Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H: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]([O:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12.[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:46]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:46])=[CH:22][CH:23]=4)=[CH:24][CH:25]=3)[C:3]=12
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C(N)=O)cc5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.200 g, 0.000394 mol) was dissolved in dioxane (3 mL), the solution of sodium hydroxide (0.15 g, 0.00197 mol) in water (2 mL) was added followed by the addition of 30% hydrogen peroxide solution in water (5 drops). The reaction mixture was heated at reflux under an atmosphere of nitrogen for 1.5 hours, cooled to ambient temperature and neutralized with 5% solution of citric acid in water. The solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide (0.120 g, 0.000223 mol) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][CH2:27][CH2:28][CH:29](OCC)[O:30]CC)=[O:25])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](=[O:25])[NH:26][CH2:27][CH2:28][CH:29]=[O:30])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Yield: 91.9 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, benzyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-[(3,3-diethoxypropyl)amino]-4-oxobutanoate (2.63 g, 5.41 mmol, obtained from Reference Example 23) in tetrahydrofuran (11 ml) was reacted with 0.5 N hydrochloric acid at room temperature for 1 hour, to provide benzyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxo-4-[(3-oxopropyl)amino]butanoate (2.05 g, 92%) as a pale yellow waxy solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials. LCMS for C12H15ClFN6O4S (M+H)+: m/z=393.0. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.19 (m, 2H), 6.96 (dd, J=6.7, 2.5 Hz, 1H), 6.71 (m, 1H), 6.26 (t, J=6.4 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=5.8 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([CH3:12])=[N:7]2
Reactant: CC(C)(C)N
Reactant: Cc1nc2cccc(Br)c2nc1F
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(Br)c2nc1NC(C)(C)C
Yield: 86.3 %

Procedure:
A solution of 5-bromo-3-fluoro-2-methylquinoxaline (Example 126f; 1.5 g, 6.22 mmol) and tert-butylamine (Aldrich; 3.27 mL, 31.1 mmol) in DMSO (15 mL) was stirred at 100° C. for 2.5 h. The mixture was subsequently diluted with DCM (150 mL), and washed with saturated aq. NaHCO3 (3×15 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude material was purified on a silica gel column (18-25% EtOAc in hexanes) to give 8-bromo-N-(tert-butyl)-3-methylquinoxalin-2-amine (1.58 g, 86% yield) as an amorphous pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79-7.86 (m, 1H), 7.71 (dd, J=8.1, 1.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.17 (s, 1H), 2.55 (s, 3H), 1.58 (s, 9H). m/z (ESI, +ve ion) 294.0/296.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C(=O)([O-])[O-].[K+].[K+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:15]=[N:14][C:16]=2[CH3:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.96 g, 5.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.05 g, 5.00 mmol), and potassium carbonate (0.898 g, 6.50 mmol) was heated to reflux for 2 hours in methanol (25 mL). After this time, the reaction mixture was cooled to room temperature and poured into water, then extracted with ether. Chromatography on silica gel (20 to 40% ethyl acetate-hexane, eluant) afforded the title compound as an off-white solid (1.01 g, 82% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.90 (m, 1H), 7.68 (m, 2H), 2.43 (s, 3H). MS (DCI+) m/z 246 (M+H), 263 (M+NH4).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5][C:4]([CH3:43])([CH3:42])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH3:42][C:4]1([CH3:43])[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:24][CH:25]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 85.3 %

Procedure:
A solution of 3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.40 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.44 g) in dichloromethane (4 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.34 g, 86%) as a colorless solid.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:7]=1[O:14][CH3:15])=O.Cl>C(O)C>[Cl:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([NH2:5])=[C:7]([O:14][CH3:15])[CH:8]=1
Reactant: COc1cc(Cl)c(Cl)cc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1cc(Cl)c(Cl)cc1N

Procedure:
The 2,2-dimethyl-N-(4,5-dichloro-2-methoxyphenyl)propanamide (3.70 grams, 0.01 mole) prepared in Part B was dissolved in ethanol: 12N HCl (1:1), the mixture heated under reflux overnight and then freed of volatiles under rotary evaporation. Partition between 2N HCl and dichloromethane gave and acid-soluble fraction which was worked up to give 1.1 grams (0.01 mole) or pure 4,5-dichloro-2-methoxyaniline as determined by thin layer chromatographic analysis. The dichloromethane fraction from above was freed of solvent giving starting material which was again refluxed overnight with ethanol: 12N HCl and worked up to given an additional 1.2 grams (0.01 mole) of pure 4,5-dichloro-2-methoxyaniline as determined by thin layer chromatographic analysis. NMR analysis of the product indicated the following:
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13]I>O.C(Cl)Cl>[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13][O:9][C:6](=[O:10])[CH2:7][CH3:8]
Reactant: CCSC(=O)OCI
Reactant: CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CC
Yield: 98.8 %

Procedure:
To a stirred solution of NaHCO3 (45 g, 536 mmol) in H2O (540 ml) is added TBA HSO4 (91.2 g, 268 mmol), propanoic acid (20.1 mL, 268 mmol), and CH2Cl2 (540 ml). Following stirring for 1 h at room temperature a solution of 5b (49.2 g, 200 mmol) in CH2Cl2 (100 mL) is added during 45 min keeping the temperature below 30° C. The stirring is continued for 11/2 h. The organic phase is separated, washed with H2O (200 mL), dried (MgSO4), and evaporated. The residue is stirred in Et2O (800 mL) during the night, filtered, and washed with Et2O (50 mL). The filtrate is evaporated and distilled to yield 38.0 g (98%) of 6cb, bp 71°-73° C./0.3 mbar.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=CC2C=CC=CC=2)[O:11][CH:12]=1)=[O:7])[CH3:4].[OH2:21]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=[O:21])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1coc(C=Cc2ccccc2)n1
Reactant: O
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (3.21 g, 15.00 mmol) in water (26.0) mL was slowly added to a vigorously stirred suspension of silica gel (15.0 g) in acetone (60.0 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (40.0 mL) was added and the reaction mixture was treated at rt with 2-styryl-oxazole-4-carboxylic acid ethyl ester (1.22 g, 5.00 mmol) and RuCl3 hydrate (82 mg, 0.15 mmol). The reaction mixture was stirred at rt in the dark for 30 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:9 to 1:2 EA-Hept) gave the title compound as a yellow solid. TLC: rf (3:2 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.51 min; [M+H2O+H]+=188.50.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1=NCCN1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: I
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2c(CNC3=NCCN3)cccc2c1
Temperature: 150 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide were added to methylene chloride and the reaction mixture was heated to reflux until all of the solvent evaporates. The reaction mixture is heated to 150° C. and then cooled. The resulting mixture is basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography to give (6-benzenesulfonyl-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
Prepared according to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.102 g) and 2,3-dichlorobenzoyl chloride (0.102 g) to give the title compound as a white solid (0.090 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C2CCCC2)cc1
Yield: 2.4 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and cyclopentylbromide (0.107 mL, 1.0 mmol) to give the title compound (0.004 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:23][C:24]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][N:26]2[CH2:27][CH2:28][C:24]([F:29])([F:23])[CH2:25]2)[CH:3]=1
Reactant: FC1(F)CCNC1
Reactant: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC1(F)CCN(CC#Cc2cncc(Br)c2)C1
Temperature: 80 °C

Procedure:
To a solution of methanesulfonic acid 3-(5-bromo-pyridin-3-yl)-prop-2-ynyl ester (Intermediate 223) (1 eq, 1.95 mmol, 566 mg) in DMF (6 ml) are added K2CO3 (2.5 eq, 4.88 mmol, 674 mg) and 3,3-difluoro-pyrrolidine hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.2 eq, 2.34 mmol, 336 mg). The resulting mixture is heated at 80° C. for 2 h. The reaction mixture is cooled to r.t. before adding water and extracting the mixture with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification by column chromatography yields the title compound; [M+H]+=301/303.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][CH3:13].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][CH3:13])[NH2:8]
Reactant: COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A stirred mixture of 2,6-dichloro-4-nitroanisole (4.6 g, 21 mM) and tin(II) dichloride dihydrate (23.4 g, 104 mM) in ethanol (72 mL) was refluxed for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice water which was then treated with 2N sodium hydroxide until the solution became basic. The resulting mixture was filtered through diatomaceous earth and the liltrate was extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered and concentrated to obtain (3.33 g, 83.7%) the title compound as a yellow-brown solid, mp 80°-81° C.; MS(CI): 192 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH:16]=[C:15]2[C@@H:5]([CH2:6][C:7]3[C:17]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]2=4)[NH:9][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:18][N:4]1[C@H:5]2[C:15]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:17]=3[C:7]([CH2:6]2)=[CH:8][NH:9]4)=[CH:16][C@H:2]([NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3]1
Reactant: CN1C[C@@H](N)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.5 g 8α-amino-6-methyl-9,10-didehydro-ergoline in 200 ml CH2Cl2 is cooled to 0° and treated with 6.44 ml triethylamine followed by dropwise addition of 2.97 ml pivaloyl chloride. The mixture is stirred for 2 hours at room temperature and washed with water. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on 200 g silica gel using 98:2 CH2Cl2 /CH3OH and then crystallized from ether to yield 6-methyl-8α-pivaloylamino-9,10-didehydro-ergoline, m.p. 158°-159°.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 66% of theory, C32H37N7O5 (599.7); Rf value: 0.58 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=600; (M+H+Na)++=311.7; (M+Na)+=622.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@H](O)CO
Temperature: 80 °C

Procedure:
(S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (290 g, 0.5 mmol) was dissolved in methanol (5 mL). Water (0.5 mL) was added followed by p-TsOH.H2O (20 mg, 0.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (146 mg, 54%, ee>97% by SFC). ESI-MS m/z calc. 520.5, found 521.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.42-7.37 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.0 Hz, 1H), 4.91 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.42-4.38 (m, 1H), 4.10 (dd, J=8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])N.[C:9]1([OH:15])C=C[CH:12]=[CH:11][CH:10]=1>>[C:1](=[O:8])([O:15][CH2:9][CH2:10][CH2:11][CH3:12])[O:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCOC(N)=O
Reactant: Oc1ccccc1
Product: CCCCOC(=O)OCCCC

Procedure:
A liquid containing 42.6% by weight (hereinafter, “wt %”) of dibutyl carbonate, 11.4 wt % of butyl carbamate and 46.0 wt % of phenol was fed at the rate of 300 g/hr at 100° C. to a center portion of a distillation column made from glass provided with a vacuum jacket (filled Sulzer Labopacking, inner diameter 50 mmφ, height of filling portion: concentration portion 550 mm, recovery portion 550 mm) and the continuous distillation was performed under a top section pressure of 20 mmHg in the distillation column. The distillation column was operated in a reflux ratio of 3 and adjusted to distill out 265 g/hr of a distillate from the top section and thus steady state was maintained. In the distillation, a liquid containing 48.2 wt % of dibutyl carbonate and 51.8 wt % of phenol was obtained as a distillate of the top section. Butyl carbamate content in the liquid thus obtained was below 0.05 wt %. A liquid containing 98.0 wt % of butyl carbamate and 2.0 wt % of phenol was obtained at the rate of 35 g/hr from the bottom section. Dibutyl carbonate content in the liquid thus obtained was below 0.05 wt %. In this distillation, the top section temperature was 94° C. and the bottom section temperature was 118° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]1[CH2:19][N:18]([C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=O)[CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]1CCCC1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]1[CH2:16][CH2:17][N:18]([C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:19]1=[O:29])[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)CC1=O
Product: C[C@H](c1ccccc1)N1CC[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
In an atmosphere of nitrogen, 1Mborane-tetrahydrofuran complex (14.8 ml) was added dropwise to a tetrahydrofuran solution (40 ml) of 4-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (2.03 g, 5.28 mmol) under ice-cooling, and then the mixture was stirred at room temperature for 17 hours. After evaporation of the solvent under a reduced pressure, the resulting residue was dissolved in 80% hydrous ethanol (40 ml) and heated under reflux for 1 hour in the presence of triethylamine (1 ml). After spontaneous cooling of the reaction solution, the solvent was evaporated under a reduced pressure, chloroform (100 ml) was added to the resulting residue, and then the resulting organic layer was washed with saturated ammonium chloride aqueous solution (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with chloroform to chloroform:methanol (97:3), 1.54 g (79%) of the title compound was obtained as white crystals.