Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C@H:18]2[CH2:22][NH:21][C@@H:20]3[C@@H:23]([OH:26])[CH2:24][O:25][C@H:19]23)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O.O1CCOCC1>[OH:26][C@@H:23]1[C@H:20]2[N:21]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:22][C@H:18]([O:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=3)(=[O:16])=[O:15])[C@H:19]2[O:25][CH2:24]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 0.58 h
Yield: 95 %

Procedure:
A solution of sodium carbonate (281 mg, 2.65 mmol) in water (5 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate in 1,4-dioxane (5 mL). A solution of benzyl chloroformate (0.225 mL, 1.96 mmol) in 1,4-dioxane (2.5 mL) was added over 20 minutes then the mixture stirred for 35 minutes, then water (50 mL) was added and the product extracted into dichloromethane (2×50 mL). The organic layer was washed with brine (50 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 25:75 to 50:50 gave bicyclic alcohol (34) (518 mg, 95%) as a white solid. TLC (Rf=0.25, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=17.86 min., HPLC-MS 434.2 [M+H]+, 456.1 [M+Na]+, 889.3 [2M+Na]+; [α]D16.5 −23.1° (c=1.190, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.96 (0.4H, d, J=4.11 Hz, OH minor), 2.43 (1.8H, s, aryl-CH3 major), 2.44 (1.2H, s, aryl-CH3 minor), 2.59 (0.6H, d, J=3.42 Hz, OH major), 3.35 (0.4H, dd, J=13.43 and 3.71 Hz, CbzNCH2 minor), 3.41 (0.6H, dd, J=13.31 and 3.80 Hz, CbzNCH2 major), 3.74-3.88 (3H, m, 2×OCH2CHOH and 1×CbzNCH2), 4.29 (0.4H, s, CbzNCH minor), 4.31 (0.6H, s, CbzNHCH major), 4.37 (0.4H, brs, OCH2CHOH minor), 4.49 (0.6H, brs, OCH2CHOH major), 4.51 (0.6H, d, J=4.59 Hz, TsOCHCH major), 4.64 (0.4H, brd, J=4.44 Hz, TsOCHCH minor), 4.77 (0.4H, d, J=3.43 Hz, TsOCHCH minor), 4.79 (0.6H, d, J=3.53 Hz, TsOCHCH major), 5.06-5.13 (1.6H, m, CH2Ph), 5.21 (0.4H, d, J=12.22 Hz, CH2Ph minor), 7.30 (7H, m, aromatic-CH and CH3CCH), 7.75-7.79 (2H, m, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.658 (aryl-CH3), 51.015/51.082 (CbzNCH2), 67.511/67.622 (CH2Ph), 67.953/68.902 (CbzNCH), 74.375/74.420 (OCH2CHOH), 75.322/76.156 (OCH2CHOH), 79.944/80.600 (TsOCHCH), 83.537/84.651 (TsOCHCH), 127.791, 127.837, 127.942, 128.011, 128.382, 128.485, 128.558, 128.703 and 130.102 (aromatic CH), 133.021/133.087 (CHOSO2C quaternary), 135.895/136.018 (Cbz quaternary), 145.441 (CH3C quaternary), 153.976/154.591 (Cbz C═O).
Reaction SMILES: [C:1](C(O)(CC=C)C(C)(C)C)(C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:19]([N:26]=[CH:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>CCCCC.[Cl-].[Cl-].[Zn+2]>[CH2:3]([CH:27]([NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:28]=[C:29]([CH3:31])[CH3:30])[CH:1]=[CH2:2]
Reactant: C=CCC(O)(C(C)(C)C)C(C)(C)C
Reactant: CC(C)=CC=NCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCC
Solvent: CCOCC
Product: C=CCC(C=C(C)C)NCc1ccccc1

Procedure:
The reaction was performed analogous to Example 1 with 500 mg (2.71 mmol) 3-tert-butyl-2,2-dimethylhex-5-en-3-ol, 1.93 ml (2.71 mmol) of a 1.4-molar n-butyllithium solution in pentane, 468 mg (2.71 mmol) benzyl-(3-methyl-but-2-enylidene)amine and 370 mg (2.71 mmol) ZnCl2. The raw product obtained was cleaned by means of a silica column with 25-100% diethyl ether/light gasoline. There was obtained the amine as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])C1C=CC=CC=1.N1C=CC=CC=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)cc2F)cc1
Yield: 94.3 %

Procedure:
To 2,4-difluoro-phenylamine (30, 2.0 g, 15.5 mmol) in 20 mL of dichloromethane, pyridine (1.326 mL, 16.4 mmol) and dimethylaminopyridine (0.076 g, 0.62 mmol) are added followed by the dropwise addition of 4-ethyl-benzenesulfonyl chloride (59, 3.357 g, 16.4 mmol) and the reaction is heated to reflux overnight. The reaction is concentrated under vacuum to dryness, then brought up in ethyl acetate and water for extraction. The organic layer is isolated and concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with a gradient of 10-20% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (60, 4.344 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)=[O:20])[C@@H:11]([CH3:29])[CH2:10]2)=[N:6][CH:7]=1.[C:30](Cl)(=[O:33])[CH2:31]C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:30](=[O:33])[CH3:31])=[N:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccc(Cl)cn3)C[C@@H]2C)c1
Product: COc1cccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cn3)C[C@@H]2C)c1

Procedure:
To a flask was added Pd2(dba)3 (molar 0.05 equ.), and rac-BINAP (0.1 equ.) in degassed toluene and stirred for 1 h. To the above solution was added 2,5-dichloropyridinepyridine (1.1 equ.) and NaOtBu (1.1 equ.) and stirred for 30 min. The corresponding amine, (±)-cis-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone was dissolved in degassed toluene and added to the solution and heated to 60° C. for 40 h. The reaction was diluted with ether and filtered through celite and concentrated down. The compound was purified by Biotage with 20% EtOAc/80% Hexane to give 45% of the product. (±)-Cis-[4-(5-chloro-pyridin-2-ylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(3-methoxy-phenyl)-methanone was acetylated with propionyl chloride as previously described to give (±)-cis-N-(5-chloro-pyridin-2-yl)-N-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCCc4ccccc43)c2)cc1
Yield: 82.1 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and 1,2,3,4-tetrahydro-quinoline (0.44 g, 3.36 mmol) were used to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 1.92 (2H, t), 2.54 (2H, m) 3.75 (2H, t), 6.92 (2H, d), 7.08 (7H, m), 7.82 (4H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1CNc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CNc2cc(N)ccc2C1
Yield: 91 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline (8.2 mg, 0.042 mmol) in ethyl acetate (1 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 6.2 mg (89%) of 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (structure 61A of Scheme XLVIII, where R1-2 =R4 =H, R3 =methyl) that was used without further purification for the next step: Compound 436 was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (6.2 mg, 0.038 mmol), ZnCl2 (8.0 mg, 0.057 mmol) and ethyl 4,4,4-trifluoroacetoacetate (5.5 mL, 0.038 mol) to afford 5.8 mg (54%) of Compound 436 as a yellow solid. Data for Compound 436: 1H NMR (400 MHz, DMSO-d6) 11.80 (bs, 1 H), 7.11 (s, 1 H), 6.95 (s, 1 H), 6.37 (s, 2 H), 3.26 (m, 1 H), 2.83 (m, 2 H), 2.51 (dd, J=15.7, 10.3, 1 H), 1.88 (s, 1 H), 0.97 (d, J=6.6, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[CH:8]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 66.7 %

Procedure:
2-Cyano-4-methylthiopyridine (2.36 g, 15.7 mmol) and methyl thiosalicylate (5.28 g, 31.4 mmol) were dissolved in toluene (100 ml), and triethylamine (9.9 ml, 70.7 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (3.00 g, 68%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:7]=1.[Br:20][C:21]1[CH:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24](Cl)=[N:25][CH:26]=1.[F-].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]([NH:1][C:2]2[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[CH:7]=2)=[N:25][CH:26]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1cc(N)cc(-c2c(F)cccc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ncc(Br)cc2[N+](=O)[O-])cc(-c2c(F)cccc2F)c1
Yield: 28 %

Procedure:
A solution of N-(5-amino-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (1.4 g, 6.1 mmol), 5-bromo-2-chloro-3-nitropyridine (1.6 g, 6.1 mmol, 1.0 eq.) and potassium fluoride (0.53 g, 9.0 mmol, 1.5 eq.) in DMF (8 ml) was heated at 110° C. for 4 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude product which was purified by column chromatography (60-120 silica gel, 30% Ethyl acetate in hexane) to give the title product in 28% yield (0.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[CH:28]=1)=[O:26]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[CH:28]=1)=[O:26])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Reaction time: 72 h
Yield: 84.3 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (24.0 g) was dissolved in acetonitrile (330 mL), and triethylamine (15.6 mL) was added. A solution of 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g) in acetonitrile (170 mL) were added. Reaction mixture was stirred over 3 days and evaporated under vacuum. Oil was dissolved in dichloromethane (100 mL), extracted with water (50 mL) and with NaHCO3 solution (50 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-30% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (39.2 g, 84%) as a tan solid.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH:13]=[N:12][C:11]([SH:14])=[N:10]1.C[O-].[Na+]>CO>[NH:9]1[CH:13]=[N:12][C:11]([S:14][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10]1
Reactant: BrCC1CCCCC1
Reactant: Sc1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CCCCC2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Cyclohexylmethyl bromide (42 ml; 0.30 mol) was added over 5 min to 1,2,4-triazole-3-thiol (30.3 g; 0.30 mol) and sodium methoxide (17.3 g; 0.32 mol) in dry methanol (250 ml) under dry nitrogen. The mixture was refluxed for 4 h, stirred at room temperature overnight and evaporated. The residue was dissolved in ethyl acetate (400 ml) and water (200 ml). The organic phase is separated, washed with water (100 ml), dried (Na2SO4), filtered and its volume reduced by evaporation, causing a solid to precipitate. The solid was filtered off and dried, to afford cyclohexylmethyl 1,2,4-triazol-3-yl sulfide (48.0 g; 81%) as white plates, m.p. 74°-78° C. (Found, C: 54.98; H: 7.85; N: 21.32; S: 16.13. C9H15N3S requires C: 54.79; H: 7.66; N: 21.30; S: 16.25%). NMR - d(CDCl3 ; 90 MHz) 0.50-2.10 (11H, m), 3.1 (2H, d, J=6.4 Hz), 8.13 (1H, s) and 13.9 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].O>ClCCl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:10]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(Cc2csc3ccc([N+](=O)[O-])cc23)c(OC)c1

Procedure:
Stannic chloride (0.41 g.) was added to a stirred solution of 5-nitrobenzo[b]thiophene (0.28 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.61 g.) in dichloromethane (5 ml.). The mixture was heated under reflux for 18 hours. The cooled mixture was poured into water (10 ml.) and extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil was purified by flash chromatography on silica gel (100 ml.) eluting with 1:9 v/v ethyl acetate:hexane. The solid obtained was crystallized from hexane to give methyl 3-methoxy-4-(5-nitrobenzo[b]thien-3-ylmethyl)benzoate (I) as a solid (0.16 g., 30%): NMR: (250 MHz, CDCl3): 3.92 (s, 3 H, OCH3), 3.98 (s,3 H, OCH3), 4.28 (s,2 H, CH2 --Ar), 7.15 (d,1 H), 7.22 (s,1 H), 7.56 (m,2 H), 7.93 (d,1 H), 8.19 (dd, 1 H): 8.73 (d,1 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1Br)=[O:18])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O>[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cnn(C)c1Br
Reactant: Oc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnn(C)c1Oc1ccccc1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
Phenol (30.3 g; 322 mmol) is dissolved in DMA and K2CO3 (88.9 g; 643 mmol) is added portion wise. It is stirred for 10 minutes, then 5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (50.0 g; 215 mmol) is dropped to the reaction mixture and heated up to 140° C. for 16 hours. A 10% citric acid solution is added and extracted with DCM. The organic layer is washed with sodium bicarbonate and brine, then dried and purified through column chromatography.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]=[C:29]=[O:30])=[C:18]([F:31])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([F:31])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: Cc1nnc(-c2cc(N=C=O)c(F)cc2Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.04 g of sodium hydride (oil, purity: 55%) in 75 ml of dimethylformamide, a solution of 4.3 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 58 ml of toluene was added dropwise at 0° C. over a period of 15 minutes. Thereafter, the solution was stirred at 0° C. for 15 minutes and then cooled to -30° C., followed by dropwise addition of a solution of 5.7 g of 4-chloro-2-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl isocyanate in 60 ml of toluene. The resulting mixed solution was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:19]([O-:20])=[O:18])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC(C)=O)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
N-(3-methoxyphenyl)acetamide (14.23 g, 0.086 mol) was dissolved in acetonitrile (200 mL) and cooled to 0° C. Solid nitronium tetrafluoroborate (14.79 g, 0.106 mol) was added in four portions. The temperature rose to about 5° C. during each addition and was allowed to cool down to 0°0 C. between additions. After the last addition of nitronium tetrafluoroborate, water (200 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to give approximately 200 mL of a dark oil. The dark oil was dissolved in dichloromethane (200 mL) and washed with water (6×150 mL). The organic layer was concentrated under reduced pressure and dried to obtain 16.1 g of a dark red oil. The red oil was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to give 4.53 g (27%) of the crude product. The crude product was triturated with 25% ethyl acetate/hexane to give 3.0 g (17%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-Amino-N-methyl-benzamide (1.5 g, 10 mmol) and 2,4,5-Trichloro-pyrimidine (1.31 ew) were combined in DMF (30 mL). Potassium carbonate (1.3 eq) was added the mixture heated to 75° C. for 4.5 h and stirred at room temperature overnight. The mixture was poured into water and the white precipitate that ensued was filtered and dried to give 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2.7 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.86 (s, 1H), 8.54-8.48 (m, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.61 (t, J=8.7 Hz, 1H), 7.23 (t, J=8.9 Hz, 1H), 2.50 (d, J=1.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][OH:11]>>[CH3:10][O:11][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CO
Product: COc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with methanol to form p-methoxyaniline.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1>C1COCC1>[NH2:3][C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1
Reactant: N
Reactant: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc(N)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Reaction time: 6 h
Yield: 63.3 %

Procedure:
A methanol solution of ammonia (7M, 0.39 mL, 2.7 mmol) was added to a solution of the above 1-[4-chloro-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, ethyl ester (120 mg, 0.27 mmol) and THF (2 mL). The mixture was stirred 6 h, then concentrated. The residue was triturated with Et2O, providing the titled compound (72 mg, 64%). 1H NMR (500 MHz, DMSO-d6): 8.96 (d, J=0.8 Hz, 1H), 8.44-8.02 (m, 3H), 7.71 (d, J=11.9 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.12 (s, 6H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15]=[CH:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[CH:15][CH:16]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-hydrazinobenzoic acid (0.501 g, 3.29 mmol) and 4ethoxy-1,1,1-trifluoro-3-buten-2-one (0.48 mL, 3.4 mmol) in EtOH (15 mL) was heated to 75° C. for 17 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide a solid. The obtained solid was suspended in CHCl3 (15 mL), treated with P2O5 (0.50 g, 3.5 mmol), and heated at 65° C. for 6 hours. After cooling to room temperature, the mixture was treated with 1N NaOH (5 mL) and stirred for 30 minutes. The mixture was quenched with 1N HCl (6 mL) and extracted with CH2Cl2 (3×8 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated to provide the title compound as a solid.