Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]([CH3:41])=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]3[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=2)[C:29]([CH3:41])=[N:28]1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.09 g) in a mixed solvent of THF (2.40 mL)-water (0.80 mL) were added 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.14 g), potassium carbonate (0.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.09 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47](O)=[O:48])=[N:43][N:44]=1>ClCCl>[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[O:48])=[N:43][N:44]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alanine methyl ester hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:32])([C:28]([F:31])([F:30])[F:29])[C@@H:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1)[CH3:16].CCN(CC)CC.CCOC(C)=O>C(O)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:17][C@H:15]([C:14]([F:13])([F:32])[C:28]([F:30])([F:31])[F:29])[CH3:16])=[O:27])=[CH:24][CH:23]=1
Reactant: C[C@H](OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)c1ccc(Cc2c(O)c3ccccc3oc2=O)cc1)C(F)(F)C(F)(F)F
Temperature: 140 °C
Reaction time: 4 h

Procedure:
4-Hydroxycoumarin (1.367 g, 8.44 mmol) and (S)-4-formyl-benzoic acid 2,2,3,3,3-pentafluoro-1-methyl-propyl ester (2.505 g, 8.46 mmol) were dissolved in formic acid (3.0 mL) and Et3N (3.6 mL) at 0° C. After stirring at 140° C. for 4 h, the yellow solution was cooled to rt, EtOAc was added, and the organic layer was washed successively with 1 N HCl and brine. After drying over Na2SO4 and concentrating, the pale yellow solid was purified twice by silica gel chromatography (DCM:MeOH 100:6 and DCM:MeOH 100:5) to yield the title compound in 92.5% ee as determined by chiral HPLC.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[N:3]=[CH:4][CH:5]=1.[N:15]1(O)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.CN([CH:48]=[O:49])C>C(OCC)(=O)C>[OH:49][CH2:48][C@H:20]1[CH2:19][N:15]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:2]2[N:1]=[CH:5][CH:4]=[N:3]2)=[O:10])[C@H:23]([CH3:18])[CH2:22][CH2:21]1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@@H](CO)CN1C(=O)c1ccccc1-n1nccn1
Reaction time: 16 h

Procedure:
To a solution of (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid-[(3,6R)-6-methylpiperidin-3-yl]methanol (1.2 g, 3.3 mmol), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.76 g, 4.0 mmol), 1H-benzotriazol-1-ol (0.71 g, 4.7 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (0.89 g, 4.7 mmol) in DMF (22 mL) was added N,N-diisopropyl-N-ethylamine (2.3 ml, 13 mmol). The mixture was stirred at ambient temperatures for 16 hours, then diluted with ethyl acetate and washed with brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-3% methanol in dichloromethane to provide [(2R,5R)-5-(hydroxymethyl)-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(=O)n3cc(C#N)ccc3nc2s1

Procedure:
2-Methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 21), 2.6 g (0.010 mol), in 30 ml of phosphorus oxychloride and 30 ml of chloroform is refluxed on a steam bath for three hours. The chloroform and excess phosphorus oxychloride are evaporated in vacuo and the residue is treated with 200 ml of ice water. The resulting precipitate is filtered to give 2.1 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 256°-258° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:17]=[N+:18]([CH3:20])[CH3:19].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2cn(C)c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[Br:24].[CH:25]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Br:24][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:31](=[O:32])[CH2:30][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:8]([CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])[CH:7]=[CH:6]2
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)c1ccc(Cn2ccc3cc(Br)c(N)cc32)c(OC)c1
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)c(NC(=O)CC4CCCC4)cc32)c(OC)c1
Yield: 60 %

Procedure:
Using a similar procedure to that described in Example 185, but starting from methyl 4-(6-amino-5-bromoindol-1-ylmethyl)-3-methoxybenzoate (GG) and cyclopentylacetic acid, methyl 4-[5-bromo-6-cyclopentylacetamidoindol-1-ylmethyl]-3-methoxybenzoate was obtained in 60% yield as an off-white solid; partial NMR: 1.6 [br m,8H,(CH2)4 ], 3.8 (s,3H,OCH3), 3.9 (s,3H,OCH3), 5.3 (s,2H,NCH2), 6.4 (dd,1H,H3-indole), 7.1 (d,1H,H2 -indole), 7.7 (br, 1H,NH), 7.8 (s,1H,H4 -indole), 8.5 (br s,1H,H7 -indole).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(NCc2ccc(Cl)cc2)cc1
Yield: 66.2 %

Procedure:
4-Aminobenzoic acid (13.7 g., 0.1 mole) and 4-chlorobenzaldehyde (14.05 g., 0.1 mole) were mixed in dry benzene (200 ml.), 4-toluenesulphonic acid (50 mg.) was added and the mixture was boiled under reflux in an apparatus incorporating a water-trap until the theoretical amount of water (1.8 ml) had been collected. The reaction mixture was cooled in iced water, the product filtered, dried and hydrogenated in NTP in ethanol (500 ml) in the presence of platinum oxide, (Adams catalyst), (100 mg). The catalyst was filtered off and the solution added to iced water. The product was filtered, dried and crystallised from 20% aqueous ethanol to give 4-[(4-chlorobenzyl)-amino]-benzoic acid (17.32 g., 78%) which melted at 206°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 35 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49 as a yellow solid (14 mg, 4% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[N:33]1[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[N:35][CH:34]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][N:35]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(O)c1ccncn1
Product: Cc1c(N2CCN(C(=O)c3ccncn3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and pyrimidine-4-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(pyrimidin-4-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.10 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.30-3.35 (m, 2H), 3.36-3.40 (m, 2H), 3.53-3.56 (m, 2H), 3.67-3.69 (m, 4H), 3.84-3.86 (m, 2H), 6.51 (s, 1H), 7.14-7.19 (m, 1H), 7.28-7.31 (m, 1H), 7.51 (s, 1H), 7.74 (d, J=5.2 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 8.37 (s, 1H), 9.00 (d, J=5.2 Hz, 1H), 9.28 (s, 1H). Mass Spectrum (ESI) m/e=546.9 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH:11]([C:4]1[CH:3]=[C:2]([C:14]#[N:15])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=Cc1cc(Br)c2c(c1)CCO2
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(C=O)cc2c1OCC2
Yield: 61.4 %

Procedure:
To a solution of 7-bromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (1.3 g, 4.7 mmol) in dimethylacetamide (2 mL) was added copper(I) cyanide (0.41 g g, 4.7 mmol). The reaction was refluxed for 18 h, and then concentrated under reduced pressure. The residue was washed well with warm ethyl acetate. The combined ethyl acetate layer were concentrated and dried. The crude product was purified by flash column chromatography (silica gel, 4:1 and 2:1 hexane:ethyl acetate gradient) to afford the desired product (0.5 g, 50%).
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([O:11][CH2:12][C:13]([Cl:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1cccc2ccccc12
Product: O=C(Cl)COc1cccc2ccccc12

Procedure:
10 g of naphthoxy-acetic acid and 60 ml of thionyl chloride were refluxed for 2 hours and after evaporating to dryness under reduced pressure, several distillations with benzene were carried out to obtain 11.16 g of the expected product which was used as is for Step B.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[C:16]([C:32]#[N:33])[CH:15]=[N:14][N:13]2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][C:44](OC(C)=O)=[O:45]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)=[C:16]([C:32]#[N:33])[CH:15]=[N:14][N:13]2[CH:34]=1)[C:44](=[O:45])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(CNCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccccc1)Cc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Yield: 83.1 %

Procedure:
To a solution of 414A (28 mg, 0.06 mmol) and Et3N (17 μl, 0.12 mmol) in CH2Cl2 (2 ml) was added Ac2O (11 μl, 0.12 mmol), reaction completed immediately. After regular workup, the residue was purified by prep. TLC to give the 414 (25 mg, 83%) as light yellow powder (2% MeOH—CHCl3). It has a retention time of 7.23 min (standard LCl method, 8 min run). MS Found: (M+H)+=502.0
Reaction SMILES: C(N(C(C)C)CC)(C)C.O1C[CH2:14][N:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:12]C1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:45])=[C:30]([NH:32][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)=[O:34])[CH:31]=1.CN(C=O)C>O>[CH3:14][N:13]([CH3:12])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:45])=[C:30]([NH:32][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)=[O:34])[CH:31]=1)=[O:21]
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 101.4 %

Procedure:
Diisopropylethylamine (0.174 ml) was added to a stirred mixture of 3-morpholinobenzoic acid (0.104 g), N-(5-amino-2-methylphenyl)quinoline-6carboxamide (0.14 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.23 g) and DMF (1 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. There was thus obtained the title compound (0.216 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.18 (m, 4H), 3.75 (m, 4H), 7.14 (d, 1H), 7.25 (d, 1H), 7.36 (m, 2H), 7.44 (s, 1H), 7.62 (m, 2H), 7.86 (s, 1H), 8.13 (d, 1H), 8.28 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H), 9.0 (s, 1H), 10.14 (m, 2H); Mass Spectrum: M+H+ 467.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>>[CH3:8][C:9]([NH:16][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:23]=1[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Nc1ccccn1
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(-c2nc3ccccn3c2NC(C)(C)CC(C)(C)C)cc(OC)c1OC

Procedure:
Compound (33) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml 3,4,5-trimethoxybenzaldehyde solution (0.3 M, MC), and 10 Al perchloric acid (w=20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[F:39][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH2:13][C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:38])[CH2:11]1
Reactant: [F-]
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CC(=O)c2ccc3c(c2)C(F)CC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Solvent: O
Solvent: CO
Product: Nc1cc(Nc2ncc(F)c(Nc3ccc([N+](=O)[O-])c(N)c3)n2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-nitroaniline (184 mg, 1.2 mmol) was added and the mixture was refluxed for 3 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.21 (d, 1H, J=2.9 Hz), 7.89 (m, 3H), 7.56 (d, 1H, J=2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J=2.3, 9.4 Hz); LCMS: purity: 91.1%; MS (m/e): 401.00 (M+, 100).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].[OH-].[Li+].Cl>O1CCOCC1>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:6]([NH:5][CH2:4][C:3]([OH:18])=[O:2])=[O:7]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(C(=O)NCC(=O)O)cc2ccccc21
Yield: 93.2 %

Procedure:
(1-Methylindole-2-carbonyl)glycine methyl ester (1.687 g, 6.85 mmol) was dissolved in 1,4-dioxane (10 mL) and was treated with 1 N lithium hydroxide (7.0 mL, aq) with stirring. The reaction mixture turned clear immediately and was acidified with 1N HCl and concentrated to remove 1,4-dioxane to result in a purple precipitate. The precipitate was filtered, washed with water, and dried in vacuo to give the title product as a purple powder (1.482 g, 93%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1 silica gel): Rf=0.28; 1H-NMR (CD3OD): δ7.61 (dt, J=8.2, 1H). 744 (dd, J=8.5, 0.8, 1H), 7.32-7.26 (m, 1H), 7.13-7.09 (m, 1H), 7.04 (s, 1H), 4.08 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.F[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[O:22]([C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (1.18 g), methyl 4-fluoro-2-phenoxybenzoate (1.85 g), and K2CO3 (1.14 g) was stirred at 125° C. in dimethylsulfoxide (25 mL) for 24 hours. The mixture was cooled, poured into 300 mL water, extracted three times with ether, and the ether extracts were combined, rinsed three times with water, and brine, and concentrated. The residue was chromatographed on silica gel using 10-30% ethyl acetate in hexanes as eluent to give the title compound.