Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN1C(=O)CCC1>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:8]([NH:37][C@@H:34]2[CH2:35][CH2:36][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33]2)=[O:24])[CH2:15][CH2:14]1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1
Temperature: 100 °C

Procedure:
(4-tert-Butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].Cl>CC(C)=O.O>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nccc(Nc2ccccc2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Nc2nccc(Nc3ccccc3)n2)cc(OC)c1OC
Yield: 76.8 %

Procedure:
A solution of N-phenyl-2-chloro-4-pyrimidineamine (1.83 g, 8.91 mmol) and 3,4,5-trimethoxyaniline (1.83 g, 10.0 mmol) in acetone (10 ml) and water (15 ml) containing concentrated hydrochloric acid (0.2 ml) was heated at reflux for 10 h. On cooling the acetone was removed under reduced pressure, and the reaction taken to pH10 with 4N NaOH and extracted with ethyl acetate (2×75 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and the residue crystallised from ethyl acetate to give the title compound (2.41 g) as a colourless solid m.p. 191°. δH (CDCl3) 8.04 (1H, d, J 5.8 Hz), 7.37-7.34 (4H, m), 7.16-7.10 (1H, m), 7.05 (1H, br s), 6.85 (2H, s), 6.68 (1H, br s), 6.16 (1H, d, J 5.8 Hz), 3.82 (3H, s) and 3.81 (6H, s). MS m/z 353 (M+H)+. The pyrimidineamine used as starting material was prepared by heating a solution of 2,4-dichloropyrimidine (4.0 g, 26.8 mmol), aniline (2.46 ml, 27.0 mmol) and triethylamine (4.3 ml, 30.0 mmol) in ethanol (50 ml) at reflux for 2 h. On cooling a white precipitate was collectd which was washed with cold ethanol (100 ml) and recrystallised from ethyl acetate to give the desired product (6.0 g) as a colourless solid m.p. 186°. MS/mz 206 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.[CH:41]1([N:47]=C=NC2CCCCC2)CCCC[CH2:42]1.C(O)(C(F)(F)F)=[O:57]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:42](=[O:57])[CH2:41][NH2:47])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCOC(=O)CN)CC2
Reaction time: 0.33 h
Yield: 36 %

Procedure:
2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (100 mg, 0.183 mmol) and N-α-(tert-Butoxycarbonyl)glycine (32 mg, 0.183 mmol) were dissolved in dry Methylene chloride (2.00 mL, 31.2 mmol), and a catalytic amount of 4-Dimethylaminopyridine (2 mg, 0.02 mmol) was added and stirred for 20 minutes. N,N′-Dicyclohexylcarbodiimide (37.7 mg, 0.183 mmol) was then added and the reaction was stirred for 15 h at room temperature. The reaction was filtered to remove urea ppt. The filtrate was concentrated onto celite. ISCO flash column 0-8% MeOH:DCM. Product fractions were concentrated to a white solid. The Boc protected product was refluxed in DCM with 50 μL of TFA. After 3 hours reaction was sluggish and an additional 500 μL of TFA was added. The reaction was concentrated to dryness. The residue was triturated in H2O and filtered. A white solid containing no desired product was removed and the filtrate was lyophilized. The resulting white solid showed 4 TFA salts by NMR. It also contained a small amount (8%) of starting material. The solid was extracted and freebased with bicarb/DCM. The organic layer was concentrated to dryness and purified by preparative HPLC. The product was worked up again using bicarb/DCM. The product was isolated as a white foam (40 mg, 36%). mp: 77-79° C., MS (ESI+): 604 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 4.30 (t, J=7 Hz, 2H), 3.89 (s, 3H), 3.48 (s, 2H), 2.87-2.83 (m, 4H), 2.77-2.71 (m, 13H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1OC2CCC1N(S(=O)(=O)c1ccc(O)cc1)C2
Yield: 104.6 %

Procedure:
A mixture of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (1.0 g, 2.7 mmol), ethyl acetate-methanol (1:1, 100 mL) and 10% Pd on charcoal (0.22 g) was shaken under 50 psi of hydrogen for 1.5 h. Filtration through a pad of Celite and concentration of the filtrate in vacuo afforded 0.80 g of 5-(4-hydroxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc(Oc2ccc3nccn3n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from ethyl acetate to give the title compound (196 mg, 71%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CCO.CO>[CH2:14]([O:16][C:17]1[C:20](=[O:21])[C:19](=[O:24])[C:18]=1[NH:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH3:15]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CN(C)C(=O)c1cccc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 g of 3-amino-2-hydroxy-N,N-dimethyl-benzamide are dissolved in 880 ml of EtOH. 46 g of 3,4-diethoxy-3-cyclobuten-1,2-dione and 4.4 g of K2CO3 are added and the reaction mixture obtained is stirred overnight at rt. Solvent is evaporated. A residue obtained is purified by column chromatography over 500 g of silica using CH2Cl2/MeOH 98/2 as eluent. The product-containing fractions are combined and solvent is evaporated. A residue obtained is suspended in 1 l of MeOH and filtered. This process is repeated a further 3 times. The title compound is obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=2[C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:8]=1.S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:8]=[C:3]([CH:2]([F:25])[F:1])[CH:4]=[CH:5][C:6]=2[F:24])=[C:10]([C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:11]=1
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)F)ccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.1 %

Procedure:
To a solution of 66.50C (0.1666 g, 0.481 mmol) in dry DCM (3 mL) and dry DMF (0.06 mL) was added thionyl chloride (0.07 mL, 0.96 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.50D (172.1 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.46 (2H, m), 7.39 (1H, m), 7.33 (1H, m), 7.28 (1H, d, J=1.7 Hz), 7.17 (1H, m), 6.62 (1H, t), 5.51 (1H, td, J=2.3, 1.0 Hz), 4.64 (2H, s), 2.24 (2H, td, J=7.1, 2.4 Hz), 1.68 (2H, m), 0.85 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[N:7][CH:6]=1)[CH3:2].[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[N:11]=[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)[N:12]([CH3:30])[C:8]2=[N:7][CH:6]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)c1cnc(NC)c(N)c1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 40.8 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester (560 mg) was prepared by following General Procedure D starting from 5-amino-6-methylamino-nicotinic acid ethyl ester (723 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (735 mg), 1,1′-thiocarbonyldiimidazole (802 mg), and EDC (969 mg). LC/MS: m/z 437.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.44 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.52 (d, 1H), 7.37 (d, 1H), 4.33 (q, 2H), 3.65 (s, 3H), 1.36 (t, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[SH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[SH:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccnc1S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1S
Yield: 92.8 %

Procedure:
A solution of O-(2,6dichlorobenzyl)-L-tyrosine methyl ester hydrochloride (2.50 g, 6.4 mmol), 2-mercaptonicotinic acid (0.99 g, 6.4 mmol) and NMM (1.41 ml, 1.29 g, 12.8 mmol) in DMF (10 ml) was stirred at room temperature for 64 h. Solvent was removed in vacuo and the residue partitioned between DCM (30 ml) and water (25 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were washed with 10% NaHCO3 solution (30 ml), dried over MgSO4 and the solvent removed in vacuo to give a brown oil which was purified by chromatography (SiO2; gradient elution, 4:1 EtOAc/hexane to 100% EtOAc) to give the title compound as a yellow foam, (2.92 g, 93%). δH (CDCl3) 8.71 (1H, dd, J 1.8, 7.6Hz), 8.05 (1H, s), 7.61 (1H, dd, J 1.8, 6.1 Hz), 7.35 (2H, m), 7.33-7.19 (2H, m), 6.94 (2H, d, J 8.7Hz), 5.22 (2H, s), 4.97 (1H, m), 3.74 (3H, s) and 3.21 (2H, m).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:20]1([C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:1][N:2]=[N:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCCCc1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 1H-tetrazole-5-pentanenitrile (30 g, 198 mmol) in a mixture of methylene chloride (200 mL) and triethylamine (30 mL, 218 mmol) was stirred as trityl chloride (61 g, 218 mmol) was added. After 16 h, the reaction was treated with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The combined organic layers were dried and concentrated. The residue was dissolved in ether and hexane was added. The resulting solid was isolated by filtration to give 1-(triphenylmethyl)-1H-tetrazole-5-pentanenitrile as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:10]([CH3:29])[CH:9]=1)=[O:6].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C(OCC)(=O)C>[O:33]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:20]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=4)=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:10]([CH3:29])[CH:9]=2)=[O:6])=[CH:34]1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(I)c3)cc2C)n1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(-c4ccoc4)c3)cc2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-iodo-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.100 g, 0.186 mmol), furan-3-ylboronic acid (0.025 g, 0.22 mmol), [1,1′bis(diphenylphosphino)ferrocene] palladium(II) methylene chloride complex (0.0073 g, 0.01 mmol), sodium carbonate (2M solution in water, 0.20 mL, 0.41 mmol) and dioxane was heated to 80 deg. C. for 3 h. The reaction was cooled to ambient temperature and was allowed to stand overnight. Additional [1,1′bis(diphenylphosphino)ferrocene]palladium(II) methylene chloride complex (0.0073 g, 0.01 mmol) was added and the reaction was heated to 85 deg. C. for 3 hr. The reaction was cooled to ambient temperature and was diluted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was further purified by reverse-phase HPLC using acetonitrile/water/TFA as eluent to give 3-(furan-3-yl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide. MS m/z=478 [M+1]+. Calc'd for C28H23N5O3: 477.52.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1([C:23](=[O:33])[CH:24]([O:31][CH3:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:32][O:31][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:23]([CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][O:11][CH2:12]1)=[O:33]
Reactant: O=C1CCOCC1
Reactant: COC(C(=O)n1ccnc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(C(=O)C1COCCC1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.024 mL, 10.78 mmol) was added to a stirred solution of tetrahydro-4H-pyran-4-one (0.948 mL, 10.27 mmol) in toluene (3 mL) at 0° C. After 2 minutes 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone (1.110 g, 5.13 mmol) was added and the mixture was stirred at 0° C. for 5 minutes. The reaction was quenched with acetic acid (0.882 mL, 15.40 mmol) in 5 mL water. The organic layer was separated and concentrated. The crude product was purified by silica flash chromatography using ethyl acetate (0 to 40%) in heptane giving 3-(2-methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.245 g, 19%). MS (ES−) m/z 247 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18]Br)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH3:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].[Cl:40]C1C=CC=CC=1>>[ClH:40].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][N:32]([CH3:33])[CH2:31][CH2:30][C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)[N:3]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: Clc1ccccc1
Reactant: COc1cc2c(C)nn(CCBr)c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(CCN(C)CCn2nc(C)c3cc(OC)c(OC)cc3c2=O)cc1OC
Product: Cl

Procedure:
A solution of 2.5 gm (7.6 millimols) of 1-[4-methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-2-bromo-ethane in 50 ml of chlorobenzene was admixed with 1.5 gm (7.6 millimols) of 3,4-dimethoxyphenylethyl-N-methylamine and 3.0 gm of sodium carbonate, and the mixture was refluxed for 20 hours. After cooling, the precipitated solid was filtered off, and the filtrate was evaporated. The residue was chromatographed on silica gel (chloroform/methanol = 100/1), the main fractions were evaporated and the base was precipitated as its hydrochloride, yielding 1.8 gm (49% of theory) of the compound of the formula ##STR13## which had a melting point of 204-205° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24](SC)[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH:43]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:54][S:55]([O-:58])(=S)=O.[Na+].[Na+]>ClCCl.O>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:55]([CH3:43])(=[O:58])=[O:54])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: O=S([O-])([O-])=S
Reactant: CSc1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(S(C)(=O)=O)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (105 mg, 0.155 mmol) was dissolved in dichloromethane (4 ml). The solution was cooled to 0° C. and m-CPBA (75%, 79 mg, 0.343 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. Additional m-CPBA (75%, 36 mg, 0.155 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. A solution of 10% aqueous Na2S2O3 (3 ml) was added and the biphasic mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO3. The aqueous layer was extracted dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 25 mg (25%) of 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[OH:34])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH:13]([CH3:15])[CH3:14].O>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[O:34][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Reaction time: 18 h

Procedure:
Add 3-phenylpropionyl chloride (.5 g.) in benzene (1.5 cc.) with swirling to 13β-isobutyl-17β-hydroxy-gon-4-en-3-one (.5 g.) in pyridine (2 cc.) at -20°. Store the mixture at -10° for 18 hours, add water and extract the product with ether. Wash, dry and evaporate the extracts to give a residue and recrystallize from methanol to give the title compound, m.p. 101°-106°; ultraviolet absorption peak at 240 mμ (ε15,300); infrared absorption peaks at 5.75, 5.95 μ.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]5[NH:37][CH:38]=[CH:39][C:32]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[NH:37][CH:38]=[CH:39][C:32]=34)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,4-dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.115 g, step A), HCl (4N, 3 mL) and dioxane (4 mL) was stirred at RT for overnight. Sat'd NaHCO3 was added until the bubbling stopped. The aqueous phase was extracted with EtOAc 3 times. The combined organic phases were dried over Na2SO4 and evaporated to yield a light purple oil as a crude product, which was purified by chromatography through silica gel (10 g, 5% MeOH/CHCl3 with 1% NH4OH) to afford N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-nicotinamide. The material was further purified via silica gel column chromatography (10 g, 1% to 5% MeOH/CH2Cl2, stepwise gradient) to afford pure title compound. MS: (ES+) 427 (M+H). Calc'd. for C25H26N6O—426.51.