Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]([CH3:33])([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([Cl:34])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:34][C:21]1[C:22]([NH:24][C:25]([CH3:33])([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)(C)CNS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Yield: 63.3 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol, 1.0 eq), N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-propyl]-methanesulfonamide (119 mg, 0.38 mmol, 1.1 eq), and 10-camphorsulfonic acid (88 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 40 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain N-(2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-2-methyl-propyl)-methanesulfonamide as a white foam (107 mg, 63%). LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.25-7.18 (m, 2H), 7.04 (d, 1H, J=7.9 Hz), 6.87 (s 1H), 5.93-5.79 (m, 1H), 5.13 (s, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.47 (d, 2H, J=6.0 Hz), 3.38 (s, 3H), 2.99-2.88 (m, 4H), 2.78 (s, 3H), 2.81-2.68 (m, 6H), 1.50 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:5]=1[C:6]([O-:8])=[O:7])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7]
Reactant: O=C([O-])c1ccc(C=CCCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 208.1 %

Procedure:
70 mg of 5% palladium-carbon was added to 4 mL of ethyl acetate solution containing 0.35 g of 2-nitro-4-(4-phenyl-1-butenyl)benzoate and stirred under hydrogen atmosphere at room temperature for 8 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 0.40 g of tert-butyl 2-amino-4-(4-phenylbutyl)benzoate as yellow oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([OH:51])=O.CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C>[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH:66][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:51]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (138 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.029 g, 24%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of 3-butyryl-4-chloro-8-(benzoyloxymethyl)quinoline (3.68 g, 10 mmol) and 4-fluoro-2-methylaniline (1.67 ml, 15 mmol) in dioxan (40 ml) was heated at reflux for 3 hours, cooled, filtered and the solid discarded. The solution was evaporated and the residue taken up in 1% methanolic sodium hydroxide (100 ml) and stirred 2 hours at room temperature. The solid was filtered off and recrystallised from methanol to give 3-butyryl-4-(2-methyl-4-fluorophenylamino)-8-(hydroxymethyl)quinoline (1.56 g, 44%), m.p. 168°-170°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:10][C:9]=2[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 0.50 g of 5-tert-butyl-2-hydroxybenzaldehyde, 0.48 g of 4-(chloromethyl)pyridine hydrochloride, 0.78 g of potassium carbonate, 0.49 g of potassium iodide and 10 ml of DMF was stirred at 80° C. for 2 hours. Subsequently, 0.78 g of potassium carbonate was added to the reaction mixture, and the mixture was stirred at 150° C. for 8 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 4-(5-tert-butylbenzofuran-2-yl)pyridine (hereinafter, referred to as “Present Active Compound 1”).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.FC1C=CC(C[O:25][NH2:26])=CC=1>>[ClH:1].[C:6]1([CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][CH2:3][CH2:2][O:25][NH2:26])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: NOCc1ccc(F)cc1
Agent: Cl
Product: NOCCOC(c1ccccc1)c1ccccc1

Procedure:
The (2'-diphenylmethoxyethyl)-oxyamine hydrochloride is prepared from 1-chloro-2-(diphenylmethoxy)-ethane in an analogous fashion to that described in Example 10 for p-fluorobenzyloxyamine hydrochloride.
Reaction SMILES: [CH2:1]([CH:3]([CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[NH2:4])[CH3:2].BrCC(=O)C(OCC)=O.Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28]>>[CH2:30]([O:29][C:27]([C:26]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH:3]([CH2:1][CH3:2])[NH:4][CH:25]=1)=[O:28])[CH2:31][CH3:32]
Reactant: CCCOC(=O)C(=O)CBr
Reactant: CCC(N)Cc1c[nH]c2ccccc12
Agent: CCOC(=O)C(=O)CBr
Product: CCCOC(=O)C1=CNC(CC)Cc2c1[nH]c1ccccc21

Procedure:
2-Ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in a manner similar to that described in Example 1A but replacing tryptamine hydrochloride with α-ethyl tryptamine and ethyl 3-bromopyruvate with n-propyl 3-bromopyruvate; MS (ESI): 303 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH:23]1([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([CH2:26][N:27]([CH3:28])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:25][CH2:24]1
Reactant: CNCC1CC1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Solvent: Cc1ccccc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)CC1CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution of methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (100 mg, 0.31 mmol) and cyclopropylmethyl(methyl)amine (260 mg, 3.1 mmol) in toluene (5 mL) was heated at 110° C. in a sealed tube for 24 hrs. The solution was concentrated to an oily residue which was dissolved in MeOH (5 mL). To this solution was added 10 N NaOH solution (1 g). The mixture was stirred and refluxed for 1 hr and then cooled to RT. The pH was carefully adjusted to 6.5 and the resulting mixture was concentrated to a residue. The residue was diluted with MeOH (10 mL) and filtered. The solids were washed with additional MeOH (10 mL). The filtrate was concentrated to an oily residue and chromatographed on silica gel (90% MeOH, 10% pH 7 buffer [potassium phosphate based] to give a foam. The foam was then chromatographed on reverse phase C18 silica gel [40-63 microns (mesh 230-400); 60 Å; 500 m2/g; pore volume 0.8 ml/g] using 80% MeOH/10% DI H2O to give the title compound (32 mg) as a beige solid: 1HNMR (400 MHz, CD3OD): δ 0.29 (2H, s), 0.73 (2H, s), 1.05 (1H, m), 2.77 (5H, m), 3.51 (2H, t, J=4.2 Hz), 4.45 (2H, t, J=4.2 Hz), 7.79 (1H, s), 7.92 (2H, m), 8.43 (1H, s), 8.64 (1H, s). [M+H] Calc'd for C16H20N4O2, 301. Found, 301.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][C:8]([CH2:10][CH2:11][NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:7][C:6]=2[CH:19]=1.C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]([CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])[C:31](=[O:32])[O:33][CH2:34][CH3:35])=[CH:7][C:6]=2[CH:19]=1
Reactant: COC(CNCCc1cc2cc(Br)cc(Cl)c2o1)OC
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(CCc1cc2cc(Br)cc(Cl)c2o1)CC(OC)OC
Yield: 89.5 %

Procedure:
To a solution of the product obtained from step A (640 mg, 1.76 mmol) in dichloromethane (5 mL) at 0° C. was added diisopropylethylamine (0.61 mL, 3.53 mmol) followed by ethyl chloroformate (0.34 mL, 3.53 mmol). The reaction mixture was allowed to warm to ambient temperature over 2 h before addition of water (10 mL). The mixture was extracted with dichloromethane (2×20 mL) and the combined organic extracts washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) afforded ethyl 2-(5-bromo-7-chlorobenzofuran-2-yl)ethyl(2,2-dimethoxyethyl)carbamate (685 mg, 89%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.51 (s, 1H), 7.37 (s, 1H), 6.50-6.39 (m, 1H), 4.53-4.38 (m, 1H), 4.21-3.98 (m, 2H), 3.75-3.64 (m, 2H), 3.47-3.35 (m, 6H), 3.34-3.22 (m, 2H), 3.13-2.99 (m, 2H), 1.30-1.11 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN3CCS(=O)(=O)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and thiomorpholine-1,1-dioxide are processed according to the method described in Example 170 to give 6-chloro-2-[5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.93-2.98 (m, 4H), 3.12-3.18 (m, 4H), 3.81 (s, 3H), 3.87 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 415.1015 [(M+H)+ Calcd for C20H20ClN4O2S: 415.0996].
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:12][C:13]([CH3:16])([OH:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)CCl
Reactant: Ic1ccnc2c[nH]nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc2nccc(I)c2n1
Temperature: 120 °C
Yield: 43.8 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (300 mg, 1.224 mmol), 1-chloro-2-methylpropan-2-ol (133 mg, 1.224 mmol) and Cs2CO3 (399 mg, 1.224 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 30 minutes using a microwave. The reaction mixture was then purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 05-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using basic buffer to afford 1-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol (170 mg, 0.536 mmol, 43.8% yield). MS [M+H] found 318.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10](S(CCC)(=O)=O)[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].Cl>[OH-].[Na+]>[F:1][C:2]1[C:3]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8]
Reactant: CCCS(=O)(=O)N(c1ncc(F)c(I)c1F)S(=O)(=O)CCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)Nc1ncc(F)c(I)c1F

Procedure:
Crude N-(3,5-Difluoro-4-iodopyridin-2-yl)-N-(propylsulfonyl)propane-1-sulfonamide (obtained in Step 1) was stirred with 5% aqueous sodium hydroxide solution (20 ml) at 60° C. for 1 h. The cooled reaction mixture was then acidified with 10% hydrochloric acid to pH<2 and extracted with DCM. The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (20-30% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z 363.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[C:19]([S:20][CH2:21][CH2:22][C:23](OC)=O)=[CH:18][N:17]=[C:16]([NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)[CH:15]=1.CC([O-])(C)C.[K+].Br.BrC[C:43]1[CH:48]=[CH:47]C=C[N:44]=1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[C:19]([S:20][CH2:21][C:22]2[CH:23]=[CH:47][CH:48]=[CH:43][N:44]=2)=[CH:18][N:17]=[C:16]([NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(C)cs3)ncc2SCCC(=O)OC)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(C)cs3)ncc2SCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
A 20 mL vial is charged with ethyl 4-chloro-3-(5-(3-methoxy-3-oxopropylthio)-2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (0.33 mmol) and THF (0.5 mL). 1M KOtBu in THF (1.184 ml, 1.184 mmol) is added and the reaction mixture is stirred at room temperature for 30 seconds. 2-(Bromomethyl)pyridine hydrobromide (85.55 mg, 0.3382 mmol) is added and the reaction mixture is stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride is added and extracted with EtOAc. The reaction mixture is purified via column chromatography on silica gel to afford ethyl 4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(pyridin-2-ylmethylthio)pyridin-4-yloxy)benzoate.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][CH2:17]2>C(=S)=S>[Cl:11][C:12]1[CH:13]=[C:14]([C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][CH2:17]2
Reactant: O=C1CCc2cccc(Cl)c2N1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1cc(Cl)c2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of α-bromopropionyl bromide (60 g) and aluminum chloride (40 g) in carbon disulfide (100 ml) was added 8-chloro-3,4-dihydrocarbostyril (10 g). After refluxing the mixture for 5 hours, carbon disulfide was evaporated and heated at 70° to 80° C. for 5 hours. The reaction mixture was poured into ice water and allowed to stand overnight. The mixture was extracted with chloroform and the chloroform layer was washed with water, dried and treated with activated carbon followed by evaporating chloroform. The residue was washed with diethyl ether and collected by filtration. The residue gave uniform crude crystals upon TLC. The crystals thus obtained were re-crystallized from methanol to give 12 g of 8-chloro-6-α-bromopropionyl-3,4-dihydrocarbostyril.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([N:13]2[CH2:18][C:17]3([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[O:16][CH2:15][C:14]2=[O:31])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:8][CH2:9][C:10]1([N:13]2[CH2:18][C:17]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:16][CH2:15][C:14]2=[O:31])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1(CO[Si](C)(C)C(C)(C)C)CC1)C(=O)CO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1COC2(CCNCC2)CN1C1(CO)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of tert-butyl 4-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (0.988 mmol) in 1,4-dioxane (2 mL) was treated with 4N HCl in dioxane (8.00 mmol). The reaction was stirred at room temperature for 2.5 h. The reaction contents were then concentrated to dryness in vacuo, at which point it was determined that not all of the starting material had been consumed. The material was suspended in 1,4-dioxane (2 mL) and was treated with 4N HCl in dioxane (8.00 mmol). The mixture was allowed to stir at 50° C. for 2 h, at which point the reaction contents were concentrated to dryness in vacuo. The material was diluted with dichloromethane (5 mL) and was concentrated to dryness again to afford the crude title compound as a hydrochloride salt. The crude product was used directly in the next step. MS(ES)+ m/e 241.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:20](N)=[NH:21]>CCOC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][N:21]=[C:4]2[OH:5]
Reactant: N=CN
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(O)c2cc1OCCCCl
Yield: 76 %

Procedure:
In the manner described in Example 16A Step 4, methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 21.9 mmol) in EtOAc from the previous step was reacted with formamidine hydrochloride as in Example 16A Step 4 to give 6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (4.48 g, 16.7 mmol, 76%). 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7.15 (s, 1H), 4.19 (t, 2H), 3.97 (s, 3H), 3.81 (t, 2H), 2.27-2.19 (m, 2H); LC-MS (ESI) m/z 269 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[CH:13])[CH:10]=1)=[O:5])[CH3:2].I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C=O)C>O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(I)cc1
Reactant: C#CCn1cc(C(=O)OCC)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(CC#Cc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of 1-prop-2-ynyl-1H-pyrazole-4-carboxylic acid ethyl ester obtained as given in example B1 (0.200 g, 1.1 mmol), 4-iodo toluene (0.254 g, 1.1 mol), copper iodide (0.021 g, 0.11 mmol), dichlorobis (triphenylphosphine)-palladium (II) (39 mg, 0.06 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at 25-25° C. Reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate. Organic layer was washed with brine solution and dried over Na2SO4. The solvent was evaporated and crude product was purified by column chromatography (Ethyl acetate:hexane-12:78) to obtain pure 1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid ethyl ester compound (0.226 g, 75%).
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12]>C(O)C>[CH2:11]([C:10]1[S:14][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:13]=1)[CH3:12]
Reactant: CCC(N)=S
Reactant: COC(=O)C(=O)C(C)Br
Solvent: CCO
Product: CCc1nc(C(=O)OC)c(C)s1
Yield: 52.7 %

Procedure:
A mixture of methyl 3-bromo-2-oxobutanoate (16.2 g), propanethioamide (7.4 g) and ethanol (150 mL) was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4, v/v) to give methyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate as a yellow oil (8.1 g, yield 53%).
Reaction SMILES: CN1C=CN=C1.Cl[C:8]([O:10][CH3:11])=[O:9].[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1>CN(C1C=CN=CC=1)C>[C:8](=[O:9])([O:21][C:14]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[CH:12][CH:13]=1)[O:10][CH3:11]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Agent: Cn1ccnc1
Product: COC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
N-methylimidazole and 4-(N,N-dimethylamino) pyridine (DMAP) are obtained from Aldrich Chemical Co. Methyl p-nitrophenyl carbonate is prepared from methyl chloroformate and p-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(N(CC)CC)C>[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29]
Reactant: CC(C)CCCC(=O)Cl
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Solvent: CCN(CC)CC
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCC(C)C)nc2n1
Yield: 74.2 %

Procedure:
The procedure is as in example 7, but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.7 g), 5-methylhexanoyl chloride (7.8 g), triethylamine (12 cc) and 4-diemthylaminopyridine (50 mg). After the solid obtained after treatment has been recrystallized in methylcyclohexane, 2-(7-methyl-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (3.8 g), m.p. 144° C., is obtained.