Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=O)[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(Cl)Cl>C(#N)C>[CH2:12]([O:11][C:9]1[O:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCCCOc1cnc(C(=O)OCC)o1
Temperature: 60 °C

Procedure:
Butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) was dissolved in 8 L of acetonitrile in a 50 L Chemglass reactor with overhead stirrer and P2O5 (415 g, 2.92 mol) was added in large portions, watching for exotherm. The reaction was heated to 60° C. for 1 hour and LCMS showed the reaction done. After cooling, water (8 L) was added at 20° C. and the reaction was transferred to a 50 L flask. Methylene chloride (8 L) was added, the layers split and the aqueous layer was extracted with three 2 L volumes of methylene chloride. The combined organic layers were washed with two 4 L portions of saturated aqueous NaHCO3, then dried with MgSO4 and evaporated to give an oil that was purified on silica eluting with 0-30% EtOAc/heptane to give the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33](OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[C:41]1([C@H:47](O)[CH2:48][CH2:49][CH3:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.ClC1C=C(C=CC=1Cl)COC1C=CC([C@H]2COC3=CC4C[C@@H](C(O)=O)N([C@H](C5C=CC=CC=5)CCC)CC=4C=C3O2)=CC=1>>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:33][N:32]1[C@H:47]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:48][CH2:49][CH3:50])=[O:40]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Reactant: CCC[C@@H](O)c1ccccc1
Agent: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester was synthesized from (S)-2-tert-butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester and (R)-1-phenyl-butane-1-ol according to General Procedure AC. This ester was converted to (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid according to General Procedure AB.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc(C=c2[nH]c(=O)c(=CCc3ccccc3)[nH]c2=O)nc1)c1ccccc1
Temperature: 150 °C
Yield: 10.3 %

Procedure:
A reaction mixture containing compound B (0.05 g, 0.16 mmole; obtained from Example 14), benzoyl chloride (15 ml, 0.16 mmole) and 50 mL of chloroform was heated to 150° C. for 2 hr. Chloroform was removed in vacuo to produce a residue. The residue was chromatographied using silica gel column with a developing solvent (CH2Cl2) to give 0.007 g (10%) of Compound 15.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2OCC[O:15]2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([C:8]1[N:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(C3OCCO3)cn2)cc1
Agent: Cl
Product: O=Cc1ccc(Cc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 0.92 h

Procedure:
2-Benzyl-5-[1,3]dioxolan-2-yl-pyridine (7.3 g, 30 mmol) described in Manufacturing Example 210-1-3 and 2 N hydrochloric acid (100 mL) were stirred for 55 minutes at 100° C. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and a 5 N sodium hydroxide solution (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered.
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: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
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: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH2:60])[C:55]=2[CH:61]=1>CN(C=O)C>[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH:60][C:23]([C:20]3[CH:21]=[N:22][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)=[N:18][CH:19]=3)=[O:25])[C:55]=2[CH:61]=1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: NN1CCOc2ccc(F)cc21
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: O=C(NN1CCOc2ccc(F)cc21)c1cnc(-c2cccc(F)c2)nc1
Yield: 22 %

Procedure:
DIPEA (174 μL) is added to a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (218 mg), HATU (380 mg) and 6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (220 mg) in DMF (15 mL) and then heated at 800 C. overnight. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 30% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide (81 mg). MS: 369 (M+H); 1H NMR (300 MHz, DMSO-D6): δ 11.05 (s, 1H), 9.35 (s, 2H), 8.32 (dd, 1H), 8.18 (dd, 1H), 7.65 (m, 1H), 7.5 (m, 1H), 6.8-6.7 (m, 2H), 6.52-6.45 (m, 1H), 4.36-4.33 (m, 2H), 3.65 (m, 2H). IC50=12 nM.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][C:18](=O)[CH3:19]>CC(C)=O>[CH3:19][C:18]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]2[N:1]([CH:17]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: CCOC(=O)CCCCc1ccccn1
Reactant: CC(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)CCCc1c(C)cn2ccccc12

Procedure:
To a solution of ethyl 5-(2-pyridyl)pentanoate (1.07 g) in acetone (5 ml) was added bromoacetone (0.51 ml) and the mixture was refluxed for 2 hours. After removal of the solvent, the residue was dissolved in aqueous sodium bicarbonate (1 g sodium bicarbonate/20 ml water) and then refluxed for 30 minutes. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, evaporated in vacuo, and chromatographed on silica gel (dichloromethane) to give ethyl 4-(2-methylindolizin-1-yl)butyrate (778 mg).
Reaction SMILES: CS(OCCC(N1C=C([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)C=N1)C)(=O)=O.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C[N:38]([CH:40]=O)C.[H-].[Na+]>>[CH3:17][CH:16]([C:23]1([C:22]2[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:17]3=[N:18][CH:19]=[CH:20][CH:15]=[C:16]3[CH:23]=2)[CH2:40][NH:38][N:21]=[CH:22]1)[CH2:15][CH2:20][C:35]1[CH:36]=[N:32][NH:33][CH:34]=1
Reactant: c1cn[nH]c1
Reactant: CC(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(CCc1cn[nH]c1)C1(c2cc3cccnc3n2COCC[Si](C)(C)C)C=NNC1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a 0° C. solution of 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (prepared by mesylation of the alcohol as in Example 59, Step 1) (0.055 g, 0.00012 mol) and 1H-pyrazole (0.025 g, 0.00036 mol) in DMF (1 mL, 0.01 mol) was added sodium hydride (0.014 g, 0.00036 mol). The resulting solution was stirred overnight and then partitioned between ethyl acetate and 0.1 N HCl, water. The organic phase was separated and washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass (87% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO.CS(C)=O>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine (41.89 mg, 0.116 mmol) in methanol (3 ml) was treated with 4 molar HCl solution in 1,4-dioxane (0.722 mL, 2.89 mmol) and stirred at ambient temperature in a capped vial overnight. The clear reaction solution was blown down under N2 and then dissolved in 1 ml 1:1 DMSO:MeOH and purified by MDAP (Method A). The appropriate fraction was evaporated under N2 in a Radleys blow down unit to afford the title compound as a white solid (31.1 mg).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:30][C:27]5[CH:28]=[N:29][C:24]([C:23]([F:33])([F:22])[F:32])=[CH:25][CH:26]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Product: FC(F)(F)c1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cn1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-(trifluoromethyl)pyridine-3-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[2-[[6-(trifluoromethyl)pyridin-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:27]#[N:28].[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33].O>C1COCC1>[C:19]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([NH:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:3]([C:27]#[N:28])[C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: NC[C@@H](O)CO
Reactant: N#Cc1c(Cl)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61.5 mg (0.15 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}benzenecarboxylic acid (Example 72A) were initially charged in 1.6 ml of THF. After addition of 27.6 mg (0.30 mmol) of (2R)-3-aminopropane-1,2-diol, the mixture was stirred at RT overnight. 2 ml of water were added, and the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]([C:34]3[CH2:35][CH2:36][O:31][CH2:32][CH:33]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc2c(c1C1=CCOCC1)C(O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-ethyl 5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [C:1]([CH:5]([C:8]#[N:9])[C:6]#[N:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:11][NH2:12]>C(O)CCC>[C:1]([C:5]1[C:8]([NH2:9])=[N:11][NH:12][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)C(C#N)C#N
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)c1c(N)n[nH]c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
A mixture of tert-butylmalononitrile (5.01 g, 41.0 mmol) and hydrazine monohydrate (10.0 mL, 205 mmol) in 1-butanol (40 mL) was heated to reflux and stirred overnight (19 hours). The mixture was cooled to ambient temperature. Concentration afforded 6.33 g (100%) of the title compound. MS (DCI) m/z 155 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][CH:24]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C.ClCCl.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>[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: Cn1cccc(Br)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A solution of 3-bromo-1-methyl-2-pyridone (94 mg, 0.50 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (284 mg, 0.50 mmol) in DMF (3 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). bis(triphenylphosphine)palladium dichloride (40 mg, 0.057 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 20 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (20 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (20 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×5 mL) and water (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 25 g of silica gel eluting with 4:6 ethyl acetate:hexane to give N-[(1,1-dimethylethoxyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (64 mg, 33%). LRMS-Electrospray: m/z positive ion, 795 (2M+Na) 409 (M+Na) 387 (M+H). HRMS: Obs. Mass 387.1935. Calcd. Mass 387.1920 (M+H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([NH2:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 97.4 %

Procedure:
4-Amino-1,8-naphthalic anhydride (0.2 g, 0.9 mmol) and hydroxylamine hydrochloride (0.1 g, 1.4 mmol) were reacted in pyridine (20 mL) following the procedure of Example 1 to give 0.2 g of the title compound, mp>360° C.;
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>CCO>[CH3:14][C@H:15]1[CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
To a microwave vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (from Example 9, step 3) (47.8 mg, 0.164 mmol) and tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (33.7 mg, 0.157 mmol), EtOH (1.00 mL) was added, followed by DIPEA (41.5 mg, 0.321 mmol). The mixture was heated under microwave irradiation at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (44.5 mg, 75%). LCMS calc. for C18H27N4O5 (M+H)+: m/z=379.2. found 379.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:3]1[OH:26].S(=O)(=O)(O)O.[CH3:32]O>O.[OH-].[Na+]>[OH:26][C@H:3]1[C@@H:2]([O:1][CH3:32])[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCc1cn2c(C)c(C)nc2c2c1[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N2
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cn2c(C)c(C)nc2c2c1[C@H](OC)[C@H](O)[C@@H](c1ccccc1)N2
Reaction time: 16 h

Procedure:
180 mg of (7R,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine, dissolved in 10 ml of methanol, are admixed with 110 mg of concentrated sulfuric acid and allowed to stand at room temperature for 16 hours. The mixture is then diluted with 100 ml of water and adjusted to pH 8 using aqueous IN sodium hydroxide solution and aqueous saturated sodium hydrogen carbonate solution and extracted 3 times with in each case 50 ml of methylene chloride. The combined organic phases are evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: methylene chloride/methanol=100/3). This gives 100 mg of the title compound [Rf=0.62 (methylene chloride/methanol=13/1)] of melting point 126-9° C. (decomp.).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 110 °C
Yield: 100.1 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.12 g), 4-hydroxybenzaldehyde (1.83 g), potassium carbonate (2.28 g) and dimethylformaide (40 ml) was stirred under heating at 110° C. for 1 hour. The reaction solution was poured into ice-cold water, and the crystals which separated out were collected by filtration to give 4-(5-methyl-2-phenyl-4-oxazolyl)methoxybenzaldehyde (4.40 g, 99.8%). Recrystallization from ether-hexane yielded colorless prisms, m.p. 112°-113° C. Elemental analysis for C18H15NO3 ; Calcd.: C, 73.71; H, 5.15; N, 4.87. Found: C, 73.87; H, 5.26; N, 4.81.