Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].[F-].[Na+].O>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCCN
Agent: [F-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Yield: 88 %

Procedure:
34. In a 125 mL flask were mixed 14.11 g. (0.10 mole) of 4-fluoronitrobenzene, 10.22 g. (0.10 mole) of 3-(dimethylamino) propylamine and 5.00 g. (0.12 mole) of dry sodium fluoride. Upon warming, a reaction began, and after an hour the mixture was heated to 150° C. for an hour. The mixture was cooled below 100° and treated with 400 mL water containing 0.10 mole sodium hydroxide at 60° C. for one hour; it was then chilled to solidify the freed amine and the aqueous phase was decanted off. After three water washings and drying, the crude product was dissolved in methyl tertiary butyl ether, filtered and evaporated to dryness, giving 19.69 g. (88% yield) of N-(3-dimethylaminopropyl) 4-nitroaniline, m.p. 60°-61.5° C. A 2.23 g. (0.01 mole) portion of this product was dissolved in 15 mL of acetone and treated with 2.13 g. (0.015 mole) of methyl iodide in a closed vessel. There was an immediate reaction and presently a yellow solid was suddenly precipitated. The mixture was warmed for 1/2 hour at 50° C. cooled, filtered, washed with acetone, and dried; the remaining solid, weighing 3.31 g., m.p. 210°-211.5° C., represented a 90% yield of Dye No. 34.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]2[C:3]=1[C:4]1[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=1[NH:6]2.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:31]2[CH:36]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]4[C:3]=3[C:4]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=3[NH:6]4)[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenyl boronic acid using an analogous procedure to that described in the preparation of Compound 84. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.92, 2.40 Hz, 2H) 0.71 (dd, J=6.95, 2.40 Hz, 2H) 1.23 (s, 1H) 2.26 (s, 3H) 2.65 (s, 3H) 2.87 (d, J=5.05 Hz, 6H) 3.29 (q, J=5.98 Hz, 2H) 3.61 (q, J=6.15 Hz, 2H) 7.20 (s, 1H) 7.50 (s, 1H) 7.66 (t, J=7.83 Hz, 1H) 7.77 (d, J=7.83 Hz, 1H) 7.98 (d, J=7.83 Hz, 1H) 8.08 (s, 1H) 8.31 (d, J=1.77 Hz, 1H) 8.57-8.61 (m, 1H) 8.59 (d, J=4.55 Hz, 1H) 12.05 (s, 1H). [M+H] calc'd for C28H31N5O2 470; found, 470.4.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([OH:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC[N:22]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:22])=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)n1ncc(C(=O)O)c1-c1ccc(F)cc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Yield: 87.5 %

Procedure:
A solution of the compound (16.87 g, 64.32 mmol) obtained in step 2, WSC (16.03 g, 83.62 mmol), HOBt (11.30 g, 83.62 mmol), TEA (11.65 mL, 83.62 mmol) and ammonium chloride (4.47 g, 83.62 mmol) in DMF (200 mL) was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→85% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (14.72 g, 56.3 mmol, 88%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)nc1CBr

Procedure:
50 g (0.23 mol) of methyl 2-methyl-6-trifluoromethylnicotinate and 49 g (0.28 mol) of N-bromosuccinimide are heated for 90 minutes at 50° C. in 500 ml of carbon tetrachloride in the presence of a catalytic amount of α,α-azaisobutyronitrile with illumination by a 150 watt lamp. Precipitated succinimide is filtered off, and the product methyl 2-bromomethyl-6-trifluoromethylnicotinate is then isolated as main component by means of column chromatography (mobile phase ethyl acetate/hexane 1:15), 1H-NMR (CDCl3): 4.01, s, 3H; 5.03, s, 2H; 7.72, d (J 8.2 Hz), 1H; 8.43 ppm, d, (J 8.2 Hz), 1H. 25.6 g (35 mmol) of the above product are taken up in toluene and treated with 10.6 g (40 mmol) of triphenylphosphine. After the mixture has been heated for 2 hours at boiling point, pure (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenylphosphonium bromide of melting point 215-217° C. crystallizes out upon cooling.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:13]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)([OH:12])[CH3:9])[N:15]=[N:14]1)[CH3:21]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#CC(C)(O)c1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1cc(C(C)(O)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(6-Bromopyridin-2-yl)but-3-yn-2-ol (300 mg, 1.33 mmol) and ethyl azidoacetate (0.82 mL, 1.46 mmol) were combined in t-BuOH (3.0 mL) and water (1.0 mL). CuSO4.5H2O (17 mg, 0.066 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (53 mg, 0.27 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (10-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].CN(C=O)C.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:4]([C@H:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:16])[C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:28])([CH3:29])[C:25]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[CH:19][CH:18]=3)[C@@H:7]([CH3:32])[CH2:6]2)[C:1](=[O:3])[CH3:2])=[CH:34][CH:35]=1
Reactant: CS(N)(=O)=O
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)NS(C)(=O)=O)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid (200 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and oxalyl chloride (2 mL). A single drop of DMF was added, and the mixture was stirred at room temperature until gas evolution ceased. All volatiles were removed. The slurry was dissolved in methylene chloride (10 mL) and triethylamine (2 mL). Methanesulfonamide (200 mg, 2.10 mmol) was added and the reaction mixture was stirred for 3 hours. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparatory HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[CH:7]2O.[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[C:9](=[O:11])[C:8]2([CH3:13])[CH3:12])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)C(=O)c2c(Cl)cccc2C1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2cccc(Cl)c2C(=O)C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-3-hydroxy-2,2-dimethyl-indan-1-one (1.10 g, 5.24 mmol) in THF (50 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.0 g, 7.85 mmol), followed by triphenylphosphine (2.1 g, 7.85 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (1.8 g, 7.85 mmol) is added. The reaction is permitted to warm to room temperature and stirred for 2 hours. The reaction mixture is then cooled to 0° C., quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The organic layers are combined, dried over Na2SO4, filtered concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1) to furnish 3-(4-chloro-2,2-dimethyl-3-oxo-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 319.0 (M+H)+
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with pentaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This was then reacted with 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxycarbonyloxy]-ethyl ester as a white solid. LCMS (ES+) m/z calcd. for C45H56Cl2F2N3O12 [(M+H)+]: 938, found: 938.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.Br[C:65]1N=C(C(C2C=C(CC)C=C(OCC)C=2F)O)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:50]([O:52][C:53]([CH3:55])([CH3:56])[CH3:54])=[O:51])[C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH2:36][CH3:65])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: CCOc1cc(CC)cc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 213.1 (1.02 g, 1.74 mmol) was converted to the chloro intermediate, which was displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (688 mg, 1.91 mmol) to afford after flash chromatography (0 to 60% EtOAc/hexanes gradient) 1.47 g of Intermediate 213.2 as a pale yellow solid.
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[O:28][N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Temperature: 25 °C
Yield: 19 %

Procedure:
A stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.30 mmol), phenyl 3-isopropylisoxazol-5-ylcarbamate from the previous step (89 mg, 0.36 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol) and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) in dry tetrahydrofuran (1.5 mL), was heated at 50° C. for 30 mins. After cooling to room temperature, concentration under reduced pressure gave a residue which was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (using phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea as a colorless solid (25 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 10.30 (brs, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.39-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.00 (s, 6H), 2.90 (septet, J=6 Hz, 1H), 1.19 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[BrH:12].CS(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: Br
Reactant: CC(C)(C)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
25 g (168 mmol) of 2-tert-butylaniline are placed in 300 ml of acetic acid. 450 ml of aqueous HBr at 48% are added and the mixture is then cooled to 0° C. 150 ml of DMSO are added dropwise, the mixture having been brought back to ambient temperature is stirred for 2 hours and it is then poured into ice-cold water and basified to pH 10 with 5N NaOH. It is extracted with diethyl ether and the organic phase is then dried and concentrated to dryness. The residue is column-purified (95/5 heptane/EtOAc). 25.2 g of 4-bromo-2-tert-butylphenylamine are obtained in the form of a yellow oil (yield=65%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Br)C1C=CC=CC=1>>[C:1]([O:5][C:6]([C:8]1([CH2:29][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: BrCc1ccccc1
Product: CC(C)(C)OC(=O)C1(Cc2ccccc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 55 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with benzyl bromide afforded 170 mg (55%) of intermediate 21a. MS (ESI) 476.5 (M+H+), 498.5 (M+Na+).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Cl[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=1.Cl>CS(C)=O>[OH:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][C:14]=1[C:16](=[O:18])[CH3:17]
Reactant: CS(N)(=O)=O
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1cc(CNS(C)(=O)=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 1.60 g, 40.0 mmol) in 25 mL DMSO under Argon was added dropwise a solution of methanesulfonamide (3.80 g, 40.0 mmol) in 10 mL DMSO. The resulting mixture was stirred 30 minutes and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (3.69 g, 20.0 mmol) in 10 mL DMSO was added. The resulting mixture was stirred three hours, poured into 150 mL ice water, acidified with 14 mL 3N hydrochloric acid, and the mixture extracted with methylene chloride (3×200 mL). The extract was washed with water (50 mL) and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give an oil which was partially purified by flash chromatography eluting with 3:97 methanol:chloroform to give a gum. The gum was stirred under 25 mL water to remove residual DMSO, the aqueous supernatant was decanted, and the residue was dried in vacuo. The resulting material was crystallized from ethylacetate to remove 0.67 g of a by-product identified as N,N-bis[(3-acetyl-4-hydroxyphenyl)methyl]methanesulfonamide. The mother liquor was concentrated in vacuo to give a residue which was re-chromatography to give a solid. The solid was recrystallized from n-butylchloride to give 0.60 g (12%) product, as a white solid, mp 85°-86.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH:12]([F:15])[CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][NH2:20]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH:12]([F:15])[CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[N:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: O=Cc1cccc(F)c1N1CCC(F)C1
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)C1

Procedure:
3-Fluoro-2-(3-fluoropyrrolidin-1-yl)benzaldehyde (403.8 mg, 1.912 mmol) was taken in toluene (15 mL) and 3,3-dimethylbutan-1-amine (193.5 mg, 257.3 μL, 1.912 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. The reaction mixture was concentrated to give crude N-(3-fluoro-2-(3-fluoropyrrolidin-1-yl)benzylidene)-3,3-dimethylbutan-1-amine which was used directly in the next step without further purification.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].O>CC(O)=O>[NH2:3][C:4]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([I:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C(=O)O)cc(I)cc1C(=O)O
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of iodine monochloride (0.9 g) in glacial AcOH (1.7 ml) was added dropwise over 15 minutes to a stirred solution of 2-aminoisophthalic acid (1 g) in glacial AcOH (6.9 ml) at room temperature. The mixture was stirred for 2 hours and then poured into water (70 ml). The resultant orange solid was isolated by filtration, washed with water, diluted with MeOH and concentrated to yield 2-amino-5-iodoisophthalic acid (1.48 g); Mass Spectrum: M+H+ 308.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.F[C:10]1[C:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:17]=2)=[CH:14][C:13]([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][C@@H:44]2[CH3:53])=[CH:12][N:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:14][C:13]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:50])=[O:51])[CH2:45][C@@H:44]3[CH3:53])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: Nc1ccc(Cl)nc1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cnc2Nc2ccc(Cl)nc2)n1

Procedure:
The title compound was prepared from 6-chloropyridin-3-amine (Sigma Aldrich, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 504 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H) 8.88 (d, J=2.74 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 8.47 (dd, J=8.71, 2.84 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 7.93 (br. s., 1H) 7.78 (br. s., 1H) 7.45 (d, J=8.61 Hz, 1H) 3.94 (d, J=13.11Hz, 1H) 3.07-3.29 (m, 3H) 2.86-2.97 (m, 1H) 2.85 (s, 3H) 2.64-2.79 (m, 2H) 2.54-2.64 (m, 1H) 2.45 (s, 3H) 2.14-2.29 (m, 1H) 1.16 (d, J=6.06 Hz, 3H).