Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH:21]([C:22]3[N:23]=[CH:24][NH:25][C:26]=3[CH3:27])[CH3:20])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1[nH]cnc1CCCl
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]cnc1C(C)N1CCc2c(C)c3ccccc3n2C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (1.88 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil 1.12 g) at 5° C. After being stirred at 5° C. for 30 minutes, 4-(2-chloroethyl)-5-methyl-1H-imidazole hydrochloride (2.17 g) in N,N-dimethylformamide (30 ml) was added dropwise over 20 minutes. The mixture was stirred at 5° C. for 30 minutes and at ambient temperature for 16 hours. The reaction mixture was diluted with chilled water and extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1, 30 ml×2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (3%-methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]indol-1(2H)-one as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=O.[CH2:20](N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]2[C:17](=[O:19])[CH2:16][O:15][N:14]([CH2:13][CH3:20])[C:9]2=[S:10])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN1OCC(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
A mixture of 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), N-methyl aminooxy acetic acid hydrochloride (7.78 g), triethylamine (20 g) and chloroform (200 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness The residue (8 g) was dissolved in benzene (150 mL). Phosphorus pentachloride (7 g) was added in portions. The mixture was heated at reflux for one hour then evaporated to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with sodium bicarbonate saturated solution (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10-20% ethyl acetate in hexane). Crystallization from ethyl acetate/hexane afforded the title compound (2.1 g) as a solid, m.p. 119-121° C. Mass spectrum (El, M.+) m/z 282/284. 1H-NMR (CDCl3; 400 MHz) δ7.32 (d, 1H), 7.23 (d, 1H), 7.13 (s, 1H), 4.81 (ABq, 2H), 4.26 (m, 2H), 2.13 (s, 3H), and 1.40 ppm (t, 3H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1[CH:16]=[C:17]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:18]=[C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH:2]1([N:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[C:17]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:16]=[C:15]([CH3:14])[CH:20]=3)[CH:25]=[N:24]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3C=CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromocyclohexene (0.18 mL, 1.57 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to an oven-dried flask containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.57 mmol) dissolved in DMF (5 mL). The mixture was warmed to 80° C. and stirred overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with 1:1 water:brine (3×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford racemic N-{3-[1-(cyclohex-2-en-1-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calcd. for C21H21F3N5 [M+H]+ 400. found 400.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.C([Li])CCC.[CH:14]([NH:17]C(C)C)(C)C.[CH2:21]([O:28][CH2:29][CH2:30][CH:31]=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S(=O)(=O)(O)O>C1COCC1.CCOCC>[CH2:21]([O:28][CH2:29][CH2:30][CH:31]([OH:32])[C:6]([CH3:7])([CH3:8])[C:14]#[N:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: O=CCCOCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C#N)C(O)CCOCc1ccccc1
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
5.47 g (79.17 mmol) of isobutyric acid nitrile is added in drops at −65° C. to an LDA solution (produced from 33.64 g (79.17 mmol) of n-butyllithium 15% in hexane, (1.6 M) and 80.1 g (79.17 mmol) of diisopropylamine), and it is stirred for 20 minutes at −65° C. Then, a solution that consists of 10 g (60.9 mmol) of 3-benzyloxy-1-propanaldehyde in 20 ml of THF is added in drops (over 60 minutes). The temperature is kept at −65° C.! Then, it is stirred for one more hour. It is now heated to −20° C., a solution that consists of 20% sulfuric acid is added in drops, and the temperature is allowed to reach +10° C. Then, 50 ml of MTB-ether is added, and then the organic phase is separated. The organic phase is washed with water and then with saturated sodium bicarbonate. Finally, it is washed once more with water and then evaporated to the dry state in a vacuum.
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])=[N:7][C:6]=2[CH:17]=1.S(Cl)([Cl:23])(=O)=O>>[Cl:23][C:4]1[C:5]2[S:9][C:8]([C:10]3[C:11]([NH2:16])=[N:12][NH:13][C:14]=3[CH3:15])=[N:7][C:6]=2[CH:17]=[C:2]([F:1])[C:3]=1[O:18][CH3:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc2sc(-c3c(C)n[nH]c3N)nc2cc1F
Product: COc1c(F)cc2nc(-c3c(N)n[nH]c3C)sc2c1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
4-(5-Fluoro-6-methoxybenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (596 mg; 2.14 mmol) was mixed with 4 mL of sulfuryl chloride. The reaction was stirred at room temperature for several hours and then the reaction was quenched by the addition of water. The resulting precipitate was isolated by filtration to yield 417 mg (62%) of the title compound. MS (m/z, ES+): 364.2 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]([CH3:4])=[CH2:3].[Mg:5].[CH2:6]=[C:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][CH:10]=[O:11].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([Mg:5][Br:1])[CH:7]=[CH2:6].[CH3:4][C:2]([CH:10]([OH:11])[CH2:9][CH2:8][C:7](=[CH2:6])[CH:12]=[CH2:13])=[CH2:3]
Reactant: [Mg]
Reactant: C=C(C)Br
Reactant: C=CC(=C)CCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(=C)CCC(O)C(=C)C
Product: C=CC[Mg]Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2-Propenyl magnesium bromide is prepared under nitrogen from 2-bromopropene (50 g, 0.417 M) and magnesium (12 g, 0.5 M) in tetrahydrofuran (150 ml) in the usual manner. To this reagent, a solution of 4-methylene-5-hexenal (62 g, 0.564 M) in tetrahydrofuran (100 ml) is slowly added during a two hour period at 0° C. After the addition is complete, the mixture is allowed to warm to room temperature and then stirred overnight. The resulting mixture is poured into cold saturated ammonium chloride solution (500 ml) and the aqueous layer is extracted with ether (3×500 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed in vacuo. The residue (56.5 g) is purified by column chromatography on silica gel (350 g) with 25% ether in petroleum ether to give 2-methyl-6-methylene-1,7-octadien-3-ol (32 g, 51%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:33](=[O:42])[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:28][CH2:27]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[C:33](=[O:42])[NH:34][C:35]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:30][CH2:31]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Yield: 32 %

Procedure:
((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-acetic acid (90 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 32% yield. High resolution MS m/e (M+H)+=602.1776.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[CH3:28][N:29]([CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:30][CH2:31][OH:32]
Reactant: CNCCO
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(CCO)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol as light brown oil, MS: 395 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH3:11].[CH2:12]=O>O>[ClH:1].[CH3:9][N:10]([CH2:12][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[N:3]=1)[CH3:11]
Reactant: Oc1cccnc1Cl
Reactant: CNC
Reactant: C=O
Solvent: O
Product: CN(C)Cc1ccc(O)c(Cl)n1
Product: Cl

Procedure:
A solution of 2-chloro-3-hydroxypyridine (12.95 g), 50% aqueous dimethylamine (15 ml) and 40% aqueous formaldehyde (10 ml) in water (30 ml) was heated on a steam bath for 21/2 hours and then allowed to stand at room temperature (20°) overnight. The solution was evaporated and the residue was taken up in chloroform. The solution was decanted off from some insoluble material, dried (Na2SO4) and evaporated to small bulk. An excess of ethereal hydrogen chloride was added and the resulting hydrochloride salt was filtered off and crystallised twice from isopropanol to give 2-(dimethylaminomethyl)-5-hydroxy-6-chloropyridine hydrochloride (5.70 g), m.p. 207°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.54 g, 0.76 mmol) prepared in example 55c in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1 mL, 5.53 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-hydroxycarbonylmethylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[H-].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C1COCC1.CN(C=O)C>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH:6]2[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(C3C(=O)Nc4cc(OC)c(OC)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
A solution of 5,6-dimethoxyoxindole (107 mg, 0.56 mmol), (Chem Pharm Bull. 1971, 19, 1325-1327), in a mixture of THF (1 ml) and DMF (1 ml) was added dropwise under nitrogen to a suspension of sodiumn hydride (22 mg, 0.55 mmol, prewashed with hexane) in THF (1 ml). The mixture was stirred for 20 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (50 mg, 0.18 mmol), (prepared as described for the starting material in Example 2), in THF (1 ml) was added dropwise. The mixture was heated at 60° C. for 1.5 hours, allowed to cool and partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH7 with 1M hydrochloric acid. The organic layer was washed with brine, dried (MgSO4), and volatiles removed by evaporation. The residue was purified by column flash chromatography eluting with methylene chloride/acetonitrile/methanol (60/38/2 followed by 60/35/5). The resulting solid was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride was added. The mixture was concentrated by evaporation, the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(5,6-dimethoxyoxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (33 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]3[CH:19]=[N:20][N:21]([C:24]4[N:29]=[C:28]([NH:30]CC5C=CC(OC)=CC=5)[N:27]=[C:26]([NH:40]CC5C=CC(OC)=CC=5)[N:25]=4)[C:22]=3[CH3:23])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[ClH:1].[NH2:40][C:26]1[N:27]=[C:28]([NH2:30])[N:29]=[C:24]([N:21]2[C:22]([CH3:23])=[C:18](/[CH:17]=[CH:16]/[CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:10][CH2:11]3)[CH:19]=[N:20]2)[N:25]=1
Reactant: COc1ccc(CNc2nc(NCc3ccc(OC)cc3)nc(-n3ncc(/C=C/CN4CCN(c5cc(F)cc(Cl)c5)CC4)c3C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1c(/C=C/CN2CCN(c3cc(F)cc(Cl)c3)CC2)cnn1-c1nc(N)nc(N)n1
Product: Cl
Yield: 95 %

Procedure:
A mixture consisting of 1.26 g of the compound obtained in Example 54, 50 ml of trifluoroacetic acid, and 0.62 ml of anisole was treated in the same manner as in Example 37 to obtain 420 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
Sodium hydride (11.7 g, 60% dispersion in mineral oil, 293 mmol) was added portionwise to a cooled (0° C.) solution of 1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (130 g, 266 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (61.5 g, 293 mmol) in DMF (1.25 L). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (1.25 L). The resultant precipitate was collected by filtration (slow) and the cake washed with water, followed by methanol and then diethyl ether. The resulting cake was dried to afford the title compound as a grey solid (154 g, 94%). LCMS (Method B): RT=4.28 min, M+H+=617/619. 1H NMR (400 MHz, CDCl3): 8.49 (d, J=2.3 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.33-8.33 (m, 2H), 7.78-7.76 (m, 2H), 7.64-7.64 (m, 1H), 7.55-7.54 (m, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.43 (s, 2H), 4.28 (s, 2H), 3.96 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[C:13]1(N)[CH:18]=[CH:17][CH:16]=C[C:14]=1[NH2:19]>C(O)(=O)C.O>[CH:11]1[C:1]2[C:2](=[O:4])[N:19]=[C:14]3[CH:13]=[CH:18][CH:17]=[CH:16][C:5]3=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc2ccccc2nc2ccccc12
Temperature: 75 °C
Yield: 96 %

Procedure:
A mixture of isatoic anhydride (1 mol) and 1,2 phenylenediamine (1.1 mol) in aglacial acetic acid (60%) was heated at 75° C. for 3 hrs. The resulting mixture was diluted with water and solid filtered to obtained dibenzo[b,e][1,4]-diazepine-11-one in 96% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:29]1([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCCC1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1nc(OCC(=O)N(C)C2CCN(C3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31, cyclohexanone and sodium triacetoxy-borohydride in the same manner as in Example 32.
Reaction SMILES: Cl.CO.COC[O:7][C:8]1[CH:17]=[C:16]([O:18]COC)[CH:15]=[C:14]2[C:9]=1[C:10](=[S:23])[CH:11]=[C:12]([CH3:22])[O:13]2.O>C1COCC1>[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[C:10](=[S:23])[CH:11]=[C:12]([CH3:22])[O:13]2
Reactant: COCOc1cc(OCOC)c2c(=S)cc(C)oc2c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(=S)c2c(O)cc(O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.9 %

Procedure:
Under cooling on ice, 70 ml of hydrochloric acid/methanol was added to 70 ml of 9.47 g of 5,7-bis(methoxymethoxy)-2-methylthiochromone (30.35 mmol) in THF, and the mixture was stirred overnight at room temperature. After addition of water, the reaction solution was extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, to give 6.88 g of 5,7-dihydroxy-2-methylthiochromone. This product was subjected without purification to the following reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:21](=[O:24])[CH2:22]Cl)[C@@H:5]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:15]1([CH2:14][C@H:5]([N:4]2[CH2:3][CH2:2][NH:1][CH2:22][C:21]2=[O:24])[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN(C(=O)CCl)[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CCNCC1=O
Yield: 90.1 %

Procedure:
A solution of compound 12E (1.12 g, 2.5 mmol) and DIEA (1.4 ml, 8 mmol) in DMF (15 ml) was maintained at ambient temperature for 30 minutes. Reaction mixture was diluted with water (150 ml) and extracted with EtOAc (2×150 ml). Organic layer was washed with 5% aq. sodium bicarbonate (100 ml) and brine (100 ml), dried over anh. MgSO4 and evaporated in vacuum to provide target product (758 mg, 90%) as light yellow oil. LC-MS [M+H] 337.2 (C16H24N4O2S+H, requires 337.46).
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:17])[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:10]1[CH2:15][CH2:14][C:13](=[N:32][OH:33])[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(=NO)CC1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-1H-indole-2-carboxylic acid [1(S)-benzyl-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-amide (406 mg, 0.96 mmol) , hydroxylamine hydrochloride (80 mg, 1.15 mmol), and potassium carbonate, (159 mg, 1.15 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 18 h and concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (411 mg, 98%): HPLC (60/40) 5.13 minutes (97%); TSPMS 439/441 (MH+, 100%);