Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(O[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])C>CC#N>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: NCCN1CCNCC1
Reactant: CCOc1ccncc1[N+](=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1NCCN1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-aminoethyl)piperazine and 4-ethoxy-3-nitropyridine in CH3CN was heated at reflux for 40 hours. The reaction mixture was cooled to ambient temperature and concentrated to give 3-nitro-4-[2-(piperazine-1-yl)ethyl]aminopyridine which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][N:6]([CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:2]
Reactant: CCOC(CNc1ccccc1F)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN(C)c1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-2-fluoroaniline (1.00 g, 4.40 mmol) in anhydrous DMF (10 mL) at 0° C. was added NaH (0.16 g, 6.60 mmol) portionwise. After 30 min, MeI (0.5 mL, 8.80 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (2×100 mL), and the EtOAc solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to give N-(2,2-diethoxyethyl)-2-fluoro-N-methylaniline (0.41 g, 38%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.05-6.96 (m, 3 H), 6.83-6.81 (m, 1H), 4.69 (t, 1H, J=5.2 Hz), 3.72-3.64 (m, 2H), 3.55-3.49 (m, 2H), 3.33 (dd, 2H, J=5.2, 1.2 Hz), 2.97 (s, 3H), 1.19-1.53 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.ClCCl.Cl.[CH2:20](O)[CH3:21]>C(OCC)C>[CH2:20]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[CH3:21]
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc(N)c1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a cooled solution (−15° C.) of 3-aminophenylacetic acid (10.2, 67 mmol) in ethanol (200 mL) was added dropwise thionyl chloride (10 mL, 0.14 mol). The reaction mixture was stirred for 24 h allowing the temperature to slowly rise to rt. Evaporation of the volatiles gave a beige solid that was stripped several times with dichloromethane. The solid was then treated with hot diethyl ether and filtered to remove diethyl sulphite. Recrystallization from dietyl ether gave 14.4 g, 67 mmol, 100% of the desired compound as an off-white crystalline hydrochloride, mp 135° C. IR (KBr) cm−1 2857,2614, 1740
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:24][C@H:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[OH:29].CN1CCOCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:2]([C:7]([NH:24][C@H:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:27][C:28](=[O:29])[OH:30])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a solution of Boc-Leu-OSu and Glu-OtBu in DMF was added NMM and DMAP. The solution was stirred at ambient temperatures for 18 hours then the solvent was removed. Crude product was taken up in 100 ml CHCl3, washed 3× with pH 3 water (100 ml), once with water (100 ml) and once with brine (100 ml). Organic layer was dried with MgSO4 and filtered. Solvent was removed and solid was dried over vacuum. Solid was collected as a white powder (8.78 g, quant. yield, ˜80% purity TLC). Product was used directly without further characterization.
Reaction SMILES: [C:1]1(=[CH:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>C(OCC)(=O)C>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([S:23][C:1]2([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C=C1CCCC1
Reactant: Sc1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1

Procedure:
A mixture of cyclopentylideneacetic acid (2 mmol) and p-(phenoxy)-thiophenol (2 mmol) was heated at 110° C. under nitrogen in the presence of piperidine (100 μL) for 24 hours. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid. The organic layer was separated, dried and evaporated under reduced pressure to give crude 2-[-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid, which can be used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=4)[C:12]=3[CH:32]=2)=[CH:4][CH:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[C@H:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:29])=[O:28])=[CH:30][CH:31]=4)[C:12]=3[CH:32]=2)=[CH:4][CH:3]=1.[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[C@@H:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:29])=[O:28])=[CH:30][CH:31]=4)[C:12]=3[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)CC2C
Solvent: CCCCCC
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)C[C@@H]2C
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)C[C@H]2C
Yield: 67.5 %
Yield: 47.5 %

Procedure:
4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide (80 mg, 0.19 mmol) was separated by chiral HPLC (Daicel AD-H (250 mm×20 mm×5 μm), hexane/ethanol (0.2 diethylamine)=30:70, flow rate: 13 mL/min), then (R)-4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide (27 mg, 67.5%) and (S)-4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide (19 mg, 47.5%) were obtained. The retention times were 14.265 minute and 18.705 minute respectively in chiral prep-HPLC chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:27])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]#N)[CH2:20][CH2:19]4)[C:12]=3[S:11][C:10]=2[CH3:28])=[C:4]([CH3:29])[CH:3]=1.[OH-:30].[K+].[OH:32]S([O-])(=O)=O.[K+]>CCO.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:27])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:32])=[O:30])[CH2:20][CH2:19]4)[C:12]=3[S:11][C:10]=2[CH3:28])=[C:4]([CH3:29])[CH:3]=1
Reactant: [OH-]
Reactant: Cc1nc(N2CCC(CC#N)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCC(CC(=O)O)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 105 °C

Procedure:
A mixture of {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile (350 mg) and KOH (492 mg) in a mixture of EtOH (1.5 mL) and H2O (1.0 mL) in a sealed tube was heated at 105° C. for 3 hours. After concentration of the reaction mixture under reduced pressure, 5% KHSO4 aqueous solution was added and extracted with CHCl3. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: CHCl3/methanol=20:1) to obtain the title compound (164 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C([N:12]([CH2:15][CH3:16])CC)C.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH:15]2[CH2:16][CH:18]([CH2:17][OH:21])[CH:19]=[CH:20]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCCCO
Reactant: CCN(CC)CC
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(NC2C=CC(CO)C2)n1

Procedure:
To 14 mmol of crude 2a, 2-amino-4,6-dichloropyrimidine (3.74 g, 22.8 mmol), triethylamine (15 ml) and n-butanol (75 ml) were added and the mixture was refluxed for 48 hr. The volatile solvents were removed, residue was treated with methanol to separate the undissolved byproduct (the double pyrimidine nucleoside). The methanol solution was absorbed on silica gel (8 g) packed into a column (4.0×14 cm) and eluted with CHCl-MeOH (40:1) to yield 1.52 g (42%) of crude 4a. The product was recrystalized from ethyl acetate to yield 4a; mp 132-134° C., MS (30 ev, 200° C.); m/e 240 and 242 (M+ and M++2), 209 (M+−31), 144 (B+); IR: 3600-3000 (NH2, OH), 1620,1580 (C═C, C═N); Anal. (C10H13ClN4O) C,H,N.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2([OH:10])[CH2:9][O:8][CH2:7]2)[CH2:5][CH2:4]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]2[CH2:5][CH2:4]2)[CH2:9][O:8][CH2:7]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: OC1(C2CC2)COC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccn1)OC1(C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (315 mg, 7.88 mmol) in THF (20 mL) was added 3-cyclopropyloxetan-3-ol (750 mg, 6.57 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1421 mg, 6.57 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified via biotage (40 g column, 5-40% EtOAc:Hex) to give the expected product 3-cyclopropyloxetan-3-yl pyridin-2-yl carbonate (290 mg, 18.76% yield) as a clear thick oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.54-8.36 (m, 1H), 7.89-7.77 (m, 1H), 7.34-7.25 (m, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.84 (d, J=8.5 Hz, 2H), 4.42 (d, J=8.3 Hz, 2H), 1.67-1.56 (m, 1H), 0.81-0.72 (m, 2H), 0.72-0.63 (m, 2H).
Reaction SMILES: N([O-])=O.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:23]([O:25][C:26]([C@:28]1([N:48]=[N+:49]=[N-:50])[C@H:33]([O:34]S(C(F)(F)F)(=O)=O)[CH2:32][C@@H:31]2[C@H:29]1[C@@:30]2([F:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:27])[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]([C@:28]1([N:48]=[N+:49]=[N-:50])[C@@H:33]([OH:34])[CH2:32][C@@H:31]2[C@H:29]1[C@@:30]2([F:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.6 %

Procedure:
688 mg of potassium nitrite and 428 mg of 18-crown 6-ether was added to 701 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 6.9 mL of N,N-dimethylformamide, and the mixture was stirred for 1.5 days at room temperature and further stirred for 3.5 days at 45° C., under a nitrogen atmosphere. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 388 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2,6-diethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H:27]1[CH2:32][CH2:31][CH2:30]C[C@H:28]1[NH2:33].BrC1C=NC=CC=1>[Cu]I.O1CCOCC1>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:27]3[CH:28]=[N:33][CH:30]=[CH:31][CH:32]=3)[C:6]=2[N:14]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Brc1cccnc1
Product: NC(=O)c1cc2c3ccccc3n(-c3cccnc3)c2nc1N
Temperature: 110 °C
Yield: 164.8 %

Procedure:
To a stirred mixture of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol), Copper(I) iodide (8 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.88 mmol) under dry nitrogen was added (±)-trans-1,2-diaminocyclohexane (5 μL, 0.04 mmol) and 3-bromopyridine (43 μL, 0.442 mmol), followed by 1,4-dioxane (2 mL). The mixture was heated at 110° C. for 2 days. The reaction mixture was cooled to room temperature, extracted with methylene chloride (3×30 ml) and washed with water. The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield 2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67, 20 mg, 10%). NH4OAc standard conditions. DAD Retention time =5.99 min. M+H=310. 1H NMR (300 MHz, MeOD): δ 8.86 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.66-8.63 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.70 (dd, J=4.7, 8.2 Hz, 1H), 7.36-7.28 (m, 4H).
Reaction SMILES: NS([C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:6]=1C(OC)=O)(=O)=O.NS(C1C=C(C2C=CC=CC=2)C=CC=1[C:28]([O:30][CH3:31])=[O:29])(=O)=O.Cl[S:43]([N:46]=[C:47]=[O:48])(=[O:45])=[O:44]>ClC1C=CC=CC=1>[C:28]([C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:6]=1[S:43]([N:46]=[C:47]=[O:48])(=[O:45])=[O:44])([O:30][CH3:31])=[O:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1S(N)(=O)=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1S(N)(=O)=O
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(Oc2ccccc2)ccc1S(=O)(=O)N=C=O

Procedure:
A solution of 1.8 g of methyl 2-(aminosulfonyl)-4-phenoxybenzoate (prepared by methods analogous to the sulfonamide of Example 5) in 15 mL chlorobenzene was treated with 0.55 mL of chlorosulfonyl isocyanate at room temperature, then heated to 100° for ca. 2 hours. The dark mixture was then cooled, decanted from some tarry residue and evaporated under reduced pressure. The title compound was indicated by the presence of a band at 2240 cm-1 in the infrared spectrum (neat liquid). It was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14]/[N:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:25]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][C:28]=1[C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])([O-])=O>>[C:34]([O:33][C:31]([C:30]1[CH:38]=[CH:39][C:27]([C:26]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[C:25]=2[CH2:52][CH2:53][CH2:54][CH3:55])=[C:28]([C:40]([N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:41])[CH:29]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(Oc2ccccc2)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(Oc2ccccc2)cc1
Yield: 51.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-phenoxyphenyl)hydrazono)acetate (55 mg, 0.19 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (90 mg, 0.19 mmol) were converted to the title compound (68 mg, 50%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.44-6.82 (m, 14H), 5.02-4.98 (m, 1H), 4.48-4.39 (m, 1H), 4.34-4.27 (m, 2H), 4.14-3.98 (m, 1H), 3.58-3.35 (m, 1H), 2.83-2.50 (m, 4H), 1.61 (s, 9H), 1.27 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H), 1.16-0.89 (m, 4H), 0.65-0.60 (m, 3H); MS(ESI+) m/z 700.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[C:18]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[F:29])[NH:21]2)[C:17](O)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CC#N.C(O)(C(F)(F)F)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[N:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([F:29])[C:27]=3[CH2:28][CH:20]2[C:18]2[N:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCOCc1ccccc1
Reactant: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc2c1CC1c3nc(Cl)ccc3OC(CCOCc3ccccc3)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 3-(benzyloxy)propanal (465 mg, 2.83 mmol) and 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (500 mg, 1.89 mmol) in MeCN (15 mL) was added TFA (10 mg, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The it was basified by NaHCO3 (aq.), and then it was concentrated in vacuo, the resulting residue was purified using column chromatography (petroleum ether:EtOAc=10:1) to provide 6-(2-(benzyloxy)ethyl)-2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (540 mg, yield: 69%). 1H-NMR (CDCl3, 400 MHz) δ 7.28˜7.38 (m, 5H), 7.04˜7.10 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.50 (t, J=8.0 Hz, 1H), 5.93 (t, J=7.2 Hz, 1H), 5.02 (d, J=8.8 Hz, 1H), 4.55 (d, J=2.4 Hz, 1H), 3.62˜3.71 (m, 3H), 3.40˜3.48 (m, 1H), 2.19˜2.27 (m, 2H). MS (M+H)+: 411.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]1>C(O)(C)C>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:22][CH2:21]1
Reactant: ClCCCN1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: O=c1oc2ccccc2c(OCCCN2CCOCC2)c1-c1ccccc1
Yield: 71 %

Procedure:
This compound is obtained by the method indicated in Example 8, from 14.3 g. (0.06 mol) of 4-hydroxy-3-phenyl-coumarin and 15.6 g. (0.078 mol) of 3-morpholino-1-chloropropane hydrochloride. 15.6 g. of a white solid are isolated. Yield 71% (theoretical yield 21.9 g.); M.P. 82° C. (isopropanol).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH2:22]([N:29]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][CH:32]([NH2:37])[CH2:33]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OS(OCC)(=O)=O)C>>[CH2:22]([N:29]1[CH:30]2[CH2:36][CH2:35][CH:34]1[CH2:33][CH:32]([NH:37][S:2]([C:5]1[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=1)(=[O:3])=[O:4])[CH2:31]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: NC1CC2CCC(C1)N2Cc1ccccc1
Agent: CCOS(=O)(=O)OCC
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CC4CCC(C3)N4Cc3ccccc3)cc2c2cc[nH]c12

Procedure:
8-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is prepared according to synthesis 111, from 360 mg (1.1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 238 mg (1.1 mmol) of 8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylamine to give, after esterification according to general method C (using diethylsulfate as the dialkylsulfate) and precipitation in water, 411 mg (69% in two stages) of 8-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[C:59]([F:64])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:58]=[C:59]([F:64])[CH:60]=[C:61]([F:63])[CH:62]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:65][CH:66]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(F)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
To a solution of 80 mg (0.45 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 143 mg of TBTU (0.45 mmol) in 5 ml DMF, were added 0.38 ml (2.23 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 176 mg (0.58 mmol) of (4-tert-butyl-benzyl)-[2-(3,5-difluoro-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 166 mg light brown foam (78%). MS 464.1 (M)
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=1>>[CH3:43][C:41]1[CH:42]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:38]=[C:39]([CH3:44])[N:40]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.049, m/z=459.1; 1H NMR (CD3OD) 0.94 (s, 3H), 1.24 (s, 3H), 1.55 (d, 3H), 2.15 (s, 2H), 2.23 (m, 1H), 2.45 (m, 1H), 2.51 (s, 6H), 3.05 (m, 1H), 5.57 (m, 1H), 7.04 (d, 2H), 7.24 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (m, 1H).