Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[N:14]1([CH:3]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClC1CCCCc2cccnc21
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCCCC2N1CCCC1
Reaction time: 5 h

Procedure:
5 g of 9-chloro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine hydrochloride were dissolved in 12.5 ml of water and 8 ml of pyrrolidine were added. The mixture was refluxed with vigorous stirring for 5 hours and the excess pyrrolidine was evaporated off under reduced pressure. 25 ml of a saturated solution of sodium bicarbonate and then 50 ml of water were added followed by extraction with methylene chloride. The combined organic phases were washed with water, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and methanol (9-1) to obtain 2.25 g of the expected product with an Rf=0.20. 2.25 g of the product were crystallized from petroleum ether (b.p. 40°-70° C.) to obtain 2 g of the expected product melting about 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]2[C:16]=1[C:17]([OH:33])=[C:18]([C:28](OCC)=[O:29])[CH:19]=[N:20]2.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:28]([C:18]2[CH:19]=[N:20][C:21]3[C:16]([C:17]=2[OH:33])=[C:15]([F:14])[C:24]([F:25])=[C:23]([F:26])[C:22]=3[F:27])=[O:29])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)c(F)c2c1O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)c(F)c2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.080 mL) in 5 mL of toluene is added 0.70 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then a suspension of 0.20 g of ethyl 5,6,7,8-tetrafluoro-4-hydroxy-3-quinolinecarboxylate (U.S. Pat. No. 4,940,710) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 3 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of 10 mL of 3 M hydrochloric acid and 10 mL of crushed ice. After stirring the mixture vigorously for 20 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several h at 5° C. Filtration of this mixture gives the desired amide as 0.12 g of a solid.
Reaction SMILES: ClC1C2CN(C(OCC3C=CC=CC=3)=O)CCC=2N=C(C)N=1.CB(O)O.[CH3:27][C:28]1[N:29]=[C:30]([CH3:48])[C:31]2[CH2:37][N:36](C(OCC3C=CC=CC=3)=O)[CH2:35][CH2:34][C:32]=2[N:33]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:27][C:28]1[N:29]=[C:30]([CH3:48])[C:31]2[CH2:37][NH:36][CH2:35][CH2:34][C:32]=2[N:33]=1
Reactant: Cc1nc(C)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB(O)O
Product: Cc1nc(C)c2c(n1)CCNC2

Procedure:
Benzyl 4-chloro-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (see footnote 8) was reacted with methylboronic acid and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to generate benzyl 2,4-dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate; hydrogenolytic removal of the protecting group provided the requisite 2,4-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][C:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:20])([CH3:19])[O:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CO>C1COCC1>[Br:7][CH2:8][CH:9]([C:11]1[CH:22]=[CH:21][C:14]2[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=2[CH:12]=1)[OH:10]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OCc2cc(C(O)CBr)ccc2O1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated with borane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After the addition was complete the solution was kept between 30 and 35° C. for 1 h and then cooled in ice and 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885) (3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperature below 5° C. The mixture was stirred under nitrogen for a further 0.5 h and then methanol (4 ml) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by chromatography on flash silica gel eluting with ethyl acetate-cyclohexane (1:4) to give the title compound (3.31 g) δ (CDCl3) 7.15 (1H, dd, J 8, 2 Hz), 7.03 (1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J 10, 4 Hz), 3.50 (1H, dd, J 10, 9 Hz), 1.54 (6H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[OH:20][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)(C)c1ccc(C(=O)CCCn2ccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(O)CCCn2ccnc2)cc1
Reaction time: 1 h

Procedure:
To a 0° C. solution of 5.0 g of the above ketone in 150 ml. of anhydrous methanol was added excess sodium borohydride and the mixture stirred for one hour. After removal of the solvent, a small quantity of water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to afford 1-[4-hydroxy-4-(4-t-butylphenyl)butyl]imidazole, which was converted to the oxalate salt and recrystallized from ethyl acetate/ethanol, m.p. 205°-207° C.(foaming).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cccnc2)c1
Temperature: 115 °C
Yield: 48.4 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 42.1 mmol), 3-bromopyridine (8 g, 50.6 mmol), potassium carbonate (powder, 14 g, 101 mmol) and copper iodide (325 mesh powder, 6 g, 31.6 mmol) was heated at 115° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated in vacuo then CH2Cl2 (100 mL) was added, the reaction mixture was filtered, and the filtrate was washed with H2O (3×50 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1/Hexane:EtOAc to give the title product (6.4 g, 48% yield).
Reaction SMILES: [CH2:1](O)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCCCCCC/C=C\CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC/C=C\CCl

Procedure:
By the procedure of example 12, (Z)-2-undecen-1-ol (13 g), 27.8 g of triphenylphosphine in 100 ml of dry CCl4 were reacted under reflux for 6.5 h. Workup as described before as in example 12 gave 12.3 g of (Z)-1-chloro-2-undecene as a colorless oil: bp 65°-66° C./0.2 mmHg.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].[Cl-].[NH4+]>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:25][CH2:21][CH2:22][C:23]#[C:24][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: C#CCCO
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCNC1
Product: OCCC#Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 164.7 %

Procedure:
To a stirred solution of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (9.7 g, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.9 g, 5 mmol) in pyrrolidine (75 ml) was added a solution of 3-butyn-1-ol (7.0 g, 0.1 mol) in pyrrolidine (75 ml), then copper (I) iodide (475 mg, 2.5 mmol). The resulting solution was heated to 75° C. with stirring under nitrogen. After 2.5 h the reaction mixture was allowed to cool, treated with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to leave a residue (13.6 g). This residue was flash chromatographed over silica gel (eluted with dichloromethane/diethyl ether 4:1) to give the desired product (3.95 g, 48%) m/z, 330.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11](=O)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)CC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(CC2CCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To 5-bromo-3-[(cyclopentylacetyl)amino]thiophene-2-carboxamide (290 mg) were added 2M aqueous sodium hydroxide solution (1.75 mL) and ethanol (3.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL) was added, and the precipitate was collected by filtration to give the title compound (165 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21].OC1C2C=C(N3CCCCC3)N=NC=2N(C)C(=O)C=1C(OC)=O.Cl.NCC(OC(C)(C)C)=O>>[OH:1][C:2]1[C:11]2[CH:10]=[C:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(N3CCCCC3)nnc21
Agent: CC(C)(C)OC(=O)CN
Agent: COC(=O)c1c(O)c2cc(N3CCCCC3)nnc2n(C)c1=O
Agent: Cl
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(N3CCCCC3)nnc21

Procedure:
tert-Butyl 2-(5-hydroxy-8-methyl-7-oxo-3-(piperidin-1-yl)-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxamido)acetate. The title compound is prepared by reaction of methyl 5-hydroxy-8-methyl-7-oxo-3-(piperidin-1-yl)-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate and tert-butyl 2-aminoacetate hydrochloride according to Method 3(a).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16]([O:24]CC)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C(O)C.O>[N:6]1[CH:7]=[CH:8][C:3]([N:20]2[CH2:21][CH2:22][CH:17]([C:16]([OH:24])=[O:23])[CH2:18][CH2:19]2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 150 °C
Yield: 78.7 %

Procedure:
4-Chloropyridine hydrochloride (9.55 g) and triethylamine (26.0 ml) are dissolved in ethanol (10 ml) and water (30 ml), thereto is added ethyl isonicotinate (10.00 g), and then the reaction solution is heated at 150° C. for 96 hours in a sealed tube. After allowing to cool, ethanol is added to the reaction solution and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, the resulting residue is suspended in chloroform, the precipitates are collected by filtration and recrystallized from water-N,N-dimethylformamide to give the title compound (10.34 g).
Reaction SMILES: [O:1]1CCN=[CH:2]1.[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[Li]C(CC)C.CN(C=O)C>C1COCC1>[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:8]=1[CH:9]([OH:11])[O:10][C:2]2=[O:1]
Reactant: C1=NCCO1
Reactant: O=C(O)c1cc(F)ccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OC(O)c2c(F)ccc(F)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a -78° C. solution of the oxazoline derivative (7.95 g, 37.7 mmol), prepared from 2,5-difluorobenzoic acid in the usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.3 M solution). After 30 min, DMF (6.0 mL) was added, and the reaction was stirred at -78° C. for 2 hr. The reaction was tnen quenched with concentrated HCl (5 mL). Tne solvents were removed in vacuo, and the residue was taken up in 5 N HCl (5 mL) and heated on the steam bath overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (3×200 mL). Standard workup gave a light brown solid (6.5 g, 93%, mp 125°-128° C.).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:11]
Reactant: CCCCCCO
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOCC(OCC)OCC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Hexanol (200 g, 1.96 mol) and toluene (600 ml) were added to a 3 liter flask fitted with a mechanical stirrer and a reflux condenser. Sodium hydride (51.6 g, 2.15 mol) was added slowly to the resulting mixture, and then bromoacetaldehyde diethylacetal (385.7 g, 1.96 mol) was added dropwise. The mixture was heated to reflux temperature and maintained at that temperature for 6 hours. The mixture was then cooled to ambient temperature and was filtered to remove the resulting solids. Toluene was removed from the filtrate under reduced pressure, and the resulting product was distilled (85°-88° C.) to give 189.4 g of 2-hexyloxyacetaldehyde diethylacetal.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:27])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]([OH:27])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]c(-c2cccnc2)nc1C(O)CN1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a suspension of 1 g of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]-2-(4-phenyl-1-piperazinyl)ethanone in 5 ml of methanol, cooled in an ice-water bath, was added 0.2 g of sodium borohydride. After gas evolution ceased, this mixture was stirred in the bath for 45 minutes, with the addition of 2 ml of methanol after 5 minutes, and then at room temperature for one hour. A 0.1 g portion of sodium borohydride was added, the mixture was stirred in the ice-water bath for 30 minutes, then at room temperature for one hour. The addition of 0.1 g of sodium borohydride and the reaction conditions were repeated twice more, then the mixture was poured into ice-water. The mixture was adjusted to pH 7-8 with glacial acetic acid. The gummy solid was collected, washed with water and then triturated with 30 ml of ether for 15 minutes. The ether was decanted and the solid triturated with 10 ml of fresh ether. The solid was collected, washed with ether and dried in vacuo, giving 0.6 g of the desired product as a pale yellow solid, mp 180°-184° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]([CH3:24])[CH:3]([N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:19](OCC)=[O:20])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][CH:2]1[CH:3]([CH3:4])[N:5]2[C:9]3[N:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=[CH:13][C:8]=3[CH:7]=[C:6]2[C:19](=[O:20])[NH:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)N)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1NC(=O)c2cc3ccc(C(=O)O)nc3n2C1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.1 %

Procedure:
To a solution of diethyl 1-(3-aminobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (3.83 g, 11.5 mmol) in ethanol (45 mL) is added potassium carbonate (4.76 g, 34.5 mmol). The mixture is stirred at room temperature for 64 h. The ethanol is removed in vacuo and the aqueous mixture is acidified to pH 6 with 1N aqueous HCl. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a white solid (2.00 g, 54%). LCMS: 260.67 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([OH:16])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.2 %

Procedure:
Following the procedure as described in Example 11, except using the material from Example 24 (1.15 g, 2.66 mmol), CH2Cl2 (50 mL), TFA (5 mL, 64.9 mmol) and stirring at room temp for 18 h, 1.38 g of the title compound (quantitative yield) is obtained as a white solid as a mono TFA salt. LC/MS (Condition A): ret. T=2.86 min, (M+H)+ 376.13, and ret. T=3.03 min, (M+H)+ 376.13.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24]C)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[CH3:37][S:38]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[OH:24])=[CH:10][CH:9]=1)(=[O:6])=[O:7])(=[O:40])=[O:39]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.2 %

Procedure:
To a solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (390 mg, 0.90 mmol) and triethylamine (450 mg, 4.5 mmol) in anhydrous THF (20 mL) was added methane sulfonyl chloride (0.21 mL, 2.7 mmol) and the reaction mixture was stirred for 20 h at room temperature. The resulting precipitate was filtered and the filter cake was washed with THF (50 mL). The filtrate was concentrated and the residue was purified by flash chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product as a brown solid (250 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.14 (t, J=11.7 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.79 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.43 (d, J=9.0 Hz, 1H), 5.74 (d, J=5.4 Hz, 1H), 4.24 (t, J=10.5 Hz, 2H), 3.71 (s, 3H), 3.20 (q, J=11.7 Hz, 2H) ESI MS m/z 509 [C21H20N2O7S3+H]+
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])[CH:8]=2)[N:3]=1
Reactant: OCCNCCO
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN(CCO)CCO)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 35 μl of diethanolamine and 20 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 113 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH:41]=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.[O-:43][C:44]#N.[Na+].C(O)(=O)C>CO.[O-2].[O-2].[Mn+4]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: N#C[O-]
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of compound 4 (164 g), sodium cyanate (80 g) and manganese dioxide (500 g) in methanol (5.5l) was stirred at room temperature. Ethanoic acid (122 g) was added dropwise and the resulting reaction mixture was stirred and refluxed overnight. The reaction mixture was filtered over dicalite, and the filter residue was rinsed with CH3OH/CH2Cl2. The filtrate was evaporated. The residue was partitioned between DCM and aqueous K2CO3 solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 152 g (87%) of methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]-benzazepine-3-carboxylate (compound 6, mp. 179.3° C.).