Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:44])[N:35](C1C=CC(N)=CC=1)[CH3:36].ClC1N=C(NC2CC2)C2C=CNC=2N=1>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:35]([CH3:36])[C:34](=[O:44])[O:33][CH3:32])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: COC(=O)N(C)c1ccc(N)cc1
Agent: Clc1nc(NC2CC2)c2cc[nH]c2n1
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, Methyl-4-aminophenyl(methyl)carbamate and 2-chloro-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave methyl 4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl(methyl)carbamate (MS calcd for C18H20N6O2 352.2. found [MH] 353.0; UV 227.5, 292.6 nm).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[N:44]=[C:19]3[N:20]([CH3:43])[C:21](=[O:42])[C:22]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][CH:29]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]3[N:17]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]2[N:44]=[C:19]3[N:20]([CH3:43])[C:21](=[O:42])[C:22]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]5[NH:3][C:4](=[O:7])[O:5][N:41]=5)=[CH:30][CH:29]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]3[N:17]=2)[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C3CC3)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C)c2nc(C3CC3)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.65 g), sodium hydrogen carbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(2-cyclopropyl-4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.091 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.077 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([NH2:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:16]([C:20]1[CH:43]=[CH:42][C:23]([CH2:24][NH:25][C:26](NC(C2C=CC(NS(C)(=O)=O)=CC=2)C)=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:43]=[CH:42][C:23]([CH2:24][NH:25][C:26]([NH:15][CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([F:1])[CH:3]=2)[CH3:14])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(N)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(NC(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)cc1
Product: CC(NC(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
Through similar procedure to that in Example 102 excepting 1-[3-Fluoro-4-(methylsulfonylamino)phenyl]ethyl amine (13-12) as a starting material, N-(4-t-Butylbenzyl)-N′-{1-[4-(methylsulfonylamino)phenyl]ethyl}urea (23-1, MK-82) having following physicochemical properties was synthesized:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 3H (20.5 g) and piperazine (37.0 g) in dimethylsulfoxide (200 mL) was heated to 110° C. for 24 hours, and the mixture was allowed to cool to room temperature. The mixture was poured into water (1 L), extracted three times with dichloromethane, and the combined extracts were washed with 2× water, and brine and filtered and concentrated to give the pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1.[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28](O)=[O:29].N1C=CC=CC=1>CCOC(C)=O>[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1)=[O:29]
Reactant: C=C[C@@H](C)C(=O)O
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2N)ccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2NC(=O)[C@H](C)C=C)ccn1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a solution of 45D (1.4 g, 4.12 mmol), (R)-2-methylbut-3-enoic acid (0.58 g, 5.79 mmol) in EtOAc (41.2 ml) was added pyridine (1.001 ml, 12.37 mmol). The reaction was cooled down to 0° C. under Ar and propane phosphonic acid anhydride (4.91 ml, 8.25 mmol) was added dropwise. The reaction was then gradually warmed up to rt over night. The reaction mixture was diluted and washed with sat. aq. NaHCO3, aqueous layer back-extracted with EtOAc, combined EtOAc phase washed with brine, dried over MgSO4, filtered, concentrated. The residue was purified by silica gel chromatography to give the desired product (1.47 g, 85%) as an off white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.65-8.60 (m, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.24-7.18 (m, 3H), 7.16 (dd, J=5.0, 1.4 Hz, 1H), 5.82-5.62 (m, 3H), 5.10-5.01 (m, 4H), 4.86 (d, J=7.2 Hz, 1H), 3.03 (quin, J=7.2 Hz, 1H), 2.62 (tq, J=14.1, 6.9 Hz, 2H), 1.49-1.36 (m, 9H), 1.25 (d, J=7.2 Hz, 3H). MS (ESI) m/z: 422.1 (M+H)+.
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][C:30]=1[CH3:43]>C1(C)C=CC=CC=1.C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]([OH:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][C:30]=1[CH3:43]
Reactant: COC(=O)CCC(=O)c1ccc(F)c(C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of BH3.THF (1M, 1.2 mL, 1.2 mmol) was added to 10 mL anhydrous THF followed by the dropwise addition of (S)-2-methyl-CBS-oxazaborolidine (1M, 109 μL, 0.1 mmol) in toluene at 25° C. After stirring for 5 min, methyl 4-(4-fluoro-3-methylphenyl)-4-oxobutanoate (229 mg, 1.0 mmol) was slowly added as a solution in 5 mL THF. The mixture was stirred for 30 min at room temperature and then the reaction was quenched by the careful addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL) before being dried over Na2SO4. The solvents were removed under reduced pressure and the product isolated by silica gel chromatography to afford the title compound 181 mg, as an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=[O:15])([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([O:11][CH2:4][C:3]3[CH:7]=[CH:8][C:9]([O:15][CH3:12])=[CH:10][CH:2]=3)[CH:9]=[CH:10][C:2]=2[I:1])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1cc(O)ccc1I
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COC(=O)c2cc(OCc3ccc(OC)cc3)ccc2I)cc1
Temperature: 65 °C
Yield: 30 %

Procedure:
To a stirred solution of 2-iodo-5-hydroxybenzoic acid (prepared according to the method described in J. Am. Chem. Soc., 1984, 106, 2651) (27.15 g, 103 mmol) in anhydrous acetonitrile (400 mL) was added cesium carbonate (73.80 g, 227 mmol) and 4-methoxybenzyl chloride (33.5 mL, 247 mmol). The resulting solid mass was broken up and the mixture heated at 65° C. for 15 h. The reaction mixture was poured into sat. NaHCO3 (aq.) (400 mL) and the resultant mixture extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel with a gradient of ethyl acetate:hexanes (1:9, v/v) to ethyl acetate:hexanes (1:3, v/v) as eluent to afford 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester (15.39 g, 30.52 mmol, 30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:11][CH3:12]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Reactant: CCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,5-dichloro-2-methoxybenzoic acid (8.2 g, 37 mmol) and K2CO3 (11.8 g, 111 mmol) in DMF (100 mL), CH3I (6.3 g, 44 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]1[C:38]([CH2:43]Br)=[CH:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:6]3[O:5][N:4]=[C:3]([CH2:2][N:1]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36]4)[N:7]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CN4Cc5ccccc5C4)no3)c2[C@@H]2CCN12
Yield: 62.3 %

Procedure:
5 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 50 ml of methylene chloride, 12 ml (70 mmol) of N-ethyldiisopropylamine and 3.7 g (14 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 72 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 70 g of silica gel while eluting with methylene chloride/ethyl acetate 7/3. There were obtained 4.0 g (62%) of (S)-8-chloro-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 170°-175°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27](=[O:28])[CH2:26][Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OC(CCNCc1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
To the stirred solution of 15.6 g of N-benzyl-3-hydroxy-3,3-diphenylpropylamine in 7.0 g of di-isopropylethylamine and 150 ml of methylene chloride, that of 5.88 g of chloroacetyl chloride in 50 ml of methylene chloride is added dropwise while stirring and cooling with an ice-bath. Thereupon the solution is stirred for 15 minutes at 0°-5° and washed successively with N hydrochloric acid, 10% aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The organic layer is separated, dried, filtered and evaporated, to yield the N-benzyl-N-chloroacetyl-3-hydroxy-3,3-diphenylpropylamine showing in the I.R. spectrum a strong band at 1640 cm-1.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:9][C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]>OS(O)(=O)=O>[C:6]([NH:9][C:10]1[C:20]([N+:1]([O-:4])=[O:2])=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(Cl)cc1COC(C)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c(COC(C)=O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
Potassium nitrate (1.01 g, 10 mmol) was added to conc. H2SO4 (10 ml) at 0° C. This mixture was stirred at 0° C. for 15 min, then acetic acid 2-acetylamino-5-chloro-benzyl ester (1.92 g, 8 mmol) was added in small portions over 15 min. The reaction mixture was stirred at 0° C. for a further 1 h, and then poured onto crushed ice. The precipitate formed was collected by filtration to give a mixture of isomers, which were separated by column chromatography eluting with a gradient of 0-60% ethyl acetate in petroleum ether to give the desired acetic acid 2-acetylamino-5-chloro-3-nitro-benzyl ester as a yellow solid (0.454 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:4]([CH:18](O)[CH3:19])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH:18]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2=[CH:8][O:9][N:10]=[C:6]2[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[CH3:19])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc(Cl)c2conc2c1-c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]ethanol (0.094 g, 0.32 mmol) in methylene chloride (2 mL) was added triethylamine (0.067 mL, 0.48 mmol), followed by methanesulfonyl chloride (0.031 mL, 0.40 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting 1-[4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]ethyl methanesulfonate was used directly in the next step. LCMS calculated for C16H14ClFNO4S (M+H)+: m/z=370.0; Found: 370.1. The crude mesylate was dissolved in N,N-dimethylformamide (1 mL) and treated with sodium azide (0.105 g, 1.61 mmol) at room temperature overnight. After diluted with ethyl acetate, the mixture was washed with water, brine and then dried over magnesium sulfate and evaporated to dryness. The crude product was used in the next step (90 mg, 88%). LCMS calculated for C15H11ClFN4O (M+H)+: m/z=317.1; Found: 317.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:5][C:4]1[CH:6]=[C:7]([I:9])[CH:8]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)cc(I)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a stirred solution of 3-bromo-5-iodo-aniline (0.60 g, 2.01 mmol) and pyridine (0.65 mL, 8.06 mmol) in CH2Cl2 (15 mL) at 0° C. was added methyl chloroformate (0.17 mL, 2.22 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 12 hours. The reaction mixture was washed with twice with 5 mL 1 M HCl and 5 mL brine. The organic layer was dried over Na2SO4 and concentrated to give 0.71 g (99%) of (3-bromo-5-iodo-phenyl)-carbamic acid methyl ester.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15](C)[C:16]([NH2:18])=[O:17])=[CH:11][CH:10]=1.[CH2:20](N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH3:20])=[O:17])=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CN(C(N)=O)c1ccc(CCO)cc1
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
47 g (0.412 mole) methanesulfonyl chloride in dichloromethane was added in small portions to a solution of 20 g (0.103 mole) N-[4-(2-hydroxyethyl)phenyl]-N1-methylurea and 41.7 g (0.412 mole) triethylamine in 500 ml dichloromethane at 0° C. After stirring at room temperature over night the reaction mixture was washed with 2 M hydrochloric acid and sodium bicarbonate. The organic phase was dried and concentrated by evaporation in vacuo and the formed precipitate was collected by filtration to give 8.81 g (yield 31%) of 4-(methylaminocarbonylamino)phenethyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:27]([CH3:38])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@H:27]([CH3:38])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)c1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a 50 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (30.5 mg, 0.181 mmol) and tert-butyl (R)-4-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (45 mg, 0.120 mmol) in DMSO (0.60 mL). Triethylamine (84 μL, 0.60 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. Additional triethylamine (84 μL, 0.602 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (10 mg, 0.060 mmol) were added and the mixture was heated for another 3 hours at 80° C. The cooled mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a white solid (51 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48-1.52 (m, 12H), 1.54 (d, J=6.82 Hz, 3H), 2.39 (s, 3H), 2.79-2.86 (m, 1H), 2.89-3.09 (m, 3H), 3.35 (br s, 1H), 3.78 (s, 3H), 4.05 (d, J=9.85 Hz, 1H), 4.34 (br s, 1H), 5.27 (br s, 1H), 5.94 (quin, J=6.76 Hz, 1H), 6.66 (d, J=3.28 Hz, 1H), 7.24 (d, J=3.28 Hz, 1H), 7.31 (d, J=7.83 Hz, 1H), 7.40 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][C@H:39]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 51 %

Procedure:
A solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea from Example 95B (50 mg, 0.111 mmol), (R)-3-hydroxy-1-tert-butoxycarbonylpyrrolidine (31 mg, 0.167 mmol), triphenylphosphine (44 mg, 0.167 mmol) and diisopropylazodicarboxylate (34 mg, 0.167 mmol) in dry tetrahydrofuran (1 mL) was stirred at room temperature for 15 h. The reaction mixture was partitioned between aqueous 1M sodium hydroxide solution (20 mL) and 10% methanol in dichloromethane (50 mL) and the organic layer was separated and washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 100% dichloromethane to 10% methanol in dichloromethane to afford (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate as a colorless oil (35 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 9.30 (brs, 1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.26-7.39 (m, 2H), 7.00 (m, 1H), 5.95 (s, 1H), 5.12 (s, 1H), 4.02 (s, 3H), 3.50-3.80 (m, 5H), 2.20-2.40 (m, 2H), 1.50 (s, 9H), 1.30 (s, 9H); LC-MS (ESI) m/z 619 (M+H)+.