Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C(#N)C>[Br-:19].[CH2:12]([N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccnc2ccccc12
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc[n+](Cc2ccccc2)c2ccccc12
Product: [Br-]
Temperature: 93 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of lepidine (37.82 g) and benzyl bromide (6.471 g) in acetonitrile (100 mL) were stirred and heated to reflux in an oil bath at 93° C. for 20 hours. Cooled the reaction mixture to room temperature, added ethyl acetate (50 mL) and stirred for 30 min. The resultant solid was collected, washed with ethyl acetate (4×20 mL) and dried in the air. The filtrate was concentrated to a small volume and a second crop of solid was also collected. The combined solid was dried in an oven under high vacuum at 50° C. overnight. There was obtained 11.52 g (96.9%) of product.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C([O-])(O)=O.[Na+].[OH:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@:17]3([OH:32])[CH2:18][CH2:19][C@@H:20]2[CH:30]=O)[CH2:12]1>O1CCOCC1.O>[CH3:3][O:2]/[N:4]=[CH:30]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:32])[C@H:16]3[C@H:25]([CH2:24][CH2:23][C@:21]12[CH3:22])[C@:26]1([CH3:29])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:28][CH2:27]1)[CH2:14][CH2:15]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 36.7 %

Procedure:
To a suspension of 0.16 g of methoxylamine hydrochloride and 0.19 g of NaHCO3 in 12 ml of dioxane and 10 ml of water a solution of 0.50 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 6 ml of dioxane was added dropwise at room temperature. After 15 minutes the solution was diluted with water and extracted with chloroform; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/ethyl acetate 60/40; the fractions containing the rifle compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether/ethanol to give 0.20 g of the title compound (I-aa), as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[OH:22])[OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[CH2:1]([O:8][CH2:9][C@H:10]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:24][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=1)[OH:22])[OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]([C@H](O)[C@@H](COCc1ccccc1)OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccccc2)cc1

Procedure:
The product of example 71 was further alkylated with 4-nitrobenzyl bromide affording after purification by flash chromatography the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[CH:12]1([CH2:15][CH2:16]OS(C)(=O)=O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]1([CH2:15][CH2:16][N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]2=[O:9])[CH2:14][CH2:13]1
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: CS(=O)(=O)OCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccn(CCC2CC2)c(=O)c1C#N
Temperature: 105 °C
Yield: 45.8 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (19.81 g, 131.98 mmol) in acetonitrile (520 ml) were added intermediate 1 (34.36 g, 171.57 mmol) and potassium carbonate (56.73 g, 410.3 mmol) and the mixture was heated at 105° C. for 12 hours. The mixture was cooled to room temperature and the solid was filtered off The filtrate was evaporated till dryness. The crude product was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 20% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 3 (13.18 g, 46%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].Cl.C(OC(C)C)(C)C>O1CCOCC1>[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminometyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50° C. for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-(acetylaminomethyl)-6-bromoacetylpyridine (50.3 g) as an oil. lR (Film): 1710, 1650 cm-1NMR (CDCl3 δ): 2.11 (3H, s), 4.63 (2H, d, J=5.3 Hz), 4.80 (2H, s), 7.43-7.59 (1H, m), 7.78-8.08 (2H, m)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 86.8 %

Procedure:
To a stirring solution of 4-amino-benzoic acid methyl ester (0.594 g, 3.93 mmol) in a mixture of dichloromethane (15 mL)/pyridine (15 mL) is added 4-methanesulfonyl benzenesulfonyl chloride (1.0 g, 3.93 mmol) and the mixture is allowed to react for 6 h at ambient temperature. The reaction is diluted with ethyl acetate and washed with 1N HCl. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated to give 1.26 g (87%) of the title compound. MS (ES−) (m/e) 368.0 (M−1)−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16](OCC)C>C[Li]>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:16])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12
Reactant: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: CCOCC
Agent: [Li]C
Product: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.10 g, 18.28 mmol) in diethyl ether (300 mL), methyllithium (23 mL, 1.6 M solution in diethyl ether) is slowly added at rt. The reaction mixture becomes clear, yellow and slightly warm (26° C.), and is stirred for 15 min before it is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (2.80 g) as a pale yellow crystalline solid; LC-MS: tR=1.06 min; [M+1]=223.17; 1H NMR (CDCl3): δ 3.00 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.26 (s, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (s, 6H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:25]4[CH2:26][CH2:27][CH2:28][N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:24]4=[N:23][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.O>[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:25]4[CH2:26][CH2:27][CH2:28][N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:24]4=[N:23][C:18]=3[CH:19]=[N+:20]2[O-:9])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1cnc3cc(Br)ccc3c12
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1c[n+]([O-])c3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
MCPBA (800 mg of approximately 60% pure material) was added to a solution of tert-butyl 3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (940 mg, 2.3 mmol) in chloroform (50 mL). The reaction was stirred for one hour at room temperature, and an analysis by LC/MS indicated the presence of starting material. Additional MCPBA (540 mg) was added, and the reaction was stirred for an additional 30 minutes and then diluted with water and chloroform. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 0.97 g of tert-butyl 3-bromo-5-oxido-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]Cl)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:35])[CH2:24][C:25]1[C:26]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:27]=2[S:28][CH:29]=1.COC(=O)CC1C2C=CC(OCC3C=CC(OCC4C=CC(C(F)(F)F)=CC=4)=CC=3)=CC=2SC=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:34][C:31]2[CH:32]=[CH:33][C:26]3[C:25]([CH2:24][C:23]([OH:35])=[O:22])=[CH:29][S:28][C:27]=3[CH:30]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Agent: COC(=O)Cc1csc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Product: O=C(O)Cc1csc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12

Procedure:
The title compound was prepared from compounds 7B and 5C in a manner analogous to compound 5F. MS m/z 487 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.N[C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1.N([O:21][CH2:22][CH2:23]C(C)C)=O.C(OCC)C>C(O)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH2:22]([O:21][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1)[CH3:23]
Reactant: Nc1cncc(C2CC3CCN2CC3)c1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOc1cncc(C2CC3CCN2CC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-(5-amino-3-pyridyl)-1-azabicyclo[2.2.2]octane trihydrochloride (25 mg, 0.08 mmol) in dry ethanol (3 mL) was added isoamyl nitrite (0.10 mL, 0.74 mmol) and the mixture was refluxed for 2 h. When TLC analysis of the reaction mixture showed absence of starting material, the mixture was allowed to cool to ambient temperature. The solvent was removed by rotary evaporation to yield a thick brown oil, which solidified upon addition of dry diethyl ether. The product thus obtained was dissolved in chloroform and kept overnight at 4° C. to induce crystallization. The resulting solids were filtered, washed with diethyl ether and finally dried under vacuum for 24 h, to yield 2-(5-ethoxy-3-pyridyl)-1-azabicyclo[2.2.2]octane dihydrochloride (10 mg, 51%) as colorless needles.
Reaction SMILES: CCCP(=O)=O.[CH:7]1([C:10]2[C:11]([NH2:25])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1.[N:26]1([C:30]([C:32]2[CH:36]=[N:35][N:34]([CH3:37])[C:33]=2[C:38](O)=[O:39])=[O:31])[CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH:7]1([C:10]2[C:11]([NH:25][C:38]([C:33]3[N:34]([CH3:37])[N:35]=[CH:36][C:32]=3[C:30]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])=[O:39])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Propylphosphonic anhydride solution (50% in ethyl acetate, 0.59 ml) was added to a cooled (0° C.) solution of 6-cyclopropyl-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (100 mg, 0.40 mmol), 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (Step 3, 167 mg, 0.51 mmol), and N,N-diisopropylethylamine (311 mg) in ethyl acetate (3 ml). The mixture was stirred for 30 min at 0° C. and overnight at r.t. The reaction mixture was taken up in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The title compound (31 mg, 18%) was isolated from the residue by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=441.3 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:3]1=[O:28].Cl[C:30]1[C:31]2[CH:43]=[C:42]([Cl:44])[CH:41]=[N:40][C:32]=2[N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=1>>[C:22]1([S:19]([CH2:18][C@@H:8]2[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]2[N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:30]3[C:31]4[CH:43]=[C:42]([Cl:44])[CH:41]=[N:40][C:32]=4[N:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[N:35]=3)[C:3]2=[O:28])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: FC(F)(F)c1nc(Cl)c2cc(Cl)cnc2n1
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](Nc3nc(C(F)(F)F)nc4ncc(Cl)cc34)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
The titled compound was prepared from (3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one and 4,6-dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine using the conditions described in Example 106, part C. MS (ES+)=639 (M+H)+.
Reaction SMILES: C(OC([C:6]1[C:7]([N:15]2[CH2:20][CH2:19][C:18]([NH2:32])([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=O)C.O>[OH-].[K+]>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2([NH2:32])[CH2:19][CH2:20][N:15]([C:7]3[CH:6]=[CH:11][N:10]=[C:9]4[NH:12][N:13]=[CH:14][C:8]=34)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(C(C)(C)C)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(CC2(N)CCN(c3ccnc4[nH]ncc34)CC2)cc1
Yield: 46.7 %

Procedure:
4-[4-Amino-4-(4-tert-butyl-benzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (23 mg, 0.053 mmol) was suspended in 2M potassium hydroxide (1 mL) and irradiated in a microwave reactor (250W) for 2 hours at 120° C. After cooling, water (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2×4 mL). The organic layers were dried (Na2SO4) and concentrated to give a yellow solid (9 mg, 47%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH2:62].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:62][CH:61]=[CH2:60])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OC
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (510 mg) in 6.6 ml 33% methylene chloride in cyclohexane, was added allyl trichloroacetimidate (266 mg neat) and the reaction mixture was allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (12 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction mixture was diluted with ethyl acetate and washed with saturated sodium carbonate, water and brine. The organic layer was dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:9))+1% methanol) gave the title compound (434 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH:22]([CH3:21])[CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:7]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C(C)CN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)CO2

Procedure:
6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48, 440 mg, 2.5 mmol) was deprotonated with sodium hydride (125 mg, 60% in oil, 3.2 mmol) and alkylated with tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperazine-1-carboxylate (Intermediate 120, 2.5 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/2-propanol (95:5) gave 1.25 g (quantitative) of the product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:20])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Yield: 46.3 %

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine (4.0 g, 0.18 mole), dimethyl sulphate (2.55 g, 0.0201 mole), potassium carbonate (10.0 g, 0.072 mole) and dry acetone (100 ml) were stirred at room temperature for 20 hours. The reaction mixture was filtered and the inorganic residue was washed with more acetone. Evaporation of the combined filtrates gave a brown residue which was extracted with dilute sodium hydroxide solution. The aqueous extract was washed with dichloromethane, treated with charcoal, filtered and acidified. The resulting precipitate was collected, washed with water and crystallised from ethanol to give 3-chloro-6-(2-hydroxy-4-methoxyphenyl)pyridazine (2.2 g, 49%; m.p. 156°-157° ).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:14]=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:14](=[O:15])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C=Nc1ccccc1C1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2C2CCCCC2)CC1

Procedure:
A solution of the product of step (a) (˜9.8 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 11.8 mmol) in DMF (19.7 mL) was stirred at room temperature for 24 h and then the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (20 mL) and this mixture was washed with 1N hydrochloric acid (2×10 mL), 1N aqueous sodium hydroxide (2×10 mL) and brine (10 mL), and then dried (MgSO4), filtered and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1(C(OC)=O)[CH:7](O)[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:5](=[O:14])[NH:4][C:3]1=[O:15].FC(F)(F)C(O)=O>O>[F:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: COC(=O)C1(F)C(=O)NC(=O)N(C2CCCO2)C1O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 15 ml. of water is dissolved 30 mg. of methyl 5-fluoro-1-(2-tetrahydrofuryl)-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and the solution is cooled in an ice-water bath. To this solution is added 1 ml. of trifluoroacetic acid and the mixture is left standing in a refrigerator. 5-Fluoro-1-(2-tetrahydrofuryl)uracil formed can be quantitatively determined spectrophotometrically (λmaxpH 1.0 272 mm, (ε 9000)).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.Cl.CCOC(C)=O>C1COCC1>[C:17]([C:11]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:18]
Reactant: N#CC1CCCCC1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2(C#N)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Solid KHMDS (4.36 g, 22.0 mmol) is dissolved in THF (80.0 mL) and cooled to 0° C. Cyclohexanecarbonitrile (2.38 g, 22.0 mmol) is added, and the resulting solution is stirred for 40 minutes. A solution of 4-fluorobenzonitrile (1.33 g, 10.95 mmol) in THF (10.0 mL) is added, and the mixture is stirred for 2 hours at 0° C. and 10 hours at room temperature. 1N HCl (50.0 mL) is added, and the aqueous phase is extracted with EtOAc (4×50.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 30% EtOAc) (1.55 g, 7.38 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23-1.38 (m, 1H) 1.52-1.68 (m, 2H) 1.68-1.78 (m, 1H) 1.78-1.93 (m, 4H) 2.00-2.11 (m, 2H) 7.75 (d, J=8.79 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H).