Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 127-129° C.; 1H NMR (300 MHz, CDCl3): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 4.11-4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.07-0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.25 (m, 1 H); HRMS (ESI) calcd for C19H21N3O2Cl2F (M+H)+: 412.0995; found m/z 412.1001.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.Cl.[CH3:24][NH:25][O:26][CH3:27]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzoic acid (5.0 g, 22.83 mmol) in dichloromethane (100 ml) was added WSC (8.8 g, 45.66 mmol), N,O-dimethylhydroxylamine hydrochloride (4.5 g, 45.66 mmol) and stirred at room temperature for 5 h. The solvent was removed and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and concentrated to afford 5.47 g of the titled compound as a yellow oil. The compound was used for the next reaction directly.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C:24]1[C:33]([NH2:34])=[C:32]2[C:27]([C:28](SC)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>CC(O)=O.O1CCOCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][CH:15]=[N:16][C:8]=2[C:7]1[C:2]([C:30]2[N:29]=[CH:28][C:27]3[C:32](=[C:33]([NH2:34])[CH:24]=[CH:25][CH:26]=3)[N:31]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Reactant: CSc1ncnc2c(N)c(C)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1cccc2cnc(-c3ncccc3-c3ncnc4c3ncn4C3CCCCO3)nc12
Reaction time: 6 h

Procedure:
A 250 ml flask was charged with 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2.92 g, 9.74 mmol) and 7-methyl-4-(methylthio)quinazolin-8-amine (2.00 g, 9.74 mmol) along with 20 ml of dioxane. 1.0 M LiHMDS in THF (29.2 ml, 29.2 mmol) was then added dropwise at RT. The reaction was stirred for 6 hrs and then treated with 5 ml of HOAc. The volatiles were removed under vacuum. The residue was dissolved in chloroform and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel eluting with a gradient of 20 to 60% EtOAc in hexanes to give 7-methyl-4-(methylthio)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylquinazolin-8-amine as a yellow solid. MS Found: (ESI pos. ion) m/z 485 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cncc(Cl)n2)cc1

Procedure:
2,6-Dichloropyrazine (2.98 g, 20.0 mmol), [4-(methylsulfonyl)phenyl]boronic acid (2 g, 10.0 mmol), tetrakis(triphenylphospine)palladium (1.15 g, 1.0 mmol), potassium phosphate (10.2 g, 48 mmol) and dimethylformamide (90 ml) were heated to 80° C. for 16 hours. The solvent was removed in vacuo and the product was dissolved in chloroform and filtered through celite. The filtrate was washed with water then separated. The residue was purified by column chromatography eluting with a mixture of ethylacetate:hexane (4:6) to afford the title compound. MS (ES+) m/e 270 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[OH:17])([CH3:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[N+:27]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[O:17][C:7]1[CH:8]=[CH:9][C:10]([C:12]([CH3:15])([CH3:16])[CH2:13][CH3:14])=[CH:11][C:6]=1[C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(Oc2ccncc2[N+](=O)[O-])c(C(C)(C)CC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 2,4-bis(1,1-dimethylpropyl)phenol (9.23 g, 0.039 mol) in dry tetrahydrofuran (30 mL) was stirred at room temperature under nitrogen atmosphere. Sodium hydride (1.14 g of 80% dispersion, 0.04 mol) in dry tetrahydrofuran (10 mL) was added and the mixture stirred for 30 minutes to give a clear, green solution. 4-Chloro-3-nitropyridine (5.0 g, 0.032 mol) was added and the mixture heated to 50° C. for 4 hours. The mixture was cooled and submitted to aqueous, acidic work-up. The crude product was purified by chromatogaphy on silica gel with dichloromethane eluent to give the product 3-nitro-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine in 65% yield. Analyses by proton NMR and mass spectroscopy were consistent with the proposed structure.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[C:14]1([CH2:22]Br)[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1>CN(C)C=O>[OH:7][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:22][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:6]([OH:7])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:16][CH:15]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CC(C)(C)NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N(O)Cc1ccc(CN(O)C(C)(C)C)cc1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
A suspension of 3.0 g tert-butylhydroxylamine hydrochloride, 5.0 g of anhydrous sodium carbonate and 3.15 g of p-xylylene dibromide in 20 ml of N,N-dimethylformamide is heated at 80° C. under nitrogen for 3 hours. Dilution of the reaction mixture with water followed by crystallization from heptane affords 2.1 g of product as a white solid; m.p. 137°-138° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:13]([C:34]([OH:36])=[O:35])[CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>>[Cl:32][C:27]1[CH:26]=[C:25]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]2[C:34]([OH:36])=[O:35])=[O:33])[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 155.6 %

Procedure:
A mixture of 0.63 g (1.19 mmole) of (S)-4-(benzyloxycarbonyl)-1-[N-(3,5-dichlorophenyl)-N-phenylcarbamoyl]piperazine-2-carboxylic acid and 12 mL of 30% HBr/acetic acid was stirred at room temperature for 40 min, and residual HBr was then removed by bubbling nitrogen through the solution for 3 hr. The mixture was then concentrated in vacuo. The residue was treated with 25 mL of water and the pH adjusted to 7 with aqueous sodium hydroxide. To this mixture was added 45 mL of ethyl acetate, and the ethyl acetate layer was extracted with 5×25 mL of water. The combined water layers were treated with aqueous sodium hydroxide to adjust the pH to 7, and the aqueous was concentrated in vacuo to give 0.73 g of an oily solid, which was carried on immediately in Step F) below.
Reaction SMILES: C(O[C:9]1([C:17]2C(O)=C[CH:20]=[C:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:22]=2[F:23])[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]1O)C1C=CC=CC=1.[C:36]([OH:39])(=O)[CH3:37]>[Pd]>[F:23][C:22]1[CH:17]=[C:9]([C:14]2[C:36]([OH:39])=[CH:37][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:10]=[CH:20][C:21]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:25])=[O:26]
Reactant: CC(=O)O
Reactant: COc1ccc(S(=O)(=O)c2ccc(O)c(C3(OCc4ccccc4)C=CC(F)=CC3O)c2F)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
The subtitle compound was prepared by the method of example 12 step (iii) using the product of step (ii) and 10% Pd/C in acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:12][C@H:13]([C:15]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23](=[O:31])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3Cl)[N:16]=2)[CH3:14])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:33][C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][C@H:13]([C:15]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23](=[O:31])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[C:37]3[CH:36]=[N:35][C:34]([CH3:33])=[N:39][CH:38]=3)[N:16]=2)[CH3:14])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Nc1nc(N)nc2cccnc12)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(-c2cccc3nc([C@H](C)Nc4nc(N)nc5cccnc45)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of (S)-2-(1-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (30 mg, 0.067 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (22 mg, 0.1 mmol) in 1,4-dioxane-H2O (4:1, 2 mL) in a sealed tube, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (15.6 mg, 0.034 mmol), palladium(II) acetate (3.8 mg, 0.017 mmol), and Na2CO3 (21 mg, 0.20 mmol) were added sequentially. The mixture was degassed and backfilled with argon (three cycles), and then stirred at 120° C. for 1 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH/DCM) to afford compound I-91, (S)-2-(1-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-5-(2-methylpyrimidin-5-yl)-3-phenylquinazolin-4(3H)-one (17 mg, 50% yield). ESI-MS m/z: 502.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]4[N:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH2:21]([C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:7]3[NH:6][C:5]4[CH:23]=[CH:24][C:2]([C:27]5[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=5[F:25])=[CH:3][C:4]=4[N:8]=3)[CH2:10][CH2:11]2)=[N:20][CH:19]=1)[CH3:22]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4[nH]3)CC2)nc1
Product: CCc1cnc(N2CCC(c3nc4cc(-c5ccc(S(C)(=O)=O)cc5F)ccc4[nH]3)CC2)nc1
Yield: 26.2 %

Procedure:
Following the General Procedure-1, the titled compound (25 mg) was prepared from Intermediate 2 (80 mg, 0.199 mmol) and Intermediate 3 (79 mg, 0.26 mmol) as a yellow solid. M.P.: 186.5-190° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.41 (d, J 4, 1H), 8.26 (s, 2H), 7.90-7.80 (m, 3H), 7.79-7.50 (m, 2H), 7.40-7.32 (m, 1H), 4.66 (d, J 13.1, 2H), 3.29 (s, 3H), 3.21 (t, J 8.3, 1H), 3.09 (t, J 11.7, 2H), 2.43 (q, J 7.73, 2H), 2.06 (d, J 12.5, 2H), 1.82-1.71 (m, 2H), 1.13 (t, J 7.5, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.[NH2:32][CH2:33][CH:34]([C:36]1[CH:37]=[CH:38][C:39]([OH:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1)[OH:35]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([NH:32][CH2:33][CH:34]([OH:35])[C:36]5[CH:37]=[CH:38][C:39]([OH:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=5)[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)[S:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(CC5SC(=O)NC5=O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.60 (m, 2H), 1.85-2.05 (m, 2H), 2.50-3.50 (m, 7H), 2.93 (s, 3H), 3.59 (brd, J=11.9 Hz, 2H), 4.28 (dd, J=7.0, 3.8 Hz, 1H), 4.60-4.65 (m, 1H), 6.70-6.90 (m, 5H), 7.05 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H); MS (ES) m/z: 690.0 (MH+); HRMS Calcd. for C30H36N5O8S3 (MH+): 690.1726. Found: 690.1714.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[C:35]=[O:36].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:35]([NH:34][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(NC(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.4 %

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18.18 mg, 0.18 mmol) in dichloromethane (6 ml) was added 1-isocyanato-4-methoxybenzene (26.82 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound Yield: 25 mg (22.82%); 1H NMR (DMSO-d6, 300 MHz): δ 8.785 (s, 1H), 7.81-7.94 (m, 4H), 7.62-7.69 (m, 3H), 6.95 (s, 1H), 6.47-6.63 (m, 4H), 3.51 (s, 3H), 1.79 (s, 6H); MS: m/z 556 (M+).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].I[CH2:7][C:8]1([N:32]=[C:33]=[S:34])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[O:11][CH:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1>C(Cl)(Cl)Cl>[C:1]([NH:5][C:33]1[S:34][CH2:7][C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH:16]=3)[O:11][CH:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:32]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(CI)(N=C=S)CC(c2ccccc2)O3)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC1=NC2(CS1)CC(c1ccccc1)Oc1ccc(-c3cccc(C#N)c3)cc12
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
t-BuNH2 (55 mg, 0.75 mmol) was added to 3-(4-iodomethyl-4-isothiocyanato-2-phenyl-chroman-6-yl)-benzonitrile (190.5 mg, 0.375 mmol) in CHCl3 above and the mixture was stirred for 20 minutes. The solvent was removed in vacuo to give the residue, which was purified by preparative TLC to give 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (35 mg, 21%).
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: O
Reactant: CC(C)c1nc(Cl)c(C=O)[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)c1nc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A solution of sodium chlorite (0.92 g, 10.2 mmol) and sodium dihydrogen phosphate monohydrate (0.81 g, 5.9 mmol) in water (2.2 mL) was added to a stirred solution of 4-chloro-2-(1-methylethyl)-1H-imidazole-5-carbaldehyde (0.165 g, 1.0 mmol), 2-methyl-2-butene (6.2 mL of a 2M solution in THF, 12.4 mmol), and tert-butanol (0.8 mL) in THF (3.1 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×10 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.173 g, 92%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 12.82 (br. s., 1H), 2.95 (sept, 1H), 1.20 (d, 6H). ES-LCMS: m/z 189.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[BrH:28].C(O)(=O)C>>[Br:28][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1
Reactant: Br
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Cl)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Br)n2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 45 %

Procedure:
The product from Step A (2.0 g, 6.6 mmol) was dissolved in a 30% solution of hydrobromic acid/acetic acid (18.0 mL). This mixture was stirred at room temperature for four days. The mixture was poured into aqueous 1M sodium carbonate (150 mL) and then extracted with ethyl acetate (5×50 mL). The combined extracts were dried (MgSO4) and then evaporated. The solid residue was recrystallized from hexane to afford 1.0 g (45%) of the title compound melting at 74°-76° C. 1H NMR (400 MHz, CDCl3) δ 10.64 (br s, 1H), 8.92 (s, 1H), 8.66 (s, 1H), 8.38 (m, 1H), 729-7.43 (s, 1H), 7.29-7.32 (m, 1H), 2.39 (s, 3H), 1.33 (s, 9H). Mass spec (EI) m/e 349 (1XBr).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37](=[O:38])[CH2:36][O:35][CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added methoxyacetyl chloride (30 μL, 0.331 mmol), and the mixture was stirred at room temperature for 2 hr. Methoxyacetyl chloride (15 μL, 0.165 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→20/80), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (74.5 mg, 65%) as a colorless powder.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][C:31](=O)[CH2:30]2)=[CH:25][CH:24]=1)([CH3:20])[CH3:19]>O1CCCC1>[C:7]([CH:9]=[C:31]1[CH2:32][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:34])=[CH:24][CH:25]=2)[CH2:30]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)NC(=O)c1ccc(N2CC(=O)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a cooled (at −6 to 0° C.) solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (7.10 mL, 7.10 mmol) was added dropwise a solution of diethyl cyanomethylphosphonate (1.20 mL, 7.43 mmol, Aldrich: Cat. #D91705) in tetrahydrofuran (10.0 mL) over a period of 10 minutes and at −6 to 0° C. The reaction was warmed and stirred at room temperature for 1 hour. The reaction mixture was re-cooled at −6° C. To the reaction mixture was then added a solution of N-isopropyl-4-(3-oxoazetidin-1-yl)benzamide (1.30 g, 5.60 mmol) in tetrahydrofuran (10.0 mL) over a period of 10 minutes. During this time the temperature of the reaction mixture was between −5 to 0° C. The reaction was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was filtered through a pad of silica gel and washed with ethyl acetate. The filtrate was concentrated, and the residue was treated with ether. The precipitates formed were collected by filtration to give 0.60 g desired product. The mother liquid was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 30-80%) to afford the desired product (0.21 g). the total product is 0.81 g (57%). LCMS (M+H)+: m/z=256.1.