.20%. C22H24N2O requires C, 79.47%; H, 7.28%; N, 8.43%.); MS (EI) m/e 332 (M+); δH (200 MHz, solvent CDCl3): 1.51 (18H, s), 5.55 (1H, s), 7.39 (2H, s), 7.75-8.00 (3H, m).
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([O:3][CH3:4])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([O:17][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)Cc1cc(O)cc(CC(=O)OC)c1
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(CC(=O)OC)cc(OCC=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2.00 g (9.0 mmoles) if 3,5-di-(carbmethoxymethyl)phenol in 75 ml acetone is added 1.24 g (9.0 mmoles) of K2CO3 followed by 1.77 g (9.0 mmoles) of cinnamylbromide. This reaction mixture is refluxed for 2 hours, cooled to room temperature, filtered and concentrated down in vacuo. Purification by flash chromatography affords 1,3-di-(carbomethoxymethyl)-5-cinnamyloxybenzene which is used directly in the next step.
Reaction SMILES: [I:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.O.[OH-].[Li+]>O1CCCC1.O>[I:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2ccc(OC)c(I)c2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1I)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To the solution of 0.4 g (0.93 mmol) of ethyl 8-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 8 mL of tetrahydrofuran was added a solution of 155 mg (3.7 mmol) of lithium hydroxide hydrate (LiOH—H2O) in 15 mL of water. The resulting solution was heated to reflux for one h. After cooling to room temperature, the volatiles were removed, the residue was acidified at 0° C. to pH=1.5 with dilute hydrochloric acid. The product was extracted with ethyl ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concd in vacuo to afford 0.30 g (81%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.67(s, 1H), 7.18(d, J=8.4 Hz, 1H), 6.51(d, J=8.4 Hz, 1H), 5.78(q, J=6.8 Hz, 1H), 3.92(s, 3H). MS (ESI+) 400.9 (M+1, 100). MS(ES−) 398.9(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C12H7F3O4): 398.9336, found 398.9368.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[N:15][C:16]([NH2:29])=[C:17]([O:19][CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[CH:18]=1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:28])[C:21]=1[CH2:20][O:19][C:17]1[C:16]([NH2:29])=[N:15][CH:14]=[C:13]([C:9]2[NH:8][CH:12]=[CH:11][CH:10]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cnc(N)c(OCc2c(Cl)cccc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2ccc[nH]2)cc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylic acid tert-butyl ester (Example 6, 30 mg, 0.069 mmol) in ethanol/water (2:1, 10 mL) was added sodium carbonate (100 mg, 0.95 mmol). The mixture was refluxed overnight. The reaction was cooled to ambient temperature and extracted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica gel column to afford 3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-yl)-pyridin-2-ylamine.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[C:6]=1[NH2:7])([CH2:3][CH3:4])[CH3:2].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].CC#N.C([O-])([O-])=O.[K+].[K+]>O.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>[CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]([CH3:15])[CH3:14])[C:6]=1[NH2:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(Br)c1N
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(C)c1cccc(C(C)C)c1N

Procedure:
(−)-2-Sec-butyl-6-bromoaniline (2) (0.684 g, 3 mmol), isopropenylboronic acid pinacol ester (1 g, 6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol), MeCN 10 ml and K2CO3 (5 ml, 1M solution) were heated in a microwave at 160° C. for 400 sec. The reaction mixture was diluted with water (75 ml). Products were extracted with ethyl acetate (50 ml). The organic layer was washed with 5% NaHCO3, brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the compound purified by silica gel chromatography (CombiFlash, 30 g column, hexane-ethyl acetate). The reduction was then performed in MeOH (40 ml) over 5% Pd/C (˜0.3 g), hydrogen pressure 60 psi overnight (0.48 g, 72%).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH:42]([CH3:43])[CH3:44])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:29][N:30]([CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CNCC(C)C
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)CC(C)C)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,2-dimethylpropan-1-amine via General Procedure E to give 10.1 mg of 285 following reverse phase purification. MS (Q1) 449.2 (M)+
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[N:7]=[CH:6][C:5]=1[C:19](O)=[O:20])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]([O:62][C:63]([NH:65][C:66]([NH2:68])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C)C=O>[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:19]([C:5]1[CH:6]=[N:7][N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:20])=[NH:67])=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)c1c(C(=O)O)cnn1-c1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(C(=O)NC(=N)NC(=O)OC(C)(C)C)cnn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
To a solution of 5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid (336.7 mg, 1.2 mmol) in 5 ml dimethylformamide was added N,N-diisopropylethylamine (0.42 ml, 2.39 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (582 mg, 1.32 mmol) and tert-butoxycarbonylguanidine (210 mg, 1.32 mmol). The resulting solution was stirred at room temperature for 2 h, then heated to 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated to dryness in vacuo. The solid residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated to dryness in vacuo. The solid residue was triturated with methanol (1.5 ml), filtered, washed with diethyl ether and dried to yield the title compound as a white solid (114.3 mg, 22.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:5][CH:4]=1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][NH:28][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1ccc(Sc2cccc(C=O)c2)cc1
Product: COc1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 72A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: O.[OH-].[Li+].C[C:5]1([C:22]([O-:24])=[O:23])[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:7][CH2:6]1>O.CO>[C:18]([O:17][C:15]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([C:22]([OH:24])=[O:23])=[CH:6][CH:7]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC2=CCC(C)(C(=O)[O-])C=C2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Reaction time: 4 h

Procedure:
Lithium hydroxide monohydrate (5.8 g, 0.136 mol) dissolved in water (73 ml) was added to a solution of 2-tert-butyl 7-methyl-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (7.9 g, 0.027 mol) in methanol (110 ml), and the mixture was stirred for 4 h. The solvent was removed in vacuo. Water and diethyl ether were added to the residue, and the phases were separated. The aqueous phase was adjusted to an acidic pH with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 5.8 g (76%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C@@H:26]([NH2:28])[CH3:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][C@H:26]([C:25]([CH3:30])([CH3:29])[CH3:24])[CH3:27])=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@H](N)C(C)(C)C
Product: C[C@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)C(C)(C)C

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (2S)-3,3-dimethyl-2-butylamine (41.4 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[(2S)-3,3-dimethyl-2-butyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (20.5 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[SH:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1>C(O)C.[OH-].[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([S:15][CH2:2][C:3]3[N:8]=[C:7]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:6]=[CH:5][N:4]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: ClCc1nccc(N2CCCCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(N4CCCCC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A mixture of 2-chloromethyl-4-piperidino-pyrimidine (2.89 g) and 2-mercapto-5-methoxybenzimidazole (2.46 g) in ethanol (40 ml) and 1N sodium hydroxide (15 ml) was stirred at room temperature for 16 hours. After stripping the residue was washed with water and recrystallised from acetonitrile to give 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (3.5 g) m.p. 145°-147°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:10]([CH:15]=[N:17][N:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Solvent: CCCCO
Product: Brc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 3.76 g. of 3-(p-bromophenyl)-6-chloropyridazine, 1.80 g of formylhydrazine and 50 ml. of butyl alcohol is heated to reflux and allowed to reflux overnight. The reaction mixture is allowed to cool and the precipitated product is washed with water, air dried and recrystallized from methyl alcohol, m.p. 209°-211° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57]O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])=[O:35])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: COCCOCCO
Product: COCCOCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 4d from 70 mg (0.10 mmol) of (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.