Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21]C(OC(C)(C)C)=O)[CH:16]=2)=[CH:9][N:8]=1)[CH3:2].C(O)(C(F)(F)F)=O.N([O-])=O.[Na+].[N-:42]=[N+:43]=[N-].[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[N+:42]=[N-:43])[CH:16]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(C(=O)Nc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CSc1ccc(C(=O)Nc2cccc(N=[N+]=[N-])c2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 118.6 %

Procedure:
To a 0° C. solution of [5-(3-tert-butoxycarbonylaminophenyl-carbamoyl)pyridin-2-ylsulfanyl]-acetic acid ethyl ester (41 mg, 0.10 mmol) in DCM (3 mL) was added TFA (3 mL) followed by stirring for 15 minutes. The mixture was concentrated in vacuo and was taken up in a mixture of acetic acid (3 mL) and water (1 mL), cooled to 0° C., and treated with a solution of sodium nitrite (15 mg, 0.23 mmol) in water (1 mL). After 5 minutes, the mixture was treated with neat sodium azide (15 mg, 0.22 mmol) and the solution was allowed to warm to an ambient temperature over 30 minutes. The mixture was poured into water and was extracted with ethyl acetate (3×25 mL) and the combined extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration gave 42.4 mg (100%) of the [5-(3-azido-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid ethyl ester as a solid: 1H NMR (300 MHz, acetone-d6) δ 9.73 (bs, 1H), 8.98 (m, 1H), 8.18 (m, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.45 (m, 1H, 7.39 (m, 1H), 6.85 (m, 1H), 4.15 (m, 2H), 4.07 (s, 2H), 1.22 (m, 3H); MS (EI) m/z 356.11 (M−H)−.
Reaction SMILES: [C-:1]#[N:2].[K+].[C-]#N.[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][C@@H:27]1[N:31]([CH3:32])[C:30](=[O:33])[CH2:29][CH2:28]1>CC#N>[CH3:32][N:31]1[C:30](=[O:33])[CH2:29][CH2:28][C@@H:27]1[CH2:26][C:1]#[N:2]
Reactant: CN1C(=O)CC[C@@H]1CBr
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)CC[C@@H]1CC#N

Procedure:
KCN (1.26 g, 25.7 mmols), NaCN (2.78 mg, 42.7 mmols) and 18-crown-6 (793 mg, 3 mmols) were added to a CH3CN (60 ml) solution of the (5R)-5-(bromomethyl)-1-methylpyrrolidin-2-one (2.67 g, 13.9 mmols), and the mixture was heated for 44 hours under reflux. The inorganic matter was filtered off, and the filtrate was diluted with AcOEt (50 ml). The dilution was washed with a saturated aqueous solution (30 ml) of NaCl, and dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 100 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2R)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile as a mixture (1.49 g) with impurities difficult to separate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[OH:32][C@@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c([C@@H](C)O)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of (R)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 mL) was added DIPEA (24 μL, 0.14 mmol) and isobutyryl chloride (14 μL, 0.13 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-8%) affording 860 (16 mg, 24%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.96-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.25 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J=6.34 Hz), 4.36-4.09 (4 H, brd s), 4.35 (1 H, t, J=8.22 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95-3.94 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67 (1 H, dd, J=9.77, 5.28 Hz), 3.24-3.23 (3 H, m), 2.45-2.44 (1 H, m), 1.60 (3 H, d, J=6.49 Hz), 0.98 (3 H, d, J=1.77 Hz), 0.97 (3 H, d, J=1.79 Hz)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]1[N:30]2[C@H:24]([CH2:25][O:26][CH2:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=32)[CH2:23][CH2:22]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]4[C@H:24]([CH2:25][O:26][CH2:27][C:28]=3[CH:34]=2)[CH2:23][CH2:22][CH2:21]4)=[N:3][CH:4]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)COC[C@@H]1CCCN21
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)COC[C@@H]2CCCN32)ncc1Cl

Procedure:
Following an analogous procedure to that described in Example 5, the reaction of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and (S)-(2,3,3a,4-Tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amine gave 2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide, upon purification by flash chromatography (Dichloromethane: MeOH 98:2) followed by trituration with Et2O, as solid (32%)2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide; 1H NMR (400 MHz, DMSO-d6) δ9.30 (s, 2H), 8.56 (m, 1H), 8.22 (s, 1H), 7.79 (m, 2H), 7.63 (m, 1H), 7.44 (s, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.81 (d, J=8.71 Hz, 1H0, 4.53 (d, J=13.04 Hz, 1H), 4.27 (d, J=13.01 Hz, 1H), 3.88 (d, J=9.54 Hz, 1H), 3.31-3.19 (2m along with water peak, 2H), 2.88 (m, 1H), 2.43 (d, J=4.73 Hz, 3H), 2.07 (m, 1H), 1.84 (m, 1H), 1.47 (m, 1H); MS (m/e) 501, 502 (M+H); mp 187-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH2:6][OH:7].[CH3:12][N:13]=[C:14]=S.CI.CCOCC>CO>[OH:7][CH2:6][CH2:5][N:4]1[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:12]1[NH:13][CH3:14]
Reactant: Nc1ccccc1NCCO
Reactant: CN=C=S
Solvent: CI
Solvent: CCOCC
Solvent: CO
Product: CNc1nc2ccccc2n1CCO
Temperature: 0 °C
Yield: 21.4 %

Procedure:
According to the procedure of B. Agai, et al., Tetrahedron, 32, 839, (1976), to a cooled (0° C.), stirred suspension of 2-(2-aminoanilino)ethanol (30.4 g, 0.200 mol) in MeOH (100 mL) was added a solution of CH3NCS (14.6 g, 0.200 mol) in MeOH (60 mL) dropwise. The resulting mixture was stirred at room temperature for 4 hours and then heated under reflux for 15 minutes. CH3I (28.4 g, 0.200 mol) was added and the mixture was heated under reflux for 10 minutes, cooled to room temperature and stirred for 2 hours. Ether (200 mL) was added and the resulting precipitate was collected by filtration, taken up in nBuOH (140 mL), and heated under reflux for 10 hours. The mixture was cooled in the freezer for 3 hours and the white crystals were filtered. The material was dissolved in H2O and the solution was neutralized with 10% aqueous K 2 CO3. The white solid was collected by filtration to give 8.2 g (21%) of product m.p. >200° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([CH:13]([F:31])[F:12])=[N:19][CH:18]=1)[CH2:23][C:24]1([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=468.0, tR (minutes, Method F)=2.84. [α]D20=+27.80 (c=3.41 mg/mL,CHCl3)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[O:16])[N:7]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CCOCC3)N2)n1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (105d, 0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and morpholine (0.1 mmol, 8.3 μL). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone (102, 5.7 mg, 22%) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.83 (s, 3H) 3.15 (dd, J=17.31, 10.23 Hz, 2H) 3.43-3.51 (m, 2H) 3.63 (d, J=5.31 Hz, 2H) 3.65-3.71 (m, 4H) 3.89 (s, 3H) 4.71 (s, 2H) 4.97 (dd, J=10.36, 3.79 Hz, 1H) 5.96 (br. s., 1H) 6.77 (d, J=8.34 Hz, 1H) 7.03 (d, J=7.07 Hz, 1H) 7.14 (dd, J=9.35, 2.78 Hz, 1H) 7.19 (td, J=8.40, 2.65 Hz, 1H) 7.63 (dd, J=8.84, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C26H28FN7O4, 522.22; found 522.00.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1.[OH:14][C:15]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:21])[C:16](OCC)=O.CCOC(C)=O.CCCCCC>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[N:9]=[C:16]([C:15]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:14])[CH3:21])[O:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(O)c1ccncc1
Reactant: NC(=NO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccncc1)c1nc(-c2ccc(F)cc2)no1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
Sodium hydride (60%, 6.00 g, 150 mmol) was taken up in THF (250 mL) under nitrogen atmosphere, and then a solution of 4-fluoro-N′-hydroxybenzimidamide (Step 2; 23.22 g, 150 mmol) in THF (250 mL) was added. The resulting reaction mixture was heated at 50° C. for 15 min, and then a solution of ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate (Step 1; 25 g, 120 mmol) in THF (250 mL) was added. The mixture was stirred for 1 hr at 50° C. The progress of reaction was monitored by TLC using solvent system EtOAc:Hexane (7:3). After completion of reaction, the solvent was concentrated to one third of the total volume. The crude mixture was poured into ice water and extracted with EtOAc (3×500 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The crude residue was washed with water several times to obtain a solid which was then washed with hexane (100 mL) followed by 50 mL of chilled ether to obtain 14 g (38%) of 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol as a colorless solid. HPLC purity: 99.4%; 1H NMR (400 MHz, DMSO-d6): δ 8.58 (d, 2H, J=5.6 Hz), 8.06-8.03 (m, 2H), 7.51 (d, 2H, J=6.4 Hz), 7.39 (t, 2H, J=8.8 Hz), 7.09 (s, 1H), 1.96 (s, 3H); LC-MS m/z calculated for [M+H]+ 286.09. found 286.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: NCCCO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: O=C(NCCCO)c1cc2ccccc2[nH]1
Yield: 80 %

Procedure:
1H Indole-2-carboxylic acid (5.0 g, 31 mmol) and 3-amino-1-propanol (2.2 ml, 40.3 mmol) were coupled according to the procedure of Example 17 to 5.46 g (80% yield) of an off-white solid. MP 152-156° C.; 1H NMR (DMSO-d6): δ 1.6-1.7 (m, CH2),3.31-3.37 (q, CH2), 3.41-3.51 (q, CH2), 4.52 (t, NH), 7.0-7.19 (m, 3 Ar H), 7.40 (d, 1 Ar H), 7.58 (d, 1 Ar H), 8.46 (t, NH), 11.9 (s, NH) Electrospray Mass Spec: m/z 217.2 (M+H)+.
Reaction SMILES: [BrH:1].Br[CH:3]([CH3:6])[CH2:4][NH2:5].Cl.[CH:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(COC)OC>[CH:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:5][CH2:4][CH2:3][CH2:6][Br:1])=[O:28])=[CH:25][CH:24]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br
Reactant: CC(Br)CN
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C(NCCCBr)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a slurry of 21.80 g. of 2-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.96 g. of 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with glyme. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution is heated for four hours and cooled overnight. The solid is removed by filtration and the filtrate diluted with 200 ml. of water. The precipitate is collected and crystallized from cyclohexane. The solid is recrystallized from acetonitrile to yield the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:31][CH2:30]CC[CH2:27][CH2:26]1.Cl>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:31][CH2:25][CH2:26][CH2:27][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Agent: Cl
Solvent: CCO
Product: O=C(OC1CCCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.25 h

Procedure:
A mixture of 10.35 g (30 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 50 g of cycloheptanol and 2 g of tetraethyl orthotitanate is heated to 130° for 8 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution obtained is poured into about 20 percent hydrochloric acid. The mixture is stirred for 15 minutes, the chloroform phase is separated, washed successively with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate/hexane there is obtained cycloheptyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 179°-180°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCc1ccccc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCc1ccccc1
Yield: 90.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and benzylamine (54 μL, 0.5 mmol) to give 170 mg of the title compound (89%): mp 220°~223° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 8.46~8.55 (m, 1H), 7.19~7.37 (m, 6H), 7.14 (d, 1H, J=2 Hz), 5.09~5.19 (m, 1H), 4.21~4.35 (m, 2H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.77 (dm, 1H, J=17.1 Hz), 2.41~2.54 (m, 2H), 2.00 (dm, 1H, J=13.5 Hz), 1.72~1.90 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:14]2[C:15](=[O:18])[O:16][CH2:17][C@H:13]2[C@H:12]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[C:21]([O:28][CH3:29])[CH:20]=2)[C:11]2[C:3]1=[CH:4][C:5]1[O:9][CH2:8][O:7][C:6]=1[CH:10]=2.N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O.CCOCC>[NH2:1][C@H:2]1[C@@H:14]2[C:15](=[O:18])[O:16][CH2:17][C@H:13]2[C@H:12]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[C:21]([O:28][CH3:29])[CH:20]=2)[C:11]2[C:3]1=[CH:4][C:5]1[O:9][CH2:8][O:7][C:6]=1[CH:10]=2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 7.4 mmol of the compound of Example 14, 58.8 mmol of imidazole and 13 mmol of tert-butyldimethylsilyl chloride in 225 ml of anhydrous dimethylformarnide is stirred at ambient temperature. After reaction for 17 hours, the mixture is poured into a mixture of water and ether. After exraction with ether, the combined organic phases are dried, filtered and then concentrated under reduced pressure. The residue is subsequently recrystallised from a heptane/benzene mixture enabling the expected product to be isolated.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:18][OH:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([CH2:18][O:19][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Mesyl chloride (2.7 ml) was added to a solution of 1-benzyl-3-(dibenzylaminomethyl)-3-hydroxymethylpyrrolidine (7.88 g) and triethylamine (5.5 ml) in chloroform (80 ml) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was sequentially washed with an aqueous solution of sodium hydrogencarbonate and water, dried, concentrated and purified by silica gel column chromatography to give 6.97 g of the object compound as an oil.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[C:33]([CH2:39][C:40]3[CH:49]=[CH:48][C:43]4[O:44][CH2:45][CH2:46][O:47][C:42]=4[CH:41]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:50][O:51][C:52](=[O:65])[C@H:53]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:54]([CH3:56])[CH3:55])C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[O:44]1[C:43]2[CH:48]=[CH:49][C:40]([CH2:39][C:33]3[CH:32]=[C:31]([C@@H:12]4[O:11][C@H:10]([CH2:50][O:51][C:52](=[O:65])[C@H:53]([NH:57][C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH:54]([CH3:56])[CH3:55])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]4[OH:23])[CH:36]=[CH:35][C:34]=3[CH2:37][CH3:38])=[CH:41][C:42]=2[O:47][CH2:46][CH2:45]1
Reactant: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3R,4R,5S,65)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (4.5 g, 5.0 mmol) in ethyl acetate: methanol (1:4 mixture, 50 ml) was added palladium hydroxide (2.0 g). After stirring for overnight at room temperature, reaction mixture was filtered through celite bed, concentrated and purified by silica gel column chromatography to give 3.12 g of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[O:18]C)[CH:5]=[CH:4][C:3]=1[S:24]([NH:27][CH2:28][CH2:29]O)(=[O:26])=[O:25].[Br:31]B(Br)Br>>[Br:31][CH2:29][CH2:28][NH:27][S:24]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[OH:18])=[CH:7][C:2]=1[F:1])(=[O:26])=[O:25]
Reactant: BrB(Br)Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)c(F)c1
Product: O=c1[nH]c2ccc(O)c(-c3ccc(S(=O)(=O)NCCBr)c(F)c3)c2c2ccsc12
Yield: 78.7 %

Procedure:
Following General Procedure F, 2-fluoro-N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (52 mg, 0.12 mmol) was reacted with tribromoborane (0.80 mL, 0.23 mmol) to afford the desired product (47 mg, 81%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.52 (s, 1H), 8.45 (t, J=5.7 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.46 (d, J=10.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.30 (dd, J=8.0, 1.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 3.53 (t, J=6.3 Hz, 2H), 3.42 (q, J=6.0 Hz, 2H); ESI MS m/z 499 [C19H14BrFN2O4S2+H]+; HPLC 98.3% (AUC), tR=15.61 min.