Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ncc(CO)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2cc(CO)cnc2C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 5 ml. of anhydrous pyridine was added 0.86 g. of p-anisoyl chloride dropwise under cooling. After standing overnight the resulting mixture was poured into ice water and extracted with chloroform.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[S:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=S)c1ccc(OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
Di-t-butyl dicarbonate (10.8 g, 49.5 mmol) was added to a solution of 4-(benzyloxy)benzohydrazide (10 g, 41.3 mmol) in dichloromethane (206 mL) at 0° C. The resulting mixture was stirred for 2 d at room temperature, then concentrated and the residue was triturated with diethyl ether to yield tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate. A mixture of tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate (13.7 g, 40 mmol) and Lawesson's reagent (8.1 g, 20.0 mmol) in THF (200 mL) THF was stirred for 2 d. Solvent was removed under vacuum and the residue was chromatographed (silica gel, heptane-ethyl acetate) to yield tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate. A solution of tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate(12 g) in 1,4-dioxane (34 mL) and 4.0 N HCl (34 mL) in 1,4-dioxane was stirred for 5 h. The resulting solid was collected and washed with diethyl ether to yield 4-(benzyloxy)benzothiohydrazide.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][CH2:43][O:44][C:37]=3[CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[CH3:46][C:47]1[O:51][N:50]=[C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48]=1[NH2:58]>>[CH2:43]1[CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:35]([NH:34][C:32]3[C:31]([F:45])=[CH:30][N:29]=[C:28]([NH:58][C:48]4[C:49]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)=[N:50][O:51][C:47]=4[CH3:46])[N:33]=3)=[CH:36][C:37]=2[O:44]1
Reactant: Cc1onc(-c2ccccc2)c1N
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1onc(-c2ccccc2)c1Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-methyl-3-phenyl-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine. LCMS: ret. time: 20.90 min.; purity: 96%; MS (m/e): 420 (MH+).
Reaction SMILES: [C:1]([NH:6][N:7]([CH3:11])[C:8]([NH2:10])=[O:9])(=O)[CH:2]([CH3:4])[CH3:3].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OC(=O)C)C>[CH:2]([C:1]1[NH:10][C:8](=[O:9])[N:7]([CH3:11])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)NN(C)C(N)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CC(C)c1nn(C)c(=O)[nH]1

Procedure:
2-Isobutyryl-1-methylhydrazinecarboxamide was cyclized with 10-camphorsulfonic acid at reflux in ethylacetate to give 3-isopropyl-1-methyl-1H-1,2,4-triazol-5(4H)-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)[CH2:22][NH:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)C>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[CH2:22][N:21]([C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[N:20]=2)=[CH:15][CH:14]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: FC(F)(F)c1ccc(C2CNN=C2c2ccc(Cl)cc2)nc1
Agent: CC=O
Solvent: ClCCl
Product: CSc1ccc(NC(=O)N2CC(c3ccc(C(F)(F)F)cn3)C(c3ccc(Cl)cc3)=N2)cc1

Procedure:
4-(Methylthio)phenyl isocyanate (2.8 g, 17 mmol) was added to a stirring slurry of 3.8 g (3.0 mmol) of the product of Example 6 in methylene chloride (25 mi) at 21° C. causing rapid formation of a pale precipitate. TLC showed complete conversion after 19 hr and the precipitate, which was the corresponding bisaryl urea, was removed by gravity filtration. The filtrate was diluted with saturated aqueous sodium bicarbonate and the layers separated. The organic layer was dried over sodium sulfate, filtered, and evaporated to obtain a red oil which solidified on standing. This was purified by column chromatography eluting with 100:0 to 90:10 methylene chloride/ethyl acetate solvent. The product was recrystallized by dissolving in ethyl acetate and then adding hexane to obtain 0.44 g (29 percent of theory; 9 percent from the ethanone) of the title compound as fine white needles melting at 225°-226° C.;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3Br)[C:15]=2[CH3:27])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>COCCOC.CCO.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[C:15]=2[CH3:27])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1-c1cccc(Cl)c1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
To a stirring solution of 1-(2-bromophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (4-methanesulfonyl-phenyl)-amide (100 mg, 0.23 mmol) and 3-chlorophenylboronic acid (0.95 g, 0.57 mmol) in DME/EtOH (2:1, 5 mL), 1M Na2CO3 (0.80 mL) and Pd(dppf)2Cl2 (38 mg, 0.046 mmol) were added. The reaction mixture was degassed and heated at 80° C. under Argon for 1 h and monitored by LC-MS. The mixture was diluted with DCM (20 mL) and washed with 15 mL of brine. The aqueous phase was extracted with DCM (20 mL) twice. The combined extracts were dried over anhyd Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel, eluting with EtOAc-Hex (0-50%) to yield the title compound (53 mg, 48%) as a pale yellow solid. 1H-NMR (CDCl3): δ 7.89 (2H, d), 7.80 (2H, d), 7.65 (1H, s), 7.57 (3H, m), 7.26 (3H, m), 7.04 (1H, t), 6.87 (1H, m), 6.13 (1H, s), 3.03 (3H, s), 2.23 (3H, s), 1.89 (3H, s). MS (ESI): 479 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(CO)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A quantity of 1.9 gm (5.1 mmol) of 5-methoxycarbonyl-2-(2'-methoxy-4'-methanesulfonylamino-phenyl)-benzimidazole, dissolved in 300 ml of absolute tetrahydrofuran, was added dropwise, under stirring, to a suspension of 700 mg of lithium aluminium hydride in 50 ml of absolute tetrahydrofuran. After the solution was stirred overnight at ambient temperature, 30 ml of water were added, any insoluble components were filtered off, and the filtrate was concentrated to dryness in vacuo. The crude product thus obtained was purified by chromatography over 200 gm of silica gel (eluant: methylene chloride with 3 to 10% of ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Cl)cc1F
Product: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 4-chloro-1,2-difluorobenzene (25.0 g, 168.3 mmol) cooled to 0° C. was added fuming nitric acid (50.0 ml, 168.3 mmol) dropwise over 30 minutes. The solution was warmed to room temperature and stirred for 2 hours. The solution was poured slowly over ice and the resultant mixture extracted with diethyl ether. The diethyl ether layers were washed with brine, dried with Na2SO4, filtered and concentrated to afford the product (28 g, 81% yield) as orange oil. 1H NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.46 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20](O)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc([N+](=O)[O-])cc3)nc3ccccc13)C2
Yield: 99.5 %

Procedure:
Reaction of 2-(4-nitrophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 95 (99.5% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.91 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74-3.80 (2s, 3H), 4.41 and 4.93 (2s, 2H), 6.31 and 6.78 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.75-7.84 (m, 1H), 7.87-8.03 (2d, 1H), 8.16-8.26 (m, 2H), 8.41-8.46 (m, 2H), 8.72-8.79 (m, 3H); MS (ESI) m/z 457 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1>C(N)C(C)C>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[N:10]=[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][CH:18]([CH3:19])[CH3:23])[N:7]=2)[CH:19]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)oc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: CC(C)CN
Product: CC(C)CNc1nccc(-c2oc(N3CCCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 45 °C
Yield: 138.3 %

Procedure:
To a 8 mL vial N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.100 g, 0.193 mmol) was taken up in isobutylamine (2 mL) to give a yellow solution. Vial was capped and heated to 45° C. for 2 h. The solvent was removed and residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were diluted with EtOAc and washed with saturated aq. NaHCO3, dried over Na2SO4 and solvent removed to give title compound as a yellow solid (0.074 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.18 (d, J=5.1 Hz, 1H), 7.81 (br. s., 1H), 7.59-7.73 (m, 2H), 7.24 (t, J=9.1 Hz, 3H), 7.14 (d, J=7.9 Hz, 1H), 6.97 (t, J=5.7 Hz, 1H), 6.57 (d, J=1.6 Hz, 1H), 3.52 (t, J=6.3 Hz, 4H), 2.76-2.90 (m, 1H), 1.92-2.01 (m, 4H), 0.55-0.94 (m, 6H). MS-ESI m/z 555 (M+H).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9])[CH2:2][CH3:3].[F:10][C:11]1[C:12](=[O:18])[NH:13][C:14](=[O:17])[NH:15][CH:16]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([S:4][CH2:5][CH2:6][NH:7][C:8]([N:15]1[CH:16]=[C:11]([F:10])[C:12](=[O:18])[NH:13][C:14]1=[O:17])=[O:9])[CH2:2][CH3:3]
Reactant: CCCSCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCSCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
To the above solution of 2-propylthioethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 8 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-propylthioethyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[S:15]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)(=[O:17])=[O:16])([O-])=O.Cl[Sn]Cl>Cl.CCO>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:13])([F:12])[F:14])[CH:7]=[CH:6][C:5]=1[S:15]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)(=[O:16])=[O:17]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(OC(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 75.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, 2-nitro-N-quinolin-8-yl-4-trifluoromethoxy-benzenesulfonamide (Intermediate 271) (500 mg, 1.21 mmol), SnCl2 (918 mg, 4.84 mmol), 6N HCl (5 drops) and EtOH (10 ml) gave the title compound (350 mg, 75%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C1N=[CH:22][N:21](C(N2C=NC=C2)=O)[CH:20]=1.CNC.C1COCC1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:21]([CH3:22])[CH3:20])=[O:15])[CH2:6][CH2:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: CNC
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(C)C)O2
Yield: 73.9 %

Procedure:
Following the amide coupling procedure described in protocol A, 504 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 361 mg CDI (2.23 mmol) and 1.1 mL of a 2.0 M solution of N,N-dimethylamine in THF (2.2 mmol) produced 412 mg of 6-hydroxy-N,N,2,5,7,8-hexamethylchroman-2-carboxamide as amorphous powder.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.C1(C2NC3C(C(=O)C=2)=CC(OC)=C(OC)C=3)CC1>C(N(CC)CC)C>[CH:16]1([C:19]([NH:6][C:5]2[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(N)c(C(C)=O)cc1OC
Agent: COc1cc2[nH]c(C3CC3)cc(=O)c2cc1OC
Solvent: CCN(CC)CC
Product: CCOc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Yield: 101.5 %

Procedure:
2-Acetyl-5-ethoxy-4-metoxyaniline (550 mg), cyclopropylcarbonyl chloride (410 mg) and triethylamine (530 mg) were reacted in the same manner as in the preparation of compound 95 to give N-cyclopropylcarbonyl-2-acetyl-5-ethoxy-4-methoxyaniline (740 mg). The compound (600 mg) and potassium t-butoxide (1.18 g) were reacted in the same manner as in the preparation of compound 95 to obtain 2-cyclopropyl-7-ethoxy-6-methoxy-4(1H)-quinolone (compound 98, 330 mg).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:31])=[CH:22][C:21]=3[F:32])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.[H][H]>CN(C=O)C.CO.ClC(Cl)Cl.[Pd]>[F:32][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Yield: 109.1 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (700 mg, 1.4 mmol) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) containing 10% palladium-on-charcoal (100 mg) was stirred under 1 atmosphere of hydrogen for 1 hour. After filtration and evaporation of the solvent, the residue was triturated with ether, filtered and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (570 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[N:11]([CH3:20])[C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2Cl)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
First, 1.20 g of 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1007) was dissolved in 6.0 ml of N,N-dimethylformamide, to which 0.83 g of potassium carbonate and 0.51 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 0.81 g (yield, 62%) of 3-(2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-332).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C1C(=O)N([Cl:22])C(=O)C1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:22][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 4-(1-methyl-1H-imidazol-4-yl)benzonitrile (Step 2, 1.05 g, 5.73 mmol) in methylene chloride (15 mL) was added NCS (765 mg, 5.73 mmol) and 3 drops of TFA. After stirring at 50° C. for 3 hrs, the reaction was diluted with 20 mL of methylene chloride and quenched with aq NaHCO3. The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 4-(5-chloro-1-methyl-1H-imidazol-4-yl)benzonitrile. LCMS: [M+1]=218.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:12])[C:10]=2[N:11]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.C(N(CC)CC)C>CC(N(C)C)=O>[NH2:12][C:9]1[C:10]2[N:11]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]3)[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1ncnc2ccc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Temperature: 100 °C
Reaction time: 42 h
Yield: 66.2 %

Procedure:
To 40 mL screw-cap vials was added 6-chloropyrido[3,2-d]pyrimidin-4-amine (2.00 g, 11.1 mmol) followed by tert-butyl N-[(3S)-3-piperidyl]carbamate (1.1 equiv., 12.2 mmol, 2.44 g) then dimethylacetamide (10 mL) and triethylamine (3 equiv., 33.2 mmol, 4.65 mL). The reaction was capped and shaken at 100° C. for 42 h, then an additional 24 h at 115° C. The reaction was cooled to room temperature, then partitioned with ethyl acetate:water. Residual chloride starting material was removed by filtration. The filtrate phases were separated, and the organics dried over sodium sulfate, filtered and concentrated, yielding 2.53 g of product. 1H NMR (400 MHz, DMSO) δ 8.19-8.13 (s, 1H), 7.81-7.74 (d, J=9.3 Hz, 1H), 7.43-7.39 (d, J=9.1 Hz, 1H), 6.95-6.85 (d, J=6.6 Hz, 1H), 4.32-4.19 (m, 2H), 3.50-3.38 (m, 1H), 3.19-3.04 (m, 1H), 2.96-2.85 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.67 (m, 1H), 1.60-1.34 (m, 11H). LCMS M/Z (M+H)=345.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].C(N(CC)CC)C.[CH3:19][CH2:20][O:21]CC.C(Cl)(=O)C>O>[C:20]([O:11][C:3]1[C:2]([CH3:1])=[CH:8][C:6]([OH:7])=[C:5]([CH3:9])[C:4]=1[CH3:10])(=[O:21])[CH3:19]
Reactant: CCOCC
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Oc1c(C)cc(O)c(C)c1C
Temperature: 25 °C

Procedure:
Stir a mixture of trimethylhydroquinone (15.2 g, 0.1 mol), triethylamine (25.3 g, 0.25 mol) and ether (500 mL) in an ice bath. Slowly add acetylchloride (19.6 g, 0.25 mol) with stirring, allow the reaction to warm to room temperature for an hour, then dilute with water and the separate the layers. Evaporate the ether layer to dryness. Dissolve the resulting diacetate in methanol (300 mL). Add strong ammonium hydroxide (11 mL) and stir the mixture at room temperature overnight. Distill off the solvents under reduced pressure and dissolve the residue in ether. Wash the ether layer with water and evaporate to dryness. Recrystallization from hexane-ether yields 4-acetoxy-2,3,5-trimethylphenol (16.7 g, m.p.=106-107° C.).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N.CO>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methylbenzenesulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (4.9 mg). MS m/z 343 [M+H]+.