Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][CH2:40]2)=[O:10])=[CH:11][CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Reaction time: 15.5 h
Yield: 80.5 %

Procedure:
To a solution of E-4-fluorocinnamic acid (1.18 g, 7.10 mmol), which is commercially available from Sigma-Aldrich, and TBTU (3.42 g, 10.6 mmol) in DMF (50 mL) was added 1-isopropylpiperazine (1.12 mL, 7.81 mmol) at ambient temperature. The reaction was stirred for ca. 15.5 h before being concentrated under reduced pressure, wherein the crude residue was dissolved in EtOAc (70 mL) and partitioned with sat. aq. NaHCO3 (25 mL). The aq. layer was separated and further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (2×20 mL) and brine (35 mL), then concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2-40 g; gradient elution: 100% DCM for 5 min, then 0% to 2% MeOH/DCM over 5 min; hold for 5 min, 2% to 4% over 5 min, hold for 5 min, 4% to 10% over 5 min, hold 10% MeOH/DCM for 5 min at 40 mL/min) to give 1.58 g 10A (80% yield) as a pale orange solid. m/z (ES+) M+1=277.4; HPLC tR=1.50 min. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J=15.6 Hz, 1H), 7.50 (dd, J=8.9, 5.5 Hz, 2H), 7.11-6.99 (m, 2H), 6.80 (d, J=15.6 Hz, 1H), 3.85-3.54 (m, 4H), 2.73 (quintet, J=6.7 Hz, 1H), 2.55 (d, J=5.2 Hz, 4H), 1.05 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4]NC(=O)C.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4][Cl:18]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1ccc([N+](=O)[O-])cc1CCl
Yield: 85 %

Procedure:
A solution of N-(2-methyl-5-nitrobenzyl)acetamide (3.12 g; 0.015 mol), phosphorus oxychloride (5.12 g; 0.032 mol) and dimethylformamide (2.19 g; 0.03 mol) in xylene (50 ml) is refluxed for one hour. The reaction mixture is then washed with water and the solvent evaporated. This treatment produces 2.36 g (i.e., 85% yield) of product having a melting point of 56° to 62° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12].C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:12][CH:7]1[C:8]2[C:3](=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CC1NCCc2c(Br)cccc21
Product: CC1NCCc2c(-c3ccccn3)cccc21

Procedure:
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
Reaction SMILES: [CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][N:10](CC1C=CC=CC=1)[CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pd].O>[CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][NH:10][CH2:9]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CN1CC2CCNCC2(Cc2ccccc2)C1=O
Yield: 77.8 %

Procedure:
To a solution of the compound of Example 200, Step D (0.034 g, 0.10 mmol) in acetic acid (18 mL) was added a slurry of palladium on carbon (10% by weight, 0.030 g) in H2O (2 mL). The reaction mixture was shaken under 50 psig hydrogen for 24 h, an additional aliquot of palladium on carbon (0.030 g) was introduced and the reaction was continued under 50 psig hydrogen for another 24 h. The reaction mixture was filtered through a bed of Celite® with the aid of MeOH, concentrated under vacuum, and the residue was partitioned between CH2Cl2 and H2O at pH 9. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the organic layers were combined and washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step E (0.019 g): +APcI MS (M+1)+ 245; 1H NMR (400 MHz, CDCl3) δ: 7.10-7.24 (arom, series of m, 5 H), 3.21 (m, 1H), 2.71 (s, 3H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:14])[CH3:13].[Cl:15][CH:16]([C:18]1[O:23][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[N:19]=1)[CH3:17].Cl>O1CCCC1.O.CCCCCC>[Cl:15][CH:16]([CH3:17])[C:18]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](=[O:24])[CH2:13][C:12]([NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1)=[O:14])=[O:23]
Reactant: CC(Cl)c1nc2ccccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(Cl)C(=O)Nc1ccccc1C(=O)CC(=O)Nc1nccs1
Yield: 70.5 %

Procedure:
191 ml of a solution of 1.4M of n-butyllithium per liter of hexane were added under argon at 0° C. to a solution of 19.05 g of N-(2-thiazolyl)-acetamide in 580 ml of tetrahydrofuran and then a solution of 14.04 g of the product of Step A in 100 ml of tetrahydrofuran were added thereto at -70° to -75° C. The mixture was poured into a mixture of water and 2N hydrochloric acid and the mixture was vacuum filtered. The product was washed with water and dried under reduced pressure to obtain 16.6 g of 2-[(2-chloro-1-oxo-propyl)-amino]-β-oxo-N-(2-thiazolyl)-benzene-propanamide melting at 204° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.Cl.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]Cl>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:13]=2[S:21]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)(=[O:22])=[O:23])=[CH:7][CH:6]=1
Reactant: CN(C)CCCl
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCCCC3)[nH]c3ccccc23)cc1
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCCCC3)n(CCN(C)C)c3ccccc23)cc1
Yield: 73.7 %

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 244 (1.32 g, 2.40 mmol) obtained in Example 245 and 2-dimethylaminoethylchloride hydrochloride (345 mg, 2.40 mmol) to give 1.1 g (yield: 74%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[Si:20]([O:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:34])=[C:31]([CH2:46][OH:47])[CH:30]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(Cl)Cl>C1COCC1>[Si:20]([O:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:34])=[C:31]([CH2:46][O:47][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[CH:30]=1)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (1.10 g, 5.48 mmol) in 40 mL of anhydrous THF was added pyridine (390 μL, 5.48 mmol) at 0° C. After stirring for 15 min, a solution of 5 (1.50 g, 3.65 mmol) in 15 mL of anhydrous THF was added dropwise within 10 min, and the mixture was allowed to warm up. Stirring was continued at room temperature for 16 h after which 50 mL DCM was added. The mixture was washed with 1M HCl (3×60 mL) and brine (1×50 mL), and the aqueous layers were re-extracted with DCM. The combined organic phases were dried over MgSO4 and the volatiles were removed in vacuo. Flash chromatography of the crude product (1:2 EtOAc-hexane) afforded 6 (97%) as a colorless solid: 1H-NMR (400 MHz, CDCl3): δ 0.11 (s, 6H), 0.94 (s, 9H), 1.49 (s, 9H), 4.79 (s, 2H), 5.58 (s, 2H), 6.71 (br s, 1H), 7.37-7.42 (m, 3H), 7.54 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.96 (br s, 1H), 8.23-8.29 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ −5.1, 18.5, 26.0, 28.3, 64.3, 68.5, 82.3, 121.9, 125.4, 126.5, 127.4, 128.3, 131.4, 133.6, 145.5, 145.7, 152.5, 155.5, 155.6, 168.0; MS (TOF) m/z=598.2 (M+Na+, 100).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1([OH:39])[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)#[CH:25]>>[OH:39][C:26]1([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: C#CC1(O)c2ccccc2-c2ccccc21
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(O)c3ccccc3-c3ccccc31)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 9-ethynyl-9H-fluoren-9-ol. MS (+ESI) m/z: 477.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:10]([CH3:20])(OCC)([O:14]CC)[O:11]CC>CC(O)=O>[C:10]([OH:14])(=[O:11])[CH3:20].[Br:1][C:2]1[C:3]2[NH:9][C:10]([CH3:20])=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nc2cncc(Br)c2[nH]1
Yield: 52 %

Procedure:
A mixture of 5-bromopyridine-3,4-diamine (20 g, 107 mmol) and (EtO)3CMe (100 mL) in HOAc (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-1H-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS (ESI) m/z: 212 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@@H:12]([OH:42])[C@@H:13]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[C:26]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:25]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.CCO>[Pd].O>[NH2:10][CH2:11][C@@H:12]([OH:42])[C@@H:13]([NH:21][C:22](=[O:23])[C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[C:26]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN)cc(N2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of [(2R,3S)-2-hydroxy-3-({1-[3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-phenyl]-methanoyl}-amino)-4-phenyl-butyl]-carbamic acid benzyl ester (D105) (820 mg, 1.4 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 100 mg, 6% w/w), NH4CO2H (800 mg, 12.7 mmol, 9 equiv), EtOH (25 ml) and H2O (10 ml) was stirred at 60° C. for 1 h. The mixture was then cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the EtOH was removed in vacuo and the residue was partitioned between AcOEt and H2O. The aqueous phase was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give N-((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (420 mg, 66%) as a white solid. [M+H]+=454.0, RT=2.63 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=1
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow foam (36%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCCCCCC>O1CCCC1>[O:16]=[C:14]1[O:19][C:17](=[O:18])[CH:10]2[CH2:11][CH:12]1[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(C(=O)O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Under a nitrogen stream, 1-(tert-butoxycarbonyl)piperidine-3,5-dicarboxylic acid (5.00 g, 18.3 mmol) was suspended in tetrahydrofuran (10.0 mL), and trifluoroacetic anhydride (3.80 mL, 27.5 mmol) was added dropwise at 20-30° C. After completion of the dropwise addition, the mixture was stirred at 20-30° C. for 1 hr. To the reaction mixture was added dropwise heptane (20.0 mL) at 20-30° C., and the mixture was cooled to 0-10° C. and stirred for 3 hr. The precipitated crystals were collected by filtration, washed with heptane (3.00 mL), and dried under reduced pressure at 40° C. to give tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3,3,1]nonane-7-carboxylate as a white crystalline powder (4.03 g, yield 86.1%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13](=[O:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:23][Mg]Br.OC1(C)C2SC(C(N)=O)=NC=2C2C=C(C#CC(O)(C)C)C=CC=2OC1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:16])([CH3:23])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: C[Mg]Br
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1cc(F)c(Br)cc1-2
Agent: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Product: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (415 mg) was reacted with methylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo{e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (272 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 23.3 mg and 27.4 mg (17.4% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18]([O:20][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH:18]([OH:20])[CH2:19]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-t-butyldiphenylsilyloxyazetidine (1.49 g, 2.82 mmol) (obtained as described in Reference Example 64(1)) in anhydrous tetrahydrofuran (75 ml) was added a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3.39 ml, 3.39 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) ethyl acetate:methanol (9:1) as the eluant to afford 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-hydroxyazetidine (582 mg, yield 71%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31](CC)CC)[CH3:30].BrCC#N>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:30][C:29]#[N:31])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC#N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (522 mg) obtained in Example 23-4 was dissolved in DMF (10 ml) and added with triethylamine (372 μl) and bromoacetonitrile (139 μl) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (469 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.[O-:15][C:16]#[N:17].[K+].C(O)(=O)C>O>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH2:17])=[O:15])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2nc(NC(N)=O)sc2C(C)(C)C1
Reaction time: 1 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (0.3mole), potassium cyanate (0.3 mole) and concentrated acetic acid (90 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. A mild exotherm is noted at the beginning of the reaction. Stirring is continued for a period of about 1 hour with no external heating. Water (90 ml) is added and the resulting mixture filtered. The filtered-off solids are recrystallized from methanol to yield the desired product N-(5,5,7,7-tetramethyl-4-5,6,7-tetrahydrobenzothiazol-2-yl)urea.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[NH:3]1.[H-].[Na+].[CH3:23]I>CN(C)C=O.O>[CH3:23][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]21[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]=[N:19][CH:20]=[C:13]21
Reactant: CI
Reactant: N#Cc1ccc2c(c1)C(=O)NC21CCCn2cncc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(C#N)ccc2C12CCCn1cncc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 mmol of 3′-oxo-2′,3′,6,7-tetrahydro-5H-spiro[imidazo[1,5-a]pyridine-8,1′-isoindole]-5′-carbonitrile (Example 13) in 5 ml of N,N-dimethylformamide is treated with 1.2 mmol of sodium hydride (60% dispersion in oil). The reaction mixture is stirred for 20 minutes at room temperature, and then 1.2 mmol of methyl iodide are added. The reaction mixture is stirred for 20 minutes at room temperature, then diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH3:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:16]([OH:20])(=O)[CH2:17]O>>[OH:20][CH2:16][C:17]1[N:14]([CH3:15])[C:3]2=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=[C:2]2[N:1]=1
Reactant: O=C(O)CO
Reactant: CNc1nc(-c2ccccc2)ccc1N
Product: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Yield: 15.3 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 4.9 g of 3-amino-2-methylamino-6-phenylpyridine (prepared as described in Preparation 109) and 5.6 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 0.9 g of the title compound, melting at 174°-177° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12]([CH3:14])[N:11](C)[CH2:10]2)=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1.Cl[O-].[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12]([CH3:14])[N:11]=[CH:10]2)=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1C=NN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 1.44 g (0.00482 mole) of 4-amino-5-chloro-2-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide in 100 ml of methanol, cooled to -30° C. and under nitrogen atmosphere was added dropwise 10.5 ml (0.007 mole) of 5% aqueous sodium hypochlorite over a 15 minute period. The mixture was slowly warmed to 0° C. at which temperature it was stirred for 1 hr. The mixture was diluted with 250 ml of chloroform and extracted successively with 100 ml of water and 100 ml of saturated sodium chloride solution. The chloroform layer was dried over sodium sulfate and concentrated in vacuo. The concentrate was filtered through silica gel (eluted with ethyl acetate:hexane:methanol, 4.5:4.5:1). The filtrate was concentrated and the residue was triturated with cold diethyl ether to give 0.58 g (43%) of the title product as white powder, m.p. 173°-175° C.