Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16](=[O:18])[CH3:17])[CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:19](=[O:21])[CH3:20].[OH-].[K+]>C1COCC1>[CH3:2][N:14]1[C:13]2[CH:12]=[C:11]([C:16](=[O:18])[CH3:17])[CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][C:4]([C:19](=[O:21])[CH3:20])=[CH:5][CH:6]=2
Reactant: CC(=O)c1ccc2c(c1)[nH]c1cc(C(C)=O)ccc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c3ccc(C(C)=O)cc3n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.747 mL, 11.94 mmol) was added to the mixture of 1,1′-(9H-carbazole-2,7-diyl)diethanone (1 g, 3.98 mmol) and potassium hydroxide (0.223 g, 3.98 mmol) in THF (20 mL) and stirred for overnight at room temperature. The solvent was then removed under reduced pressure and the crude was extracted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated to get the pure product as yellow solid.
Reaction SMILES: S(OCC)(O[CH2:5][CH3:6])(=O)=O.[CH3:10][C:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=1/[CH:19]=[CH:20]/[CH:21]([OH:23])[CH3:22].[H-].[Na+]>>[CH3:5][CH2:6][O:23][CH:21](/[CH:20]=[CH:19]/[C:12]1[C:13]([CH3:17])([CH3:18])[CH2:14][CH2:15][CH2:16][C:11]=1[CH3:10])[CH3:22]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CCC1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
74.0 g (0.48 mol) of diethyl sulphate were added dropwise to a suspension of β-ionol alcoholate [obtained from 65.8 g (0.34 mol) of β-ionol and 18.4 g (ca 0.44 mol) of 55%-60% sodium hydride in 600 ml of benzene] in such a manner that the temperature did not exceed 50° C. Subsequently, the mixture was stirred at reflux for 3 hours, cooled and worked-up as described in Example 1. Crude distillation of the crude product (72.0 g) gave 50.2 g of crude product which were subsequently purified by distillation over a 20 cm Widmer column. There were obtained 47.0 g (66.1%) of pure and olfactorily good β-ionyl ethyl ether 2 of boiling point 120°-122° C./10 mmHg.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH3:12]>C(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:12])(=[O:10])=[O:9])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: N
Agent: Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 99.8 %

Procedure:
Pyridine-3-sulfonyl chloride HCl (647.2 mg, 3.023 mmol) was suspended in DCM (9.0 mL) and NH3 (5 mL, 7N in MeOH, 35 mmol) was added. The reaction was stirred at RT under nitrogen for 50 minutes and then filtered, and the solid was washed with DCM. The filtrate was concentrated and dried under high vacuum to provide pyridine-3-sulfonamide (477 mg, 91% yield). MS (ESI pos. ion) m/z: 159 (MH+). Calculated exact mass for C5H6N2O2S: 158.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with rac-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-ylmethanol (Stage 1.1, 1.12 g, 3.60 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (789 mg, 3.60 mmol), tetrakis-(triphenylphosphine)palladium (210 mg), 2M Na2CO3 (6.5 mL) and DME (11 mL). It was heated at 150° C. under microwave irradiation for 10 min. The RM was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The reside was purified by MPLC eluting with a DCM/MeOH gradient to afford the title compound as a brown solid (tR 1.0 min(conditions 1), MH+=357).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](OC/C=C/C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 34.3 %

Procedure:
By the same procedure as in Example 9, 1a,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene (83.0 mg, 0.108 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a pale yellow oil (15.9 mg, 34%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17]>CO>[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:2][NH:3][C:15]=1[CH2:16][CH3:17]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Reactant: NN
Solvent: CO
Solvent: O
Product: CCc1n[nH]c(CC)c1CCCCCCOc1ccc(OC)cc1Cl

Procedure:
Hydrazine hydrate (15.7 ml, 0.32 m) was added over a 20 min. period to a slurry of 100 g (0.272 m) of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione in 300 ml of methanol. The internal temperature rose to a maximum of 50° C. during the addition. The reaction mixture was heated at reflux for one hour, and the solvent was then removed in vacuo. The residue was dissolved in 300 ml of methylene dichloride and the resulting solution was washed with three 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to leave 100 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18](F)(F)F)[CH:13]=2)=[CH:10][CH:11]=1)=[O:5].[O:27]1C(C2C=C(B(O)O)C=CC=2)=[CH:30][N:29]=[CH:28]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:27][CH:28]=[N:29][CH:30]=3)[CH:13]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: OB(O)c1cccc(-c2cnco2)c1
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: O=C(Nc1ccc(-c2cccc(-c3cnco3)c2)s1)c1c(F)cccc1F

Procedure:
Compound 121 was synthesized in an analogous fashion as described for Compound 117 except that 3-(oxazol-5-yl)-benzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.C[O:18][C:19]1[C:24]([O:25]C)=[CH:23][C:22]([S:27][CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])=[CH:21][N:20]=1>>[OH:25][C:24]1[C:19](=[O:18])[NH:20][CH:21]=[C:22]([S:27][CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH:23]=1
Reactant: COc1cc(SC(C)c2ccccc2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: CC(Sc1c[nH]c(=O)c(O)c1)c1ccccc1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) to from 2,3-dimethoxy-5-[(1-phenylethyl)sulfanyl]pyridine (Intermediate 9).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[NH:10][C:9]1=[O:13])=[O:6])[CH3:3].C([Li])CCC.[CH2:20]([O:22][P:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21].[Cl-].[Na+]>O1CCCC1>[CH3:12][C@@H:11]1[N:10]([P:23](=[O:27])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])[C:9](=[O:13])[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:14])[CH3:3])=[O:6]
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
(3S-trans)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-2-azetidinone (4.6 g) was dissolved in 75 ml of dry tetrahydrofuran and cooled to -78° C. in a dry ice-acetone bath under a nitrogen atmosphere, and was treated with 1.56 M n-butyl lithium (14.8 ml, 1 equivalent). The mixture was stirred for 30 minutes at -78° C. and then diethylphosphorochloridate (3.97 g) was added and stirring continued for 1 hour. The mixture was poured into saturated sodium chloride solution (60 ml) and extracted with ethyl acetate (three 40 ml portions). The extracts were combined and dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue was chromatographed on 125 g of silica gel eluted with ethyl acetate. Removal of solvent in vacuo followed by trituration with ether and drying yielding 4.72 g of the title compound, melting point 101°-103.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>CCOCC>[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(-c2cccs2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
Part B: To thiophene (0.66 g) in dry ether (25 mL) at 0° C. was added n-butyl lithium in hexanes (1.6 M, 2.7 mL) and the reaction was stirred at 0° C. for 15 minutes. After cooling to -30° C., a solution of 2-chloro-4-methylpyrimidine (1.0 g) in ether (10 mL) was slowly added and the reaction was stirred at -30° C. for 30 minutes and at 0° C. an additional 30 minutes before quenching with a mixture of acetic acid (glacial, 0.45 mL), water (0.5 mL) and tetrahydrofuran (1.0 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. before aq. sodium hydroxide solution (3 M, 50 mL) was added. The organic layer was separated, washed with water, and dried with magnesium sulfate. The solvent was evaporated and the resultant crude oil was chromatographed on silica gel (30% ethyl acetate in hexanes; Rf 0.55) to yield 2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g). Anal. Calc.: % C: 51.46: % H: 3.33: % N: 13.33. Found: % C: 51.77: % H: 3.35; % N: 12.97.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[ClH:32].N>C1COCC1.O.CO>[ClH:32].[ClH:32].[NH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in THF and water and cooled to 0° C. was added HCl (1 N in Et2O). After 30 min the mixture was warmed to room temperature and the solution was stirred for 48 h. 2 M NH3 in MeOH was added. The solvents were evaporated and the mixture purified by column chromatography (SiO2, 0-5-10% (2 M NH3 in MeOH)/CH2Cl2). The compound was dissolved in DCM/MeOH and 1 N HCl in Et2O added. The solvents were evaporated to give pure 3-amino-2-(4-(hydroxymethyl)phenyl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E144).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH2:19])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1Cl)CC1C2C(=CC=C(OC)C=2)CCC1N.[OH-].[Na+]>ClCCl>[NH2:19][CH:8]1[CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)[C:16]2[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(N)CC2
Agent: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
1-(4-chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (13.18 g, 43.7 mmol, prepared analogously to 1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine cf. example 3) was dissolved in dichloromethane (200 mL). The solution was cooled to −10° C. and a 1 M solution of borontribromide in dichloromethane (131 mL, 131 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 h. The reaction mixture was poured on ice water and sodium hydroxide was added until pH 8 was reached. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 8.89 g (30.9 mmol, 71%, colorless solid).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[CH:10]2>CN(C=O)C.O>[CH2:1]([S:3][CH2:15][CH2:16][CH2:7][O:6][C:16]1[CH:15]=[C:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:6][CH3:5])[CH3:2]
Reactant: CC[S-]
Reactant: COc1ccc2ncncc2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 108.4 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4-chloro-2-fluoroanilino)-73chloropropoxy)6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4-chloro-2-fuoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2F)[C:5](=[S:8])[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][C:11]1[C:10]2[O:1][CH2:2][C:3]3=[CH:7][S:6][C:5](=[S:8])[N:4]3[C:9]=2[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1F)OCc1csc(=S)n1-2
Temperature: 110 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
4-Hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (60 g) prepared in the same manner as in Reference Example 19 was dissolved in N,N-dimethylformamide (450 ml) and thereto potassium carbonate (60 g) was added and the mixture was stirred at 110° C. for 3 hours. After the reaction mixture was evaporated to dryness, water was added to the residue and the resultant was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (51 g) as pale yellow crystals, m.p. 163°-167° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:45])([CH3:44])[CH2:28][C:29]([NH:31][C@@H:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH2:37][CH2:38][C@@H:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])([CH3:45])[CH3:44])[C:33]2=[O:43])=[CH:4][CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4-bromomethyl-2'-acetoxy-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) by the procedure described in Example 1, Step Q. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 6H), 1.45 (s, 9H), 1.85 (m, 1H), 2.02 (s, 3H), 2.35-2.65 (m, 5H), 4.52 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.30 (d, 15 Hz, 1H), 6.71 (d, 7 Hz, 1H), 7.1-7.4 (m, 12H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[C:9]3=[C:10]4[C:5]([C:6](=[O:11])[CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:18]=2)=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C1CCCc2ncccc21
Solvent: Cc1ccccc1
Product: O=C1CCc2c(-c3ccc(Cl)cc3)cn3cccc1c23
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (35 g) was dissolved in 80 ml of toluene. To this solution was added 4-chlorophenacyl bromide (55.6 g) gradually and refluxed for 18 hours. The reaction mixture was cooled to room temperature, and depositing crystals were collected by filtration (78 g). These solids were dissolved in 700 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (30 g) and triethylamine (34 ml), then the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. To the residue was added 300 ml of water, and extracted with 200 ml of methylene chloride three times. This methylene chloride solution was washed with 100 ml of brine and dried over anhydrous sodium sulfate. The dark brown solution that obtained after removing drying agent by filtration was concentrated under reduced pressure, the resultant dark brown residue was purified by alumina column chromatography. The title compound was obtained as dark red crystals (29 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](N3C4C(=CC(OC(F)F)=CC=4)C=N3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(OC(F)F)ccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2nccnc12
Reaction time: 15 h
Yield: 103.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (130 mg, 245 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After 15 h, then mixture was concentrated in vacuo and 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 245-difluoromethoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (55.3 mg, 56%). MS: (M+H)+=401; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 7.78 (d, J=2.3 Hz, 2H), 7.43 (dd, J=9.0, 2.5 Hz, 2H), 7.31 (s, 1H), 1.51 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=[CH:30][C:29]=2[Cl:37])[CH:24]=[CH:23][N:22]=1.N12CCCN=C1CCCCC2.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:37][C:29]1[CH:30]=[CH:31][C:32]2[O:33][CH2:34][O:35][C:36]=2[C:28]=1[NH:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:13][C:11]2[CH:10]=[C:9]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:26]=1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Reactant: Clc1nccc(Nc2c(Cl)ccc3c2OCO3)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Clc1ccc2c(c1Nc1ccnc(Nc3cc(N4CCOCC4)nc(N4CCOCC4)c3)n1)OCO2
Temperature: 120 °C
Yield: 29.5 %

Procedure:
2,6-Dimorpholinopyridin-4-amine (140 mg, 0.53 mmol), 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)pyrimidin-4-amine (150 mg, 0.53 mmol), 1,8-diazabicyclo-[5.4.0]-undec-7-ene (0.158 mL, 1.06 mmol), bis(dibenzylideneacetone)palladium(0) (45.5 mg, 0.08 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (92 mg, 0.16 mmol) were dissolved in dioxane (3 mL) and sealed into a microwave tube. The reaction was degassed, purged with nitrogen and heated at 120° C. overnight. The reaction mixture was filtered off and washed thoroughly with dichloromethane. The filtrate was concentrated to dryness, diluted with dichloromethane (15 ml), washed with water (30 ml) and brine (15 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N2-(2,6-dimorpholinopyridin-4-yl)pyrimidine-2,4-diamine (80 mg, 29.6%) as a pale beige foam. NMR Spectrum: (DMSOd6) 3.09-3.25 (m, 8H), 3.57-3.70 (m, 8H), 6.00 (s, 2H), 6.17 (d, 1H), 6.52 (s, 2H), 6.91 (d, 1H), 7.04 (d, 1H), 8.02 (d, 1H), 9.02 (s, 1H), 9.03 (s, 1H); Mass spectrum: MH+ 512.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:29])=[O:2])=[O:14])=[CH:18][CH:19]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
The ester 32 (1.30 g, 3.4 mmol) was dissolved in 25 ml methanol, then treated with 200 mg LiOH in 5 ml water. After 30 minutes at 50° C., the mixture was poured into excess water, made acidic with dilute HCl, and extracted. Recrystallization yielded about 1.12 g of 2-(biphenyl-4-ylmethoxycarbonylamino)-3-phenyl-propionic acid 33, mp. 141.7-142.2° C.