Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[NH2:22][C@@H:23]([CH3:26])[CH2:24][OH:25]>O>[N+:8]([C:7]1[C:2]([NH:22][C@@H:23]([CH3:26])[CH2:24][OH:25])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 114.3 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 2-chloro-3-nitropyridine (4.0 g, 25.2 mmol), potassium carbonate (4.18 g, 30.3 mmol), and DMF (25 mL). Next, (S)-2-aminopropane-1-ol (1.990 g, 26.5 mmol) was added at rt. The yellow mixture was stirred at rt for 45 min, then was heated to 50° C. for 22 h. Heating was discontinued, and after the mixture had cooled, it was diluted with water (50 mL) and extracted with ethyl acetate. The organic phase was separated and washed with 5% aqueous sodium chloride solution (3×25 mL). The combined aqueous layers were extracted with ethyl acetate. The combined organic phases were concentrated to yield (S)-2-(3-nitropyridin-2-ylamino)propane-1-ol (5.68 g, 28.8 mmol, 114%) as a dark yellow syrup. MS (ESI, pos. ion) m/z 198 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:20][OH:21])=[C:15]([CH3:19])[C:16]=1[O:17][CH3:18])=[O:11])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1sc(C=O)c(C)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN1CCCC1CNC(=O)c1sc(CO)c(C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±) N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2-carboxamide (1.15 g) in ethanol (30 ml) was added sodium borohydride (0.154 g) in one portion. The solution was stirred at room temperature for 2 hours and then water (50 ml) added. After extraction with ethyl acetate, washing the organic extracts with water, drying over magnesium sulphate and filtering, the solvent was removed in vacuo to give the title compound as a golden oil, fumarate salt, m.p. 118°-119° C. (ex ethylacetate-ethanol ether as recrystallising solvent).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[N:23][C:24]#[N:25])[N:14]([C:15]4[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:28])[C:13](=[N:23][C:24]#[N:25])[N:14]([C:15]4[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: COc1ccc(-n2c(=NC#N)[nH]c3cnc4ccc(Br)cc4c32)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(Br)cc4c32)cn1
Reaction time: 0.25 h

Procedure:
To a solution of N-(8-bromo-1-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (compound of step 4, 0.674 mmol) in 5 ml of dry DMF at 0° C. was added NaH (60% dispersed in mineral oil, 1.011 mmol). The reaction mixture was stirred for 15 minutes followed by addition of methyl iodide (1.011 mmol). Reaction mixture was stirred at 0° C. for another 1 h and quenched with water. The solvent was removed; aqueous layer was extracted with DCM. Organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.62 (d, J=3 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.18 (dd, J=9 Hz, 3 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.80 (dd, J=9 Hz, 3 Hz, 1H), 7.21 (d, J=9 Hz, 1H), 7.03 (d, J=3 Hz, 1H), 4.01 (s, 3H), 3.83 (s, 3H); MS (m/z): 409 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH:6]2[C:11]([O:13]C)=[O:12])[O:4][CH2:3][CH2:2]1.[OH-].[K+]>C(O)C>[O:4]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH:6]2[C:11]([OH:13])=[O:12])[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CSCCC12OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CSCCC12OCCO2
Yield: 63 %

Procedure:
A solution of 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxylic acid, methyl ester (prepared according to Baldwin, J. J. et al. U.S. Pat. No. 4,803,286; 30.00 g, 0.137 mol) in ethanol (500 mL) and a solution of potassium hydroxide (16.80 g, 0.299 mol) in ethanol (300 mL) were combined and heated under reflux for 7 h. The solution was concentrated in vacuo and water was added. The mixture was extracted with ether, and the ether layer was discarded. The aqueous layer was made acidic and extracted with ether. The ether layers were washed, dried, and evaporated, and the residue was recrystallized from benzene/hexane to give 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxylic acid (17.8 g, 63%) as white crystals, mp 99-101° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:22])=[CH:19][N:18]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(Cl)nc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 6-chloronicotinoyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (47.7 mg, 47%). HPLC, Rt: 3.00 min. (purity 98.6%). LC/MS, M+(ESI): 340.2, M−(ESI): 338.2.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][S:29](C)=O>>[CH3:28][S:29][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
3.62 mmol of 2-fluoro-naphthacene-5,12-dione (prepared according to U.S. Pat. No. 4,522,754), 3.98 mmol of NaSCH3, 10.86 mmol of potassium carbonate and 10 ml of DMSO are stirred at 25° C. for 3 minutes. The mixture is poured onto water. The crystals are filtered off and dissolved in tetrahydrofuran/toluene and the solution is dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield 1 g (83%); melting point 195°-196° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]([OH:14])=[O:13])=[CH:17][C:18]=1[F:23])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)c(F)c1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
1.18 g (60%, 29.39 mmol) of sodium hydride were added to a solution of 4.0 g (13.36 mmol) of (R)-2-tert-butoxycarbonylamino-3-(3-fluoro-4-hydroxyphenyl)propionic acid in 23 ml of DMF while stirring at 0° C., and the mixture was stirred at this temperature. After 15 min, 1.27 ml (1.78 g, 14.7 mmol) of allyl bromide were added, and stirring was continued for 1 h while the mixture reached RT. It was quenched with methanol and, after cooling, excess methanol was removed in a rotary evaporator. Dilution with diethyl ether was followed by acidification with 1N hydrochloric acid, and the aqueous phase was extracted twice more with diethyl ether, and the combined organic phases were washed with saturated sodium chloride solution, dried over NaSO4, filtered and concentrated. 4.50 g of a yellowish oil were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([NH2:16])=[O:15])[CH:7]=[CH:6]2.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:9]2[C:8](=[CH:7][CH:6]=[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]3=2)[CH2:13][C:14](=[O:15])[NH:16]1
Reactant: O=Cc1ccccc1F
Reactant: COc1ccc2cc(CC(N)=O)ccc2c1
Product: COc1ccc2c3c(ccc2c1)CC(=O)NC3c1ccccc1F

Procedure:
Prepared from 6-methoxy-2-naphthylacetamide and 2-fluorobenzaldehyde.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48](Br)[CH:49]=[CH2:50]>C1COCC1>[CH2:50]([CH:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:49]=[CH2:48]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of di-tert-butyl N-trityl-L-glutamate (1.99 g, 1.85 mmol) in THF (50 mL) was cooled to −70° C. and a 1.0 M solution of lithium bis(trimethylsilyl)amide 47 mL, 47 mmol) in THF was added slowly (over a period of 20 min). The solution was stirred for 2 h at −70° C., and allyl bromide (1.44 g g, 11.9 mmol) was added drop wise at −70° C. After stirring for 1.5 h, the reaction mixture was quenched with saturated aqueous solution of NH4Cl, and warmed up to room temperature, and concentrated under vacuum. The resulting aqueous solution was extracted with dichloromethane, the combined organic phase was washed with water and was dried over sodium sulfate. After filtration, the solution was evaporated and the crude product was purified by flash chromatography (silica, ethyl acetate/n-hexane) to give the di-tert-butyl 4-allyl-N-trityl-L-glutamate (1.01 g, 46%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Br

Procedure:
To a solution of 2-bromo-4-fluorophenol (28 g) in a solution of sodium hydroxide (7 g) in water (100 ml), methyl chloroformate was dropwise added thereto at a temperature below 10° C. The produced crystals were collected by filtration and washed with water to give methyl 2-bromo-4-fluorophenylformate (41 g). M.P., 80.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COCCOCOc1cc(N)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COCCOCOc1cc(NCc2ccc(F)cc2)ccc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
To a solution of 4-amino-2-(2-methoxy-ethoxymethoxy)-benzonitrile (666 mg; 3 mmol) in 1,2-dichloroethan (15 mL) was added 4-fluorobenzaldehyd (496 mmol; 4 mmol) and carefully sodium triacetoxyborohydride (933 mg; 4.4 mmol). The mixture was stirred at 60° C. for 6 hours. The reaction mixture was added 1 M NaOH (aq.), dried by filtering through a silicone filter, evaporated onto SiO2 and purified by column chromatography (SiO2-heptane/EtOAc=2:1) to yield 700 mg pure product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH2:29]([N:37]([CH2:39]NC1C=CC=CC=1)[CH3:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:38][N:37]([CH2:39][C:9]1[CH:8]=[CH:7][C:12]([NH:4]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(CCc1ccccc1)CNc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and (N-phenethyl-N-methyl-aminomethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/ethanol=10:1) C34H33N3O3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=O.N1CCCCC1.Cl>C(O)C>[C:9]([C:8](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c(O)c1)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
To a mixture of 758 mg (5.00 mmole) of 4-chlorophenylacetonitriie (purchased from Tokyo Kasei), 691 mg (5.00 mmole) of 3,4-dihydroxybenzaldehyde (purchased from Tokyo Kasei) and 10 ml of ethanol (purchased from Kokusan Kagaku) were added 0.54 ml of piperidine (purchased from Wako Junyaku Kogyo), the mixture was refluxed with heating for 6 hours and air-cooled, the reaction product was added to 100 ml of 1N hydrochloric acid, and deposits were filtered, washed with water, dissolved in ethyl acetate, washed with a 20% sodium hydrogensulfite solution twice and subsequently with saturated saline once and dried over sodium anhydrous sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified according to silica gel column chromatography (effluent with a ratio of hexane to ethyl acetate of 5:1 to 5:2 used) to obtain 919 mg (yield: 67.6%) of α-cyano-4-chloro-3',4'-dihydroxystilbene (yellow crystal) represented by the following formula: ##STR147##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(N)CN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Yield: 50.7 %

Procedure:
198 g of 4,7-dichloroquinoline, 97 g of 1,2-diamino-2-methyl-propane and 101 g of triethylamine were stirred in 1 l of N-methyl-2-pyrrolidone at 150° C. under argon for 5 hours. The solvent was evaporated in a vacuum and the residue was taken up in 1 l of water. The pH was adjusted to 1 using 220 ml of 25% hydrochloric acid and the mixture was diluted with 6 l of water and extracted four times with 0.5 l of ethyl acetate each time. The clear aqueous solution was treated with about 900 g of KOH, whereby the pH rose to 14 and the product separated in crystalline form. This was filtered off under suction, rinsed with about 3 l of water and, for further purification, recrystallized from 4 l of acetonitrile. There were obtained 126.7 g (73%) of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, m.p. 182-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:12]1[C:13]2[C:4]([N:5]=[C:6]3[C:11]=1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[CH:7]3)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)NCCCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCNC(C)(C)C)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available N1-tert-butylbutane-1,4-diamine, the title compound was obtained; MS (Found M+1=386).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:27])[CH:18]=2)[C:6]1=[O:28]>O1CCOCC1.O>[CH:29]1([C@@H:4]([N:5]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH3:26])[N:19]([CH3:27])[CH:18]=3)[C:6]2=[O:28])[C:3]([OH:35])=[O:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)[C@@H](C1CCCCC1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n([C@@H](C(=O)O)C3CCCCC3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-cyclohexyl-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid methyl ester (124 mg, 0.26 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is purified by flash chromatography with 3.5% MeOH in dichloromethane as the eluent to afford the title compound. LCMS (ESMS): m/z 460.86 (M+H+)
Reaction SMILES: [OH-].[K+].[C:3]([C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[CH:14]=[CH:15][C:16]([O:18]C)=[O:17])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:3]([C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[CH:14]=[CH:15][C:16]([OH:18])=[O:17])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
Aqueous 5M potassium hydroxide (10 mL, 50 mmol) was added to a solution of methyl 3-benzoylcinnamate (2.5 g, 9.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and acidified to pH 1 using 1M aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give 3-benzoylcinnamic acid (2.2 g, 93%) as a yellow solid.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.C([NH:20][C:21]1[C:26]([NH2:27])=[C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[C:23]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)[N:22]=1)C1C=CC=CC=1>C1COCC1>[NH2:20][C:21]1[C:26]2[NH:27][C:6](=[O:7])[N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]=2[CH:24]=[C:23]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)[N:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(-c2ncco2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
CDI (821 mg, 5.06 mmol) was added to a solution of N*2*,N*4*-Dibenzyl-6-oxazol-2-yl-pyridine-2,3,4-triamine (940 mg, 2.53 mmol) in THF (15 ml). The solution was heated at 60° C. for 18 hrs under nitrogen. The reaction mixture was allowed to cool then concentrated in vacuo. The crude mixture was then dissolved in concentrated H2SO4 (15 ml) and left for 30 minutes at room temperature. The dark brown solution was added drop-wise onto crushed ice. The pH was adjusted to ˜9 by addition of a saturated aqueous solution of K2CO3 then the mixture was filtered. The solid was washed with EtOAc (200 ml) then the organic and aqueous filtrates were transferred to a separating funnel. The layers were separated and the aqueous was re-extracted with EtOAc (200 ml). The organics were combined, dried (MgSO4) and evaporated to an orange gummy solid. The crude material was triturated with EtOAc and toluene. The solid obtained was filtered and washed with EtOAc to give an off-white solid. This material was purified by HPLC on a Phenomenex Gemini 5 μm column (150×21.2 mmid), eluted with 0.05% formic acid (aq) and 0.05% formic acid in MeCN at a flow rate of 15 ml/min. The gradient was isocratic at 5% organic for 0.6 minutes, then increased linearly from 5% to 80% organic over 12 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[OH-].[K+].[CH2:18](I)[CH3:19]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:14]=1
Reactant: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Compound 1B (1.0 g, 3.7 mmol) was dissolved in 25 mL of DMSO and added to a prestirred 2.0 M solution of potassium hydroxide (415 mg, 7.4 mmol) in DMSO. Next, ethyl iodide (0.6 mL, 7.4 mmol) was added and the reaction stirred at room temperature overnight. The reaction was quenched with 75 mL of water and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and excess solvent removed to yield 1.04 g (95%) of desired product. MS (electrospray): mass calculated for C13H16BrNO2, 297.04; m/z found 298, [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O>>[CH2:21]([CH:18]([N:13]1[C:12]([C:32]2[S:31][CH:35]=[CH:34][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1cccs1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 37.2 %

Procedure:
The title compound (35 mg) was prepared as in Example 177, Steps C and D, using 148 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 122 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16; found, m/z 290.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.72-7.67 (m, 1H), 7.25-7.21 (m, 1H), 7.13-7.09 (m, 1H), 4.01-3.94 (m, 1H), 3.43-3.38 (m, 2H), 3.34-3.28 (m, 2H), 3.20-3.14 (m, 2H), 2.86-2.80 (m, 2H), 1.95-1.85 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).