Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.[BH4-].[Na+].Cl.[CH3:25]O>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: CO
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cc1ccc2c(c1)C(OC)c1ccccc1CO2

Procedure:
A mixture of 5.64 g. of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate, 0.4 g. of sodium borohydride and 250 ml. of methanol is stirred at 0°-2° for four hours. The reaction product is treated with 1 N hydrochloric acid and extracted with chloroform, and the chloroform extracts are washed with saturated sodium bicarbonate solution and dried with sodium sulfate. The chloroform is evaporated to leave methyl 6, 11-dihydro-11-methoxydibenz[b,e]oxepin-2-acetate as an oil;
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N+:13][O-:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2ccc(C#N)nc2c1
Solvent: ClCCl
Product: Cc1ccc2ccc(C#[N+][O-])nc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
7-Methylquinoline-2-carbonitrile (181 g, 1.1 mol, 1.0 equiv.) was dissolved in dichloromethane (3.3 L, 0.3 M). m-Chloroperbenzoic acid (500 g, 2.9 mol, 2.6 equiv) was added and the reaction mixture was heated to 40° C. After 3 hr mCPBA (7 g, 40 mmol, 0.04 equiv.) was added and the mixture was allowed to stir overnight at room temperature. The mixture was extracted with 3 L of 1N NaOH aq., washed twice with 20 ml of dichloromethane and the combined organic phases were washed with DI water then dried over MgSO4. The organics were filtered and the solvent was removed to give 192 g of 7-methylquinoline-2-carbonitrile N-oxide (1-4). LRMS m/z (M+H)4 185.2 found, 185.2 required.
Reaction SMILES: [S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][CH:21]4[CH2:23][CH2:22]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@@H:6]1[O:24][Si](C(C)(C)C)(C)C)[NH2:2]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1>[S:1](=[O:32])(=[O:33])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][CH:21]4[CH2:22][CH2:23]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@@H:6]1[OH:24])[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1COS(N)(=O)=O
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(NCC4CC4)ncnc32)C[C@@H]1O
Reaction time: 3 h
Yield: 4.4 %

Procedure:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate (88.0 mg, 0.178 mmol) was dissolved in THF (1.00 mL) and pyridine (3.00 mL). Pyridine hydrofluoride (12 drops) was added and the reaction was stirred for 3 h. The reaction was quenched using saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in DCM. The compound was re-purified via silica gel chromatography eluting with 10% MeOH in DCM to afford the title compound (3.00 mg, 4.4%). 1H NMR (400 MHz, CD3OD, δ): 8.05 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.6 Hz, 1H), 5.45-5.32 (m, 1H), 4.56 (br s, 1H), 4.45 (br s, 1H), 4.33 (dd, J=7.6, 7.6 Hz, 1H), 4.15 (dd, J=7.4, 7.4 Hz, 1H), 3.34 (d, J=6.9 Hz, 2H), 2.83-2.68 (m, 1H), 2.35-2.08 (m, 3H), 2.05-1.93 (m, 1H), 1.33-1.03 (m, 3H), 0.93-0.77 (m, 1H) ppm. LC/MS: Rt=0.85 min, ES+ 382 (FA standard).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH2:22]>C1COCC1>[O:9]=[C:1]([CH2:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH:2]([C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:10][CH2:11][CH3:12]
Reactant: NCCCCNCCCN
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(NCCCCNCCCNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Reaction time: 72 h

Procedure:
11.9 g (69 mmol) of diethyl maleate were added to a solution of 5 g (34.5 mmol) of spermidine in 5 ml of THF. The reaction mixture was stirred for 3 days at 60° C. After removing the solvent in vacuo, the product was obtained quantitatively as a yellow liquid.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:34][CH2:33][N:32]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:11])[CH2:31][CH:30]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(C2=CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-Morpholin-4-yl-5-nitro-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 470.1 (M−H, 100%)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCO)nc2c1C#N
Yield: 92.2 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.13 ml, 0.76 mmol) and N-methylethanolamine (62.0 μl, 0.78 mmol) were added. After heating under reflux for 3 hours, N-methylethanolamine (62.0 μl, 0.78 mmol) was added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain a pale yellow oil (0.21 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH:11]1([C:14]2([F:18])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][C:14]([CH:11]3[CH2:13][CH2:12]3)([F:18])[CH2:15]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC1(C2CC2)CN(c2cc(Cl)nc(Cl)c2)C1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A solution of 2,4,6-trichloropyridine (3.0 g, 16.4 mmol), 3-cyclopropyl-3-fluoroazetidine hydrogen chloride (2.49 g, 16.4 mmol) and DIPEA (7.09 ml, 41.0 mmol) in ethanol (40 ml) was heated under reflux for 1 h. Reaction mixture cooled to room temperature then concentrated to dryness in vacuo. Crude product purified by flash chromatography on silica (0 to 100% EtOAc: petrol) to give title compound as a white solid (1.56 g, 36%). 1H NMR (CDCl3) 0.52-0.48 (2H, m), 0.72-0.67 (2H, m), 1.42-1.31 (1H, m), 3.91 (2H, ddd), 4.05 (2H, ddd), 6.20 (2H, s). ES+261.30.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 157. 1H NMR (CDCl3) δ: 7.69 (d, 1H, J=8.0 Hz), 7.64 (d, 1H, J=7.7 Hz), 7.52 (t, 1H, J=7.5 Hz), 7.38 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.2 Hz), 6.22 (d, 1H, J=2.2 Hz), 4.48 (broad s, 2H), 3.67 (ABq, 2H, JAB=15.6 Hz), 3.57-3.50 (m, 1H), 3.40-3.30 (m, 2H), 3.15-2.90 (m, 6H), 2.60 (dd, 1H, J=13.2, 9.6 Hz), 2.20-1.97 (m, 2H). LRMS (ES)+: 420.4 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>CCO.[OH-].[Na+]>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:30])([C:22]([F:25])([F:23])[F:24])[C:26]([F:27])([F:28])[F:29])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
Reflux for 3 hours a solution of 2.3 g (5 mmole) 4-acetamido-4'-(hexafluoro-2-hydroxy-2-propyl)benzenesulfonanilide in 30 ml EtOH and 4 g 50% NaOH. Pour onto water, acidify with concentrated HCl, extract with Et2O, dry and concentrate. Recrystallize from CHCl3 -Et2O to give the product; m.p. 160°-161° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:5])=O.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]#[N:5])=[O:12]
Reactant: NC(=O)[C@H]1CCCN1
Reactant: O=C(Cl)CCl
Product: N#C[C@H]1CCCN1C(=O)CCl
Yield: 66 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, D-proline amide (3.2 g) was reacted with chloroacetyl chloride (2.5 ml) and then subjected to dehydration reaction to give the title compound (3.2 g, Y.:66%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[CH:4][C:3]=2[O:2]1.Cl[Sn]Cl.O>CCO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(/C=C/c1cccc([N+](=O)[O-])c1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)c1
Yield: 21.3 %

Procedure:
A solution of Example 60 (1.36 g, 2.9 mmol), SnCl2.H2O (2.8 g, 5 equiv.) in EtOH was refluxed overnight. After evaporation of the solvent, the residue was taken up in 50 mL of NaOH (1N). The aqueous phase was extracted with 2×100 mL of DCM and 2×50 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, DCM:MeOH (95:5) and recrystallization from EtOH:DCM gave the title compound (0.27 g, 21%) as a pale yellow powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=O.[OH-].[Na+]>ClCCCl>[N:20]1[CH2:24][CH2:23][CH2:22][C:21]=1[N:20]1[CH2:24][CH2:23][CH:22]=[C:21]1[N:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1CCCN1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C1=C(N2c3ccccc3Sc3ccccc32)N(C2=NCCC2)CC1
Reaction time: 4 h
Yield: 17 %

Procedure:
Phosphorus oxychloride (38.3 g., 0.25 mole) in 50 ml. of 1,2-dichloroethane is added in one portion to a stirred mixture of phenothiazine (49.8 g., 0.25 mole) and 2-pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2-dichloroethane. The mixture is stirred for 4 hr. at room temperature, permitted to stand for a period of 15 hr. and then poured into a mixture of 200 ml. of 5N sodium hydroxide and 100 g. of crushed ice. The 1,2-dichloroethane layer is separated and the aqueous layer extracted with 100 ml. of additional 1,2-dichloroethane. The combined 1,2-dichloroethane fractions are sequentially extracted with 300 ml. of 1.5N hydrochloric acid and 200 ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydroxide and extracted repeatedly with chloroform. After drying over magnesium sulfate, the chloroform solution is concentrated and the residual material thus obtained stirred with 200 ml. of acetone to remove the acetone soluble 10-[2-(1-pyrrolinyl)]-phenothiazine by-product and filtered. The filter cake is washed with additional acetone and dried providing 14.1 g. (17% yield) of 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE as the free base, m.p. 199°-201° C. The bis-pyrrolinyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200-250 ml. of anhydrous ether provides the hydrochloride salt. Crystallization of the hydrochloride salt from absolute ethanol-anhydrous ether affords analytically pure 10-[1-(1PYRROLIN-2-YL)-2-PYRROLIN-2-YL PHENOTHIAZINE] HYDROCHLORIDE solvated with 1/5 mole of ethanol as an off white solid, m.p. 237°-239° C. (corr.).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.CCCCCC.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1COCC1>[N:22]1[CH:23]=[CH:24][C:19]([CH:18]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[OH:25])=[CH:20][CH:21]=1
Reactant: O=Cc1ccncc1
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a stirred solution of 2-bromothiophene (10 g, 61.34 mmol) in dry THF (42 ml) was dropwise added a solution of n-butyl lithium in n-hexane (1.6M, 42.0 ml, 67.48 mmol) at −78° C. The resulting suspension was stirred at the same temperature for 30 min. After 30 min, a solution of isonicotinaldehyde (6.56 g, 61.34 mmol) in dry THF (30 ml) was dropwise added and continued the stirring at −78° C. for another 2 h. The progress of the reaction was monitored by TLC. The reaction was quenched with NH4Cl solution (10 ml) and diluted with diethyl ether (500 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated. The crude compound was triturated with hexane and diethyl ether to get the desired compound as an off-white solid (4.0 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J=4.9, 1.5 Hz, 2H), 7.45-7.38 (m, 3H), 6.97-6.93 (m, 2H), 6.45 (d, J=4.4 Hz, 1H), 5.97 (d, J=4.4 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][C:26]([F:29])([F:28])[C:25]([F:31])([F:30])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][C:26]([F:28])([F:29])[C:25]([F:30])([F:31])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
A mixture of 5-tert-Butyl-3-(4-methoxy-benzyl)-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and triethylsilane in TFA was heated to 70° C. for 22 h and evaporated to dryness. The residue was used without further purification in the consecutive step.
Reaction SMILES: [CH:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>N1C=CC=CC=1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[C:3](/[CH:1]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:4]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1c[nH]c2ccccc2c1=O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1c[nH]c2ccccc2c1=O

Procedure:
A solution of 3-formyl-4(1H)-quinolone (6 g) from Example 33 and malonic acid (18 g) in pyridine (300 ml) was heated on a steam bath for four hours. The reaction mixture was then evaporated down and the residue washed thoroughly with water. Recrystallisation from DMF/H2O gave the title compound, m.p. 242°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH:13]([C:18](=O)[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:18]([CH3:19])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc2n(c1C)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
1.40 g of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyrate were taken up in 10 ml of dimethylformamide, 100 mg of p-toluenesulphonic acid monohydrate were added and the mixture was stirred at 80° C. for 2 h. For the working up the mixture was treated with 30 ml of water and extracted 5 times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulphate, concentrated in a vacuum and purified by chromatography on 70 g of silica gel with dichloromethane containing 2% methanol. There were obtained 550 mg (41%) of methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate of m.p. 137-138° C. which was used without further purification for the step described below.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1)=[O:26]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(Cl)c1ccccc1Br
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4Br)nc3cc21
Yield: 39.3 %

Procedure:
2-Bromo-N-(7,7-dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-benzamide (136 mg) is prepared from D5 (211 mg) and 2-bromobenzoyl chloride (342 mg; 1.51 mmol) as described in Example 170.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([OH:45])=O)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:59][NH:60][OH:61].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[CH2:21][CH:20]2[C:43]([N:60]([CH3:59])[OH:61])=[O:45])=[O:18])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)O)C2)cc(OC)c1OC
Reactant: CNO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)N(C)O)C2)cc(OC)c1OC
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
Added to a solution of 148 mg (0.24 mmol) of 1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-piperazine-2-carboxylic acid synthesized by the process of Example 34 in anhydrous dimethylformamide (0.5 ml) was 44.9 mg (0.28 mmol) of 1,1′-carbonyldiimidazole. After the mixture was stirred for 15 minutes, 24.9 mg (0.30 mmol) of N-methylhydroxyamine hydrochloride and 0.050 ml (0.36 mmol) of triethylamine were added, and the mixture was stirred for an additional 15 minutes. Added to the reaction mixture was 3 ml of 0.5N hydrochloric acid to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil (179 mg) was purified by column chromatography on silica gel to obtain 134.6 mg (yield: 87%) of the title compound as pale yellow amorphous powder.
Reaction SMILES: C([Li])CCC.CN(CCN(C)C)C.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH:21]=[CH:20][C:19]=2[CH:23]=1.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C>CCOCC>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([B:28]([OH:29])[OH:27])=[CH:20][C:19]=2[CH:23]=1
Reactant: Cc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc2oc(B(O)O)cc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (35.16 ml) was added dropwise to a stirred solution of TMEDA (9.58 ml) and 5-methylbenzofuran (8.22 g) in ether (250 ml) maintaining the temperature below -60° C. throughout. The solution was warmed to about -10° C. over 45 minutes and stirred at this temperature for 30 minutes. A precipitate formed on warming. The suspension was cooled and triisopropylborate (43 ml) was added, maintaining the temperature below -60° C. The solution was warmed gradually to room temperature before quenching with 2N HCl (70 ml). The mixture was extracted with ether (3×50 ml) and the combined organic extracts washed with 2N HCl (4×30 ml), water (2×30 ml) and dried before evaporation to give the title compound as an orange solid (12.75 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].O.[N:12]1[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1>ClCCl>[N+:12]1([O-:6])[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccnc2c3ccccc3c3ccccc3c21
Temperature: 25 °C
Yield: 51 %

Procedure:
First, to a solution in which 1.36 g of dibenzo[f,h]quinoxaline was dissolved in 20 mL of dichloromethane was added 2.04 g of 3-chlorobenzoic acid (abbreviation: MCPBA) in a nitrogen atmosphere, followed by stirring at room temperature for 1 week. Water was added to this mixture, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Then, the resulting solution was filtered. The solvent of this solution was distilled off. The resulting residue was purified by silica gel column chromatography which uses a mixed solvent of dichloromethane and ethyl acetate as a developing layer. By recrystallization from dichloromethane, the object of the synthesis was obtained (as a white powder in a yield of 51%). The synthesis scheme of Step 1 is illustrated in the following (a″′-2-1).