Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NCCc2ccc(Cl)cc2)ccc1Cl
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonyl benzoic acid, 3.5 g. (0.014 mole), is added to a solution of 2-(p-chlorophenyl)ethylamine, 6.5 g. (0.042 mole) in 25 ml. methylene chloride. The resulting slurry is stirred overnight and filtered to recover 9.7 g. of residue. This is recrystallised three times from aqueous isopropanol, then dissolved in 1N aqueous sodium hydroxide, washed three times with ether, and then acidified with conc. hydrochloric acid. The resulting precipitate is recrystallized twice from aqueous isopropanol to yield the desired product, m.p. 176°-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]5[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]5)(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CC1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC(C)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 41.8 %

Procedure:
A mixture of 0.477 g of 1-(4-bromo-benzene-sulfonyl)-4-methyl-piperidine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 6 hours. To the resulting Mixture 5 ml of degassed dioxane, 0.342 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.104 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.25 g of potassium carbonate and 0.076 g of lithium chloride in 3 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 110° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. Crystallization of the residue from ethylacetate and recrystallization from acetonitril gives 0.185 g of the title compound as a solid of m.p. 186-188° C. The mass spectrum shows the molecular peak MH+ at 492.4 Da.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.6 %

Procedure:
2,2,2-Trifluoro-ethanol (7.09 g, 70.09 mmol) and stirred for 30 min. A solution of 1-Fluoro-4-nitro-benzene (10 g, 70.09 mmol) in DMF (25 mL) was added at 5-15° C., allowed to rt, stirred for 2 h, quenched with ice-water, filtered, washed with water and dried under high vacuum to obtain 14 g (89%) 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow solid. Subsequently, a solution of 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene (50 g, 226.2 mmol) in methanol (400 mL) was purged with nitrogen and 10% Pd—C (4.6 g) was added under nitrogen. This was stirred at rt under hydrogen atmosphere (balloon pressure) for 24 h. The reaction mixture was filtered through a celite bed and washed with methanol and the filtrate was removed under reduced pressure and washed with hexane to get 37 g (87%) 4-(2,2,2-Trifluoro-ethoxy)-phenylamine as a brown liquid. LC-MS: 192.4 [M+1]+. To a solution of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (12 g, 62.82 mmol) in DCM (1000 mL) was added solid NaHCO3 (52.77 g, 628.2 mmol). After 10 min, triphosgene (27.96 g, 94.24 mmol) dissolved in toluene (30 mL) was added to the reaction mixture under cooling at 10° C. and stirred for 10 min. The reaction mixture was filtered and the filtrate was concentrated, azeotroped twice with dry toluene to give 10 g 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow oily liquid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(OC(C)(C)C)(=O)C>[CH3:2][C:3]([O:8][C:7](=[O:9])[C@H:2]([C@H:3]([CH2:5][CH3:6])[CH3:4])[NH2:1])([CH3:5])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 240 h
Yield: 61 %

Procedure:
To an ice-bath cooled slurry of L-isoleucine (301.0 g; 2.29 mol) in tert-butyl acetate (2.5 L), 70% aq HClO4 (208 mL, 2.43 mol) was slowly added. The mixture was kept stirring for 10 days at room temperature. Then water (0.5 L) was poured into, followed by cooling in an ice bathand addition of NaOH pellets (100 g) and Na2CO3 (110 g) so that pH turned to basic. The mixture was extracted with EtOAc (4×0.5 L); the combined organic phases were washed with water (2×0.5 L) and brine (0.3 L), at last dried over Na2SO4. After careful removal of solvents in vacuo, the desired compound was obtained (262.2 g; 1.40 mol) and stored at −18° C. No further purification was required on the basis of TLC and NMR data. Yield 61%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:5])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:24])=[O:13])=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)COCCCC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
36 g (0.19 mol) of 4-ethoxycarbonylmethoxybutyric acid are charged to 180 ml of toluene and 0.1 ml of dimethyl formamide is added. Then 24.4 ml (0.28 mol) of oxalyl chloride are added dropwise over 30 minutes. When the addition is complete, the reaction mixture is heated to 50° C., stirred for 1 hour and concentrated by evaporation. Distillation of the residue gives 4-ethoxycarbonylmethoxybutyric acid chloride as a clear colourless liquid of b.p. 87°-89° C./2.10-2 torr.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[Cl:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.0305 mL, 0.195 mmol) to obtain 4-(3,4-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0132 g, yield 28%).
Reaction SMILES: Cl[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14].[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CO>[CH2:22]([S:29][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1C(=O)c2ccccc2C1(SCc1ccccc1)c1ccc(Cl)cc1

Procedure:
Distilled THF was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (1.06 g, 3.31 mmol) followed by benzyl mercaptan (0.855 mL, 7.29 mmol) as for general procedure C. On addition of the benzyl mercaptan, a pale pink precipitate formed which turned white over time. The ethyl acetate was mostly removed under vacuum. On leaving overnight in the fridge, clear crystals formed. The crude product was purified by flash column chromatography (20:80, EtOAc:petrol) and recrystallised in the minimum amount of hot ethyl acetate giving large colourless crystals of 3-benzylsulfanyl-3-(4-chlorophenyl)-2-propyl-2,3-dihydroisoindolin-1-one (918 mg, 2.25 mmol, 68%). Rf 0.68 (40:60 EtOAc:petrol). Mp. 131.5-133.4° C. λmax (CH3OH)/nm 223.0, Abs 0.964. IR: 3161, 2968, 1665, 1608, 1467, 1435, 1402 cm−1. 1H NMR (300 Hz, CDCl3); δ 0.72 (t, 3H, J=7.5 Hz, N(CH2)2—CH3), 1.37 (m, 1H, N—CH2—CH2—CH3), 1.57 (m, 1H, N—CH2—CH2—CH3), 2.80 (d, 1H, J=12 Hz, S—CH2), 3.10 (d, 1H, J=12 Hz, S—CH2), 3.17 (m, 1H, N—CH2), 3.36 (m, 1H, N—CH2), 6.92-7.81 (m, 13H, Ar). 13C NMR (75 Hz, CDCl3); 111.8 (N—(CH2)2—CH3), 21.5 (N—CH2—CH2), 33.4 (S—CH2), 42.6 (N—CH2), 78.2 (S—C—N), 123.2, 123.4, 127.3, 128.0, 128.5, 128.9, 128.9, 131.0, 132.8, 134.9, 135.8, 137.1, 148.3 (Ar), 167.9 (C═O). LC/MS-ES+ m/z 410.6, 408.7, 286.1, 287.1. Anal. Calcd. for C24H22ClNOS: C, 70.66; H, 5.44; N, 3.43%. Found C, 70.60; H, 5.51; N, 3.51%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a cold (0° C.) stirred solution of 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 mL) under argon was added dropwise 1.0 M 4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol). The reaction was warmed to RT for 2 hrs then quenched with sat'd aqueous NH4Cl (5 mL). The reaction mixture was extracted with EtOAc (2×50 mL), the organic layers combined and dried over Na2SO4. Pure 1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g, 96%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ 1.43 (9H,s), 1.61–2.22 (6H, m), 3.21–3031 (2H, m), 3.48–3.82 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([OH:27])=[O:26])=[C:10]1[C:28]([O:30][CH2:31][CH3:32])=[O:29].[OH-].[CH2:34]([N+](C)(C)C)[C:35]1C=CC=CC=1.C(Br)C>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([O:27][CH2:34][CH3:35])=[O:26])=[C:10]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCBr
Solvent: CS(C)=O
Product: CCOC(=O)C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Yield: 83.9 %

Procedure:
A solution of 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-butynoic acid (2.50 g), benzyltrimethylammonium hydroxide (0.87 g) and ethyl bromide (0.62 g) in dimethyl sulphoxide (5 ml) was stirred at room temperature for 48 hours, quenched into water and extracted twice into ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over MgSO4 and evaporated. The residue was crystallised from methanol to give the title compound (2.22 g), m.p. 123°-125°.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[O:13][CH2:12][CH2:11][N:10]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:9]1)(=O)=O.Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+].[I-].[K+]>CN(C)C=O.O>[Cl:35][C:30]1[CH:29]=[C:28]([C:8]2([CH2:7][CH2:6][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[O:13][CH2:12][CH2:11][N:10]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:9]2)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCOC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCOC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 86.7 %

Procedure:
200 mg (0.36 mmole) of 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol methanesulfonate [prepared as described in step (f) above], 105 mg (0.44 mmole) of 4-phenylpiperidine-4-carboxamide hydrochloride, 100 mg (1.19 mmole) of sodium hydrogencarbonate and 100 mg (0.60 mmole) of potassium iodide were suspended in 2 ml of dimethylformamide, and the mixture was then stirred under a stream of nitrogen at 80° C. for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was then washed with an aqueous solution of sodium thiosulfate, with water and with a saturated aqueous solution of sodium chloride, in that order. The organic extract was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by thin-layer chromatography, using a 9:1 by volume mixture of methylene chloride and methanol as the developing solvent and then crystallized from hexane, to give 205 mg (yield 86%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>S(Cl)(Cl)=O.CC(C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:8])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: O=C(c1cc(Cl)ccc1[N+](=O)[O-])N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Dissolved in 20 ml of thionyl chloride were 5.0 g (24.8 mmol) of 2-nitro-5-chlorobenzoic acid, followed by heating for 1.5 hours under reflux. After the reaction, the reaction mixture was concentrated and the residue was dissolved in 10 ml of acetone. The thus-obtained solution was added dropwise to a solution of 4.7 ml (62 mmol) of morpholine in 20 ml of acetone, followed by stirring at room temperature for 2 hours. Subsequent to the reaction, the reaction mixture was concentrated and then extracted with ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residue was recrystallized from ethyl acetate/n-hexane, whereby 5.64 g of the title compound were obtained as white powder (yield: 84%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][OH:36]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][CH2:35][OH:36])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (56 mg) and 3-bromo-1-propanol (0.04 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (36 mg, yield 71%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1.[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14]>C(O)CC>[ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH:10][C:13]([NH:15][C:16]([NH2:18])=[NH:17])=[NH:14])=[CH:6][CH:5]=1
Reactant: COc1ccc(CCN)cc1
Reactant: N#CN=C(N)N
Agent: Cl
Solvent: CCCO
Product: COc1ccc(CCNC(=N)NC(=N)N)cc1
Yield: 52 %

Procedure:
200 ml of n-propanol was added to 30.0 g (0.16 mol) of 4-methoxyphenethylamine hydrochloride and 14.1 g (0.17 mol) of dicyanodiamide, and the mixture was refluxed for 24 hours, and cooled. The resulting precipitated crystals were filtered off, and the filtrate was concentrated and cooled. The precipitated crystals were recrystallized from n-propanol to obtain 22.6 g of colorless crystals having a melting point of 136 to 139° C.
Reaction SMILES: [H-].[Na+].[N+](C(C)C)([O-])=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18]>C(O)C>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:4]
Reactant: Fc1c(Cl)cccc1CBr
Reactant: CC(C)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cccc(Cl)c1F
Reaction time: 0.17 h

Procedure:
Ethanol (100 mL) was added to sodium hydride (60% sodium hydride content, 4.7 g) at 0° C. under argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was added to the reaction mixture, and after the thus-obtained mixture was stirred for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The organic layer was sequentially washed with 1N aqueous sodium hydroxide, water, and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), to thereby give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily compound. Methanol (20 mL) was added to sodium hydride (60% sodium hydride content, 1.6 g) under argon atmosphere at 0° C., and the thus-obtained mixture was stirred for 10 minutes. After the reaction mixture was cooled to −20° C., a solution of the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within 20 minutes. After the reaction mixture was heated to 0° C., the mixture was stirred for 2.5 hours, and water (40 mL) was added thereto. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl acetate. The extract was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (toluene:hexane=3:17), to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g). This compound was dissolved in xylene (50 mL), and the solution was stirred at 130-140° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride). The thus-obtained compound was crystallized from diethyl ether-hexane, to thereby give the title compound (440 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20](B(O)O)[CH:21]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1nnc(N)nc1-c1ccccc1
Yield: 22.8 %

Procedure:
6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (57 mg, 22%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 5-chloro-2-methoxyphenylboronic acid (0.15 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32]Cl)=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][N:14]3[CH2:15][CH2:16][N:11]([CH2:10][CH:9]=[CH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:12](=[O:18])[C:13]3=[O:17])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc2cc(CCl)ccc12
Reactant: O=C1NCCN(CC=Cc2ccc(Cl)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(CC=Cc4ccc(Cl)cc4)C(=O)C3=O)ccc12
Temperature: 55 °C
Yield: 43.5 %

Procedure:
To a solution of 1-[3-(4-chloro-phenyl)-allyl]-piperazine-2,3-dione (60 mg, 0.23 mmol) in 1.5 mL of DMF is added NaH (10 mg of a 60% dispersion in mineral oil, 0.24 mmol). The mixture is heated at 55° C. for 20 min. To the solution is added 4-amino-7-chloromethyl-quinazoline (49 mg, 0.25 mmol), and the resulting mixture is heated at 55° C. for 20 min as a white precipitate is formed. After this time, reaction mixture is quenched with a few drops of H2O and MeOH, then concentrated. The crude product is purified by RP-HPLC, eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) over 30 minutes, and the appropriate product fractions are combined and lyopholized to provide the title compound (56 mg, 0.10 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 9.78 (bs, 2H), 8.83 (s, 1H), 8.40 (s, 1H), 7.72 (d, 1H), 7.65 (s, 1H), 7.49 (d, 2H), 7.38 (d, 2H), 6.61 (d, 1H), 6.30 (dt, 1H), 4.80 (s, 2H), 4.18 (d, 2H), 3.59 (m, 4H). ISP MS, [M+H]+=422.