Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH2:41])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([C:45]1[C:46]([N:54]=[CH:55][N:56]([CH3:58])C)=[N:47][C:48]([CH:51]([CH3:53])[CH3:52])=[CH:49][CH:50]=1)#N>C(O)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH:41][C:58]4[C:45]5[CH:50]=[CH:49][C:48]([CH:51]([CH3:52])[CH3:53])=[N:47][C:46]=5[N:54]=[CH:55][N:56]=4)=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Temperature: 150 °C
Yield: 58.2 %

Procedure:
A mixture of the product from Example 17D (23.9 g, 37.4 mmol) and N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (9.71 g, 44.9 mmol, 1.2 eq) in 450 mL of glacial acetic acid was heated in an oil bath at 150° C. for 2 h and then cooled to room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in approximately 70 mL of dichloromethane. This material was purified by silica gel chromatography using a Biotage Flash 75M cartridge, eluting first with 1:4 ethyl acetate/dichloromethane followed by 98:2 dichloromethane/methanol. The resulting product triturated with dichloromethane and filtered to provide the title compound as a white solid (17.6 g, 58%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetyl chloride (179 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (1 g) and diisopropylethylamine (735 mg) in methylene chloride that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.655 g); 1H NMR Spectrum: (DMSO d6) 1.54-1.78 (m, 2H), 1.91-2.10 (m, 5H), 3.29-3.41 (m, 2H), 3.66-3.76 (m, 1H), 3.78-3.88 (m, 1H), 3.93 (s, 3H), 4.74 (m, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7.55 (m, 2H), 7.87 (s, 1H), 836 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH2:16].C(N(CC)CC)C>CO>[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](C)Nc1ncccc1[N+](=O)[O-]
Yield: 5.9 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole), (R)-alanine methyl ester hydrochloride (50 g, 0.358 mole) and triethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in ethyl acetate (300 ml), filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed once with water. The aqueous wash was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an oil weighing 45.6 g (85%). Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane through a silica gel column gave 3.2 g of product after evaporation of solvent. Drying of a portion of the solid under high vacuum at room temperature gave 0.98 of title compound, mp 39°-40° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][C@H:17]2[CH2:18][OH:19])=[O:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O>CS(C)=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][C@H:17]2[CH:18]=[O:19])=[O:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCC(=O)N1CCC[C@H]1CO)NCCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCCc1ccccc1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
N-[3-[N-(2-phenylethyl)carbamoyl]propanoyl]-L-prolinol (490 mg; prepared in reference example 1) was dissolved in dry DMSO (5 ml). Triethylamine (0.79 ml) was added to the solution. A solution of sulfur trioxide-pyridine complex (450 mg) in DMSO (2 ml) was dropped to the solution. After 10 mins' stirring, the solution was poured into water. The mixture was extracted with ethyl acetate. The oily layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrocarbonate and a saturated brine, successively, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (371 mg) having the following physical data:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:12]=2[N:13]=1
Reactant: CN(CCc1ccc(N)cc1)Cc1nc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1nc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
Methanesulphonyl chloride (0.38 g, 3.3 mmole) and N-methyl-N-(5-aminobenzoxazol-2-ylmethyl)-4-aminophenethylamine (see Preparation 1C - 0.45 g, 1.5 mmole) in pyridine (20 ml) when reacted together under conditions similar to those of Example 2 gave the title compound, yield from ethanol 0.25 g, m.p. 174°-176°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:2]1.[CH2:29]([Zn])C.ICI.Cl.N>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@@H:10]2[CH2:29][C@H:11]2[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:28])[F:27])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:2]1
Reactant: CC[Zn]
Reactant: C[C@@H](NC(=O)/C=C/c1c[nH]c2ccccc12)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Agent: N
Solvent: ICI
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]1c1c[nH]c2ccccc12)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 3 %

Procedure:
To a solution of (R,E)-3-(1H-indol-3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide (600 mg, 1.3 mmol) in dichloromethane (10 mL) was added ethylzinc (4.1 mL, 4.1 mmol, 1.0 M) at room temperature. After being stirred at room temperature for 3 min, diiodomethane (1.8 g, 6.7 mmol) was added to the mixture. The mixture was refluxed at 55° C. with stirring for 18 hours. sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=1/1 (v/v) and preparative LC-MS to give 14 mg, (3% yield) of the title compound as a white solid (2:1 mixture of the diastereomers).
Reaction SMILES: O[C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([OH:15])[C:5]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:4]=1[O:3]2.[C:23]([OH:26])(=[O:25])[CH3:24].N1C=CC=CC=1.C1C[O:36][CH2:35][CH2:34]1>>[C:23]([O:26][C:4]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=1[C:6]1([O:15][C:35](=[O:36])[CH3:34])[C:7](=[O:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:3])(=[O:25])[CH3:24]
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2C2(O)Oc3ccc([N+](=O)[O-])cc3C12O
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1C1(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 11 %

Procedure:
4b,9b-Dihydroxy-8-nitro-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.6 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.54 ml, 5.3 mmol), pyridine (0.21 ml, 2.6 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 30 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:2 to 1:1) to afford the title compound (0.44 g, 11%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[Cl:30][CH2:31][C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22])=[O:33]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCN
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCNC(=O)CCl
Reaction time: 0.5 h
Yield: 53 %

Procedure:
1.68 Grams of 1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone was suspended in 100 ml of chloroform, then 5 ml of triethylamine was added thereto and stirred for 30 minutes. Under ice-cooling condition, 2 ml of chloroacetyl chloride was added little by little and stirred for 5 hours. The reaction mixture was washed with water, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate, then concentrated under reduced pressure, there was obtained 1 g (53%) of 1-(3-chloroacetylaminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. White powdery crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([Cl:1])[N:10]=3)([OH:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -30 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 9.86 mmol) and TMEDA (2.1 mL, 14.8 mmol) in THF (80 mL) at −78° C. was added n-BuLi (6 mL, 2.5 M in hexanes, 14.8 mmol). The resulting mixture was allowed to warm to −30° C. for 30 min then cooled back to −78° C. before the addition of a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 14.8 mmol) in THF (20 mL). The reaction mixture was slowly warmed to r.t. and stirred for 16 h then quenched with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 10-75%) affording 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.2 g, 71%). LCMS (method H): RT 3.52 min [M+H]+ 453.3
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:16])[N:4]([CH3:19])[CH:5]=[C:6]([C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH:7]=1
Reactant: O=C(c1c[nH]c(=O)c(Br)c1)N1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cc(C(=O)N2CCOCC2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-(morpholine-4-carbonyl)pyridin-2(1H)-one (430 mg, 1.498 mmol), iodomethane (0.112 mL, 1.797 mmol), and potassium carbonate (207 mg, 1.498 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 30-70% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.2 mmol) was coupled with (2R,6S)-2,6-dimethyl-piperazine (50 mg, 0.2 mmol), HOBt (36 mg, 1.1 eq.), EDAC.HCl (40 mg, 1.1 eq.) and TEA (76 mg) in DMF (25 mL) at 75° C. for 2 hours to give the titled compound.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].OCC[N:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.C1C[O:31][CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.O>[C:30]([O:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCN(CCO)CCO
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCOC(C)=O)CCOC(C)=O
Reaction time: 20 h
Yield: 99 %

Procedure:
At 20 to 30° C., acetic anhydride was added to a mixture of 9.29 g of N,N-bis(2-hydroxyethyl)-2-(methoxycarbonyl)ethylamine, 12.8 g of triethylamine, 50 mg of 4-dimethylaminopyridine and 50 ml of THF and the resulting mixture was stirred for 20 hours. Water was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was then washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by distillation under reduced pressure, whereby 13.2 g of N,N-bis(2-acetoxyethyl)-2-(methoxycarbonyl)ethylamine was obtained (boiling point: 118 to 123° C./21 Pa, yield: 99%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][CH2:33][O:34][C:35]([CH2:37]O)=[O:36].[C:39]1(=[O:45])[NH:43][C:42](=[O:44])[CH:41]=[CH:40]1>>[CH2:33]([O:34][C:35]([CH2:37][N:43]1[C:39](=[O:45])[CH:40]=[CH:41][C:42]1=[O:44])=[O:36])[CH3:32]
Reactant: O=C1C=CC(=O)N1
Reactant: CCOC(=O)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CN1C(=O)C=CC1=O

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), ethyl glycollate (0.71 ml, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C(O)(C)(C)C>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A slurry of terephthalic acid di-tert-butyl ester (6.1 g, 0.022 mole) in tert-butanol (30 mL) was added to 1N KOH (22 mL, 0.022 mole). The mixture was heated to 60° C. for 7-8 hours. After cooling the mixture was treated with water and extracted 3 times with ethyl acetate. The aqueous layer was acidified with diulute HCL and the product was extracted into ethyl acetate. After washing of the organic layer with a saturated aqueous NaCl solution and drying over MgSO4, the solvent was filtered and concentrated to yield terephthalic acid mono tert-butyl ester as a white solid (4.7 g, 96%) melting at 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([CH3:21])[C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:22]1([C:28]2[N:33]=[N:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([C:14]1[N:32]3[N:33]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=[CH:30][C:31]3=[N:34][N:35]=1)[CH3:21])=[CH:8][CH:7]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cnc2ccc(C(C)c3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.17 g, 0.90 mmol), HYDROCHLORIC ACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the solid was collected by filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=97%:3%, Flow=40 mL/min) to afford the desired product as light yellowish solid. MS m/z: 382.3 (M+H). Calc'd. for C23H19N50—381.43.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O-])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:12].[CH:13]([O-])([O-])OC>CO>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:13][NH:12][C:7]2=[O:8]
Reactant: [NH4+]
Reactant: COC([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)[O-]
Solvent: CO
Product: O=c1[nH]cnc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8 mmol) of ammonium 5-chloroanthranilate (prepared in the same manner as in Reference Example 3), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 307 mg (reaction yield: 94%) of 6-chloroquinazolin-4-one.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:24]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.108 g, 0.5 mmol), 4-(4-fluoro-phenoxy)-benzylamine (0.115 g, 0.5 mmol), and K2CO3 (0.235 g, 1.7 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[4-(4-fluoro-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.100 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.29 (s, 2H), 4.78 (s, 2H) 6.83-7.56 (m, 1H), 7.89 (d, 1H). GC-MS: m/z 333 (M)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[C:32](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)=[CH:7][CH:8]=2)[S:28]1
Reactant: CCCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Product: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 72.6 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 580 mg (1.6 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-propylbenzamide with 190 mg (1.6 mmol) of 2,4-thiazolidine dione, 530 mg (72%) of the expected product, with a melting point of 250-251° C., are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[CH2:4][C:3]([N:2]([CH3:1])[CH3:20])=[O:19])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)CC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(CC(=O)N(C)C)CC2

Procedure:
A solution of N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]acetamide (0.16 g, 1.72 mmol) in absolute ethanol (50 mL) and ethyl acetate (5 mL) was hydrogenated overnight at 45 psi with catalytic 10% Pd/C. The catalyst was removed by vacuum filtration through a celite pad which was rinsed with methanol. The filtrate was concentrated under reduced pressure and dried under high vacuum to provide 2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-N,N-dimethylacetamide. This was then carried forward without any further purification.