Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8][Br:9])[CH:7]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1.O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH:8]([Br:12])[Br:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(CBr)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: COc1ncc(C(Br)Br)cc1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-bromomethyl-2-methoxy-pyridine (6.03 g, 21.5 mmol), N-bromosuccinimide (4.09 g, 23.0 mmol), and azobisisobutyronitrile (one scoop) were combined in benzene (40 mL) and stirred at 80° C. for 4 hours. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-Bromo-5-dibromomethyl-2-methoxy-pyridine.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (25.4 g, 126.2 mmol) and imidazole (9.5 g, 138.9 mmol) in N,N-dimethylformamide (300 mL) was added tert-butyldimethylchlorosilane (20.9 g, 138.9 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (38.7 g, yield 97%) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:19]=[N:20][NH:21][CH:22]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:26]1C=C2C(=CC=1)NCC2.BrCC1C=CC(C(C)(C)C)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>[Pd]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:22]=[N:21][NH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[CH:23][CH:24]=1)([CH3:26])([CH3:3])[CH3:2]
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)c1ccc(CN2CCc3cc(-c4cn[nH]c4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(CN2CCc3cc(-c4cn[nH]c4)ccc32)cc1

Procedure:
1-(4-Isopropylbenzyl)-5-(1H-pyrazol-4-yl)indoline, 50 can be prepared by alkylation of 5-bromoindoline, 22 with 1-(bromomethyl)-4-(tert-butyl)benzene using the conditions described in Example 7, part 1 followed by palladium catalyzed coupling of the alkylation product with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, 10 followed by hydrolysis using the reaction conditions described in Example 8.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[O:20]1[CH2:21][CH2:22][N:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:6]=2)=[O:10])[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-nitro-3-trifluoromethylbenzoic acid (10 g), morpholine (3.7 g) in dichloromethane (300 mL) was added DMAP (5.2 g) and 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (12.3 g). The mixture was stirred at room temperature overnight, washed with 5% aqueous HCl, water and brine and concentrated.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:31][CH:30]=2)=[O:8])=[CH:11][C:12]=1[NH:17][C:18]1[N:19]=[CH:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[N:23]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13].C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[CH3:9][N:10]([CH2:11][CH2:12][OH:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Clc1ccncc1
Reactant: CNCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CN(CCO)c1ccncc1
Yield: 18.6 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (4.50 g), 2-(methylamino)ethanol (2.25 g) and sodium bicarbonate (7.56 g) in isoamyl alcohol (50 ml) was heated under reflux for 70 hours and then evaporated. The residue was extracted several times with hot ethyl acetate and the combined extracts were filtered and evaporated until crystallisation commenced. The solution was allowed to cool and the solid was filtered off to give the title compound, (0.85 g), m.p. 90°-91°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH:15][CH3:16].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:15]([CH3:16])[CH3:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (2.0 g, 7.9 mmol, Combi-blocks) in methylene chloride (10 mL) was added a solution of 2.0M dimethylamine in tetrahydrofuran (7.9 mL, 16 mmol) and the reaction was stirred for 15 minutes at room temperature. The reaction was then cooled to 0° C. and sodium triacetoxyborohydride (2.5 g, 12 mmol) was added. The resulting mixture was warmed to room temperature and was stirred for 24 hours. The solvents were removed in vacuo. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography, eluting with a gradient from 10-40% ethyl acetate in hexanes afforded product as a colorless oil (1.58 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.65 (s, 1H), 7.57-7.46 (m, 1H), 3.45 (s, 2H), 2.25 (s, 6H); 19F NMR (282 MHz, CDCl3) δ−63.10 (s); LCMS (M+H)+: 282.0, 284.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+]>CN(C)C=O.O>[C:10]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:11]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(C#N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Two grams of (3-methoxyphenyl)acetonitrile and 1.5 ml of ethyl 4-bromobutyrate are dissolved in 50 ml of dimethylformamide at 0° C. Six hundred milligrams of 60% sodium hydride (600 mg; 15 mmol) are progressively added to the solution. The reaction mixture is stirred at ambient temperature for 4 hours, taken up in 100 ml of acidic water and extracted with ether. The organic phase is then dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is purified on a column (eluant:ether/cyclohexane 4/6) to yield the title product in the form of a yellow oil.
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:37]1([P:43](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.Cl>[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH:29][P:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:44])[CH2:25][CH:26]([CH3:27])[CH3:28])([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](N)/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.6 %

Procedure:
To a solution of the amine 7 (400 mg, 1.01 mmol) in dry DCM (7 mL) were added Et3N (0.44 mL, 3.13 mmol), and then a solution of diphenylphosphinic chloride (Ph2POCl, 0.22 mL, 1.11 mmol) in dry DCM (3 mL) at 0° C. After being stirred at 0° C. for 15 min, the reaction mixture was allowed to warm to rt and stirred for 4 h, then diluted with DCM and 10% HCl. The aqueous phase was extracted with DCM and the combined organic layers were washed with sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford 720 mg of the crude title compound as a pale yellow solidified oil, which was used for the next step without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:16]1[CH2:21][CH2:20][C:19]([CH3:27])([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:28][CH2:29]I.C(O)(=O)C>C1COCC1>[Cl:28][CH2:29][C:22]([C:19]1([CH3:27])[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:21][CH2:20]1)=[O:24]
Reactant: ClCI
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CCl)CC1
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
Lithium diisopropylamide (30.9 mL, 46.4 mmol) was added dropwise to a solution containing ethyl N-Boc-4-methylpiperidine-4-carboxylate (2.52 g, 9.28 mmol), and chloroiodomethane (6.55 g, 37.1 mmol) in THF (100 mL) at −78° C. over 30 minutes. After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (5 mL) in THF (45 mL) was added while keeping reaction mixture below −65° C. The reaction was stirred for an additional 10 minutes and partitioned between ethyl acetate and brine, washed with saturated bicarbonate, concentrated and purified by silica gel (10%-20% ethyl acetate in hexanes) to afford tert-butyl 4-(2-chloroacetyl)-4-methylpiperidine-1-carboxylate (1.15 g, 44.92% yield).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3].[OH-].[K+].Br[CH2:28][CH2:29][CH3:30]>CS(C)=O>[CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3]
Reactant: CCCBr
Reactant: CCCNc1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCN(CCC)c1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Temperature: 60 °C

Procedure:
A mixture of the product of step F (400 mg, 1.2 mmol), powder KOH (1.0 g) and 1-bromopropane (1 mL ) in 2 mL of DMSO was heated at 60° C. for 8 hours. The excess bromopropane was then evaporated. The mixture was partitioned between water and ether. The aqueous layer was separated and extracted with ether. The combined ether extracts were washed with water and brine, dried over Na2SO4 and concentrated to an oil. The oil was purified through silica gel column chromatography to give 260 mg of the title compound as an oil. 1H NMR (CDCl3): d 0.97 (t, 6 H), 1.76 (m, 4 H), 1.96 (s, 6 H), 2.32 (s, 3 H), 2.45 (s, 3 H), 3.77 (s, 3 H), 3.40-4.30 (br, 4 H), 6.95 (s, 2 H) ppm. The hydrochloride salt prepared in Ether/HCl melted at 210-13° C.
Reaction SMILES: F[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(#N)C.C(N(C(C)C)CC)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[NH:31])[NH2:30]>>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:4]([OH:5])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:31]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: N=C(N)c1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc(-c2ccccn2)nc2ncccc12
Temperature: 90 °C
Reaction time: 27 h

Procedure:
To a stirred solution of 2-fluoro-3-pyridinecarboxylic acid (6.3 g, 44.6 mmol) in DCM (112 mL) was added thionyl chloride (15.0 mL, 205 mmol). The reaction was heated to 40° C. and stirring continued for 3.5 h. After which, the reaction mixture was concentrated in vacuo to provide 2-fluoronicotinoyl chloride as a yellow solid. The product was taken on crude to the next step. To a stirred solution of 2-fluoronicotinoyl chloride (6.3 g, 39.5 mmol) in acetonitrile (197 mL, 39.5 mmol) was added diisopropylethylamine (27.5 mL, 158 mmol) followed by picolinimidamide (5.26 g, 43.4 mmol). The reaction was heated to 90° C. and stirring continued for 27 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was placed in Et2O (100 mL) and the mixture was filtered and was further washed with Et2O. The product was dried under vacuum and used crude in the next reaction. Mass Spectrum (ESI) m/e=225.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:7]2[C@@H:8]([CH3:15])[CH2:9][N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:6]2=[C:5]([O:16][CH3:17])[C:4]=1[C:18]([O:20]CC)=O)#[N:2].[NH2:23][NH2:24]>C(O)C.C(O)(=O)C>[NH2:2][C:1]1[C:3]2[N:7]3[C@@H:8]([CH3:15])[CH2:9][N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:6]3=[C:5]([O:16][CH3:17])[C:4]=2[C:18](=[O:20])[NH:24][N:23]=1
Reactant: NN
Reactant: CCOC(=O)c1c(OC)c2n(c1C#N)[C@@H](C)CN(CC)C2=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(N)c32)C1=O
Temperature: 110 °C

Procedure:
A solution of ethyl (4S)-6-cyano-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (1.10 g, 3.60 mmol) in absolute ethanol (25 mL) was purged with argon gas for 15 minutes. The mixture was treated with hydrazine (1.16 g, 36.02 mmol) and 20 drops glacial acetic acid, and heated in a sealed tube in an oil bath at 110° C. overnight. The product mixture was cooled to 0° C. The solid precipitated collected by filtration, washed with cold ethanol and diethyl ether to afford the title compound. The filtrate was concentrated under vacuum, and the residue was subjected to preparative high pressure reverse phase column chromatography. Collection and lyophilization of appropriate fractions provided additional product, which was concentrated from its solution in acetonitrile and anhydrous DMF prior to the following benzylation. ES MS M+1=292.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][P:33]([CH3:37])(=[O:36])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].Cl>COCCO.C(O)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][P:33]([CH3:37])(=[O:36])[CH2:34][CH2:35]2)[CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)cnn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][CH:3](O)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1
Reactant: COC(C)O
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)OC)cc1
Temperature: 10 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
4.3 mL (37.5 mmol) of methoxyethanol and 10.1 g (37.5 mmol) of triphenylphosphine are added to a solution of 61 g (30 mmol) of methyl 4-hydroxybenzoate in 120 ml of THF at room temperature. 7.7 mL (37.5 mmol) of diisopropyl azodicarboxylate (DIAD) in 110 mL of THF are incorporated slowly so that the temperature is maintained to 10° C. After 18 hours at room temperature, the reaction mixture is poured onto icy water and acidified with a 1N HCl solution. The aqueous phase is extracted with ethyl acetate and the organic phase is then washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue using cyclohexane: ethyl acetate 4:1 yielded 6.6 g (98%) of pure methyl 4-(2-methoxyethoxy)benzoate as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C:13]2[C:14](=[O:18])[O:15][CH2:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO>[C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(CC2=CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Reactant: [H][H]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(C[C@H]2CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzyl acetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). A catalytic amount of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 16 hours. A fresh portion of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 24 hours. Reaction mixture was concentrated in vacuo. Residue was passed through a plug of silica gel eluting 80% ethyl acetate-hexanes. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 69% yield. MS m/e (M−H)−=376.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2>CN(C)C=O>[Cl:16][C:15]1[C:6]([CH2:5][S:2][CH3:1])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:17])[N:11]=[C:10]([O:18][CH3:19])[C:9]([O:20][CH3:21])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)c(Cl)c(CSC)c2nc1OC
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Sodium methanethiolate (22 mg, 0.312 mmol) was added to a stirred solution of 5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (see Preparation 28) (100 mg, 0.284 mmol) in dry dimethylformamide (5 ml) under nitrogen at room temperature. The mixture was stirred for 10 minutes and was then quenched with brine and extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 1:1 hexane:dichloromethane) to give 6,7-dichloro-2, 3-dimethoxy-5-methylthiomethylquinoxaline (79 mg, 87%) as a white solid, m.p. 143°-5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.C([O-])([O-])OCC.[CH2:20]([OH:22])[CH3:21]>S(=O)(=O)(O)O>[CH2:20]([O:22][C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[CH3:21]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: CCO
Agent: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Product: CCOC1=Cc2ccc(OC)cc2CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
33.5 g of 6-methoxy-2-tetralone was dissolved in 27.6 ml of ethanol, followed by subsequently adding 37.8 ml of ethyl orthoformate and one drop of concentrated sulfuric acid. The mixture2thus prepared was stirred at 100° C. for 4 hours. After distilling off the solvent under a reduced pressure, the resulting residue was subjected to silica gel column chromatography using chloroform as an eluant. Fractions of interest were pooled and concentrated to collect precipitated crystals, thereby obtaining 5.82 g of 3,4-dihydro-2-ethoxy-6-methoxynaphthalene.