Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2]1.CN(CCN(C)C)C.C([Li])CCC.[C:27](=O)([O:30]C)[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][C:27]([C:2]1[O:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1ccoc1
Reactant: COC(=O)OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1occc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of tert-butyl furan-3-ylcarbamate 32 (1.7 g, 1.0 eq) in THF (50 ml) at −30° C. was added TMEDA (1.75 ml, 1.3 eq) followed by 1.6M solution of n-butyllithium (8.4 ml, 2.25 eq, 1.6M in hexanes). Reaction mixture was allowed to warm up to 0° C. and stirred for 1 h, before being cooled back to −30° C. Dimethyl carbonate (2.4 ml, 3.0 eq) was quickly added, before the reaction mixture was allowed to warm up to room temperature for 1 hr. Reaction mixture was quenched with 2M HCl, followed by addition of saturated aq. NaCl. Mixture was extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and concentrated. The crude reaction mixture was purified by flash chromatography to yield tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate 33 (1.14 g, 51%): MS (Q1) 242 (M)+.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7]C2(C)C)[CH:3]1[CH:12]([CH3:14])[CH3:13].O>C(O)(=O)C>[CH:12]([CH:3]1[CH:4]([CH2:5][CH2:6][OH:7])[NH:9][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1C(=O)NC1CCO
Temperature: 65 °C

Procedure:
8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane 1.0 g is dissolved in 8 ml of acetic acid and 2 ml H2O is added. The mixture is heated at 65° C. for 1.25 hrs. The acetic acid and H2O are removed under reduced pressure and the residue is taken up in C6H6 and evaporated to give 3-isopropyl-4-(2-hydroxyethyl)azetidinone.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:39][CH3:40])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:24](OC2C=CC=CC=2)=[O:25])=[CH:16][C:15]=1[CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[NH2:41][C:42]1[CH:49]=[C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]([C:46]#[N:47])=[CH:44][N:43]=1.[NH4+].[Cl-]>C1COCC1>[C:46]([C:45]1[C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[CH:49][C:42]([NH:41][C:24]([N:21]2[C:22]3[C:17](=[CH:16][C:15]([CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[C:14]([CH:13]([O:39][CH3:40])[O:12][CH3:11])[N:23]=3)[CH2:18][CH2:19][CH2:20]2)=[O:25])=[N:43][CH:44]=1)#[N:47]
Reactant: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2C(=O)Oc1ccccc1
Reactant: COCCNc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C4CCOCC4)c(C(OC)OC)nc32)ncc1C#N
Temperature: -78 °C

Procedure:
A solution of LHMDS in THF (0.9 M, 2.32 ml, 2.09 mmol) was added to phenyl 7-(dimethoxymethyl)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 311, 700 mg, 0.95 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 183 mg, 0.95 mmol) in THF (10 ml) cooled at −78° C. with a dry ice/acetone bath. After stirring for 2 h at −78° C. aqueous NH4Cl was added, the mixture warmed to room temperature and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was then purified by normal phase chromatography using a 24 g RediSep® column, eluting with a gradient from hexane to 50% EtOAc in hexane. Product containing fractions were then combined and evaporated to give the title compound as a white solid. (UPLC-MS 3) tR 1.07 min; ESI-MS 511.4 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH2:11][C:10](=[N:13]O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:13][CH:10]1[CH2:9][C:8]2([CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:16][CH2:15]2)[O:12][CH2:11]1
Reactant: CC(C)(C)C1CCC2(CC1)CC(=NO)CO2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC2(CC1)CC(N)CO2
Yield: 76.6 %

Procedure:
8-t-Butyl-1-oxaspiro(4,5)-decane-3-one oxime (17.5 g, 76 mmol) in tetrahydrofuran (50 ml) was added to a solution of lithium- aluminium hydride (4.5 g, 0.125 mol) in tetrahydrofuran (100 ml). The reaction mixture was refluxed for 4 hours, cooled end excess LAH was hydrolysed by addition of saturated aqueous sodium sulfate solids were filtered off washed with tetrahydrofuran and the solvent was stripped off in vacuo. Kugelrohr distillation of the resulting pale yellow oil (16.9 g) gave a colourless oil (12.3 g). Bp.: 125° C./0.02 mbar, nD22 :1.4840.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cnc(Br)c(N)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To Fe power (2.18 g, 39.0 mmol), AcOH (10 mL) was added drop wise and heated to 80° C. To it, a solution of 2-bromo-5-methyl-3-nitro-pyridine (1.96 g, 9.07 mmol) in AcOH (10 mL) was added slowly. After 30 min, reaction mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL), filtered through a pad of celite. The filter cake was washed with EtOAc (25 mL) and filterate was concentrated. The residual liquid was slowly treated with saturated aqueous NaHCO3 solution (70 mL), followed by small portions of solid NaHCO3 to neutralize the AcOH, extracted with EtOAc (2×50 mL) and the extracts were dried (anhydrous Na2SO4) and concentrated under reduced pressure to get 2-bromo-5-methyl-pyridin-3-ylamine (1.45 g) as a brown solid in 86.3% yield. ESMS m/z (relative intensity): 187 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]2[C:16]([CH3:19])=[N:17][CH2:18][CH:13]2[C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]2[C:16]([CH3:19])=[N:17][CH:18]=[C:13]2[C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:11][CH2:10]1
Reactant: CC1=NCC2[C@H](NC(=O)OC(C)(C)C)CC[C@@H](c3cccc(F)c3F)CN12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1ncc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Manganese(IV) oxide (46.0 mg, 0.53 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-methyl-5,6,7,8,9,9a-hexahydro-1H-imidazo[1,5-a]azepin-9-yl]carbamate (20.0 mg, 0.053 mmol) in toluene (7 mL). The reaction mixture was heated to reflux. After 8 h, additional manganese (IV) oxide (46.0 mg, 0.53 mmol) was added. After 16 h, the reaction mixture was allowed to cool to ambient temperature. The mixture was filtered, washed with methanol, and concentrated. Purification by preparative thin layer chromatography (9% methanol/dichloromethane) gave the title compound (5 mg). MS 378.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23]([Cl:24])=[C:22]([Cl:25])[N:21]=[C:20]1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:25][C:22]1[N:21]=[C:20]([CH3:26])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[CH2:13][CH2:12]2)[C:23]=1[Cl:24]
Reactant: Fc1cnc(N2CCNCC2)nc1
Reactant: Cc1nc(Cl)c(Cl)n1CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(F)cn2)CC1
Yield: 82.6 %

Procedure:
A mixture of 3.5 g (0.02 mol) of 5-fluoro-2-(piperazin-1-yl)pyrimidine, 6.04 g (0.025 mol) of 1-(4-chlorobutyl)-4,5-dichloro-2-methyl-1H-imidazole and 4.14 g (0.03 mol) of potassium carbonate in 200 ml of dimethylformamide is maintained at reflux for 12 hours. The mixture is subsequently evaporated to dryness and the resulting crude product is redissolved in chloroform and washed repeatedly with water. The organic phase is dried and evaporated, and then the resulting crude product is purified by chromatography on a columm of silica gel. 6.4 g (83% yield) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14](Cl)[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CO.CN(C)[CH:31]=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:32][CH3:31])[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)c3cccc(OCc4ccccc4)c3oc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3 g.), methanol (20 ml.) and dimethylformamide (100 ml.) is stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is filtered. The residue is recrystallised from isopropanol to give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C(F)(F)F)[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CN(CCCCNC(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc2c(c1)CN(CCCCN)CC2
Yield: 68.8 %

Procedure:
A solution of 7-acetyl-2-(4-trifluoroacetamidobutyl)-1,2,3,4-tetrahydroisoquinoline (0.360 g, 1.05 mmol) was added to a stirred mixture of methanol (10 ml), water (1.5 ml) and potassium carbonate (0.769 g, 5.56 mmol) and heated at reflux for 1 h. The mixture was cooled then evaporated in vacuo and the residue partitioned between water (100 ml) and dichloromethane (50 ml). The aqueous phase was washed with dichloromethane (2×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a yellow oil (0.178 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)=[C:6]([OH:21])[C:5]2=[O:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:7]3[O:8][C:9]4[C:4]([C:5](=[O:22])[C:6]=3[OH:21])=[CH:3][C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:10]=4)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1)c1ccccc1
Yield: 79 %

Procedure:
30 mg (101 pmol) of 6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained in Example 24 was dissolved in 2 ml of methylenechloride, and the mixture was reacted with 10 molar equivalents of benzoylchloride and excess amount of potassium carbonate at room temperature for 10 hours. The resulting product was filtered, washed with methylenechloride and water, and dried to give 32 mg of the title compound in a yield of 79%.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:11]=[C:10](Br)[S:9][C:8]=1[O:13][CH3:14].CI>C1COCC1>[Br:6][C:7]1[CH:11]=[C:10]([CH3:1])[S:9][C:8]=1[O:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COc1sc(Br)cc1Br
Solvent: C1CCOC1
Solvent: CI
Product: COc1sc(C)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (2.0M in pentane, 0.97 mL, 1.93 mmol) was added to a stirred solution of 3,5-dibromo-2-methoxythiophene (Step A, 500 mg, 1.84 mmol) in THF (5 mL) at −78° C. under an atmosphere of N2. The reaction stirred at −78° C. for 1 h prior to addition of methyl iodide (114 μL, 1.84 mmol). The reaction was allowed to warm to room temperature and stirred for 20 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (15 mL0 and H2O (15 mL). The aqueous layer was re-extracted with ether (2×15 mL) and the combined organic layers were washed with H2O (15 mL) and brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 3-bromo-2-methoxy-5-methylthiophene as a yellow oil. 1H NMR (CDCl3, 500 MHz): δ 6.44 (s, 1 H), 3.95 (s, 3 H), 2.41 (s, 3 H).
Reaction SMILES: [F:1][C:2]1([CH2:18]OS(C)(=O)=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:18][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
To a solution of benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (1.3 g, 3.7 mmol) in DMF (10 mL) at RT was added NaN3 (2.4 g, 37.0 mmol). The reaction mixture was heated to 110° C. and stirred for 60 h, cooled and partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate. (0.86 g, 80% yield). M.S. (M+1): 293
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:22]([CH3:23])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(CC(=O)OC(C)(C)C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)c1cc(CC(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-benzyloxy-3-isopropyl-phenyl)-acetic acid tert-butyl ester (3.04 g, 8.16 mmol, 1 eq) in THF (99 mL) under N2, palladium on activated carbon (10 wt. % 304 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 2 days. The black suspension was filtered through Celite and the filter cake was rinsed with THF. The filtrate was concentrated in vacuo to give the title compound as a colorless oil. The product was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:9].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:8]([C:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Reaction time: 2 h

Procedure:
A solution of 2-fluoropyridine (5.83 g, 60 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (I-1, 4.22 g, 20 mmol) in toluene (40 mL) at room temperature was treated with KHMDS (48 mL of a 0.5 M solution, 24 mmol). After stirring 2 h, the reaction mixture was poured into brine (150 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (2×150 mL), dried (MgSO4), and concentrated under reduced pressure to afford tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (I-2) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 3.076 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]#[CH:17]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:17][C:16]#[CH:15])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: C#CCN1CC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using propargyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated from Et2O/hexanes to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(Br)c(N)n1
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-diaminopyrimidine (1.0 g, 9.1 mmol) in chloroform (30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2Cl2 (150 mL) and 1N NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromopyrimidine-2,4-diamine. LCMS (m/z): 189/191 (MH+). 1H NMR. (DMSO-d6): δ 7.78 (s, 1H), 6.58 (bs, 2H), 6.08 (bs, 2H).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]CC3C=CC=CC=3)=O)[N:8]=2)CCCCC1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=C=O)[CH:32]=1>C(O)=O.CO.[Pd].O1CCCC1>[CH2:12]1[CH2:17][CH:16]([C:9]2([NH:20][C:21]([NH:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:15][CH2:14][CH2:13]1
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: Cc1cccc(NC(=O)NC2(C3CCCCC3)N=Cc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
5-Cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.34 g, 0.84 mmol) was dissolved in formic acid/methanol (50 ml of a 4.5% (v/v) solution), and added, over 5 min, to a stirred suspension of 10% palladium on carbon (100 mg, 30% (w/w)) in formic acid/methanol (10 ml of a 4.5% (v/v)) solution). After 45 min the catalyst was filtered off and washed sequentially with methanol and acetone. The flitrate was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and 10% sodium carbonate solution (100 ml). The organic phase was separated, dried (Na2SO4) and evaporated to give a clear oil, which was used without further purification. A solution of the crude amine (167 mg, 0.61 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with m-tolylisocyanate (79 μl, 0.61 mmol) dropwise over 5 min. After stirring at ambient temperature for 1.5 h the solvent was removed under reduced pressure to leave a white solid. The solid was recrystallised from methanol to give the urea (70 mg, 28%) as a white solid. mp 207°-209° C. 1H NMR (360 MHz, CDCl3) δ 1.07-2.04 (10H, m), 2.29 (3H, s), 2.79 (1H, m), 3.40 (3H, m), 5.40 (1H, d, J=8 Hz), 6.71 (1H, d, J=8 Hz), 6.84 (2H, m), 7.07-7.30 (5H, m), 7.55 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:15])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)nc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Yield: 23 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (198 mg, 0.735 mmol), 1-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.809 mmol) and diisopropylethylamine (0.139 ml, 0.809 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 62.1 mg (23.0%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][O:27][CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: COCCN
Product: COCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methoxyethaneamine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 8.12-8.08 (d, J=7.6 Hz, 1 H), 7.90 (s, 1 H), 7.35-7.30 (d, J=7.6 Hz, 1 H), 7.26-7.13 (m, 2 H), 7.11-7.05 (m, 2 H), 6.06 (s, 1 H), 5.27 (s, 2 H), 4.50 (s, 2 H), 4.78-4.62 (m, 6 H), 3.35 (s, 3 H), 2.45 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[C:21]([CH3:29])[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:29])[CH2:7]1
Reactant: Cc1cc(F)ccc1CC(=O)O
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1cc(F)ccc1CC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.5 %

Procedure:
Example 19 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (4-fluoro-2-methylphenyl)acetic acid (0.034 g) to give the title compound (0.014 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])C>>[CH:35]([C:18]1[C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:37]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Yield: 65 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 161, the title compound was synthesized in the same manner as in Example 20. Yield: 65%. Melting point: 134-140° C. (hexane-ethyl acetate).