Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.COC1O[N:53]=[C:52]([C:55](Cl)=[O:56])[CH:51]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:55]([C:52]2[CH:51]=[C:10]([CH3:9])[O:12][N:53]=2)=[O:56])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methoxyisoxazole-3-carbonyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.36 (s, 2H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.41 (s, 1H), 4.42 (m, 1H), 3.88 (m, 1H), 3.13 (m, 2H), 2.83 (m, 4H), 2.45 (s, 3H), 2.30 (m, 2H), 2.10 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C30H31ClN7O3S (M+H)+: m/z=572.2.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][CH3:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]([CH3:13])[C:20]([CH2:19][CH2:18][Cl:17])=[N:14][C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCl
Reactant: CNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Product: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 80.3 g (0.286 mole) of 4-bromo-N-methyl-2-nitro-1-naphthylamine, prepared as described in the first part of Example 36, and 41 cc (0.426 mole) of 3-chloropropanoyl chloride is stirred for 2 hours at 60° C. and for a further 2 hours at 80° C. The excess of acyl chloride is distilled off at 40° C. under vacuum and the residue, taken up with methylene chloride, is washed first with a saturated NaHCO3 solution and then with water.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2N2C=CC(C)=N2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.BrC1C=CC([C@@H](O)C(F)(F)F)=[C:43]([O:53][CH2:54][CH2:55][O:56]C)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:56][CH2:55][CH2:54][O:53][CH3:43])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: COCCOc1cc(Br)ccc1[C@@H](O)C(F)(F)F
Product: COCCOc1cc(Cl)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-bromo-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol and obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.54 g), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (173 mg, 0.72 mmol) and potassium carbonate (0.25 g, 1.8 mmol) were combined in THF/H2O (20 mL/10 mL) and heated at reflux for 48 hours. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was separated, dried over MgSO4, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting sequentially with 1% methanol in dichloromethane, 2% methanol in dichloromethane, 3% methanol in dichloromethane, 6% methanol in dichloromethane, and 10% methanol in dichloromethane to give the title compound:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:12]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:24](#N)[CH3:25]>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[C@@:4]([NH2:12])([C:3]([O:2][CH2:1][C:25]1[CH:24]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23])[CH2:5][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@](N)(CC1(C)CCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid methyl ester (7.6 g, 23.8 mmol) was dissolved in a mixture of acetonitrile (82 mL) and 0.2 M aqueous NaHCO3 (158 mL) and Alcalase 2.4 L (1.1 mL) was added and the reaction mixture was stirred vigorously for 8 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The ethereal layer was concentrated to yield (R)-2-benzyloxycarbonyl-amino-3-(1-methylcyclopentyl)propionic acid methyl ester (1.9 g). The aqueous phase was filtered with Celite®, the pH was adjusted to 3 with 6N HCl, and the solution was extracted with ethylacetate. The ethyl acetate layer was dried and evaporated to yield 2(8)-benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid (1.4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C.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>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[CH:19]=[CH:18][O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ncnc2c1ncn2Cc1ccccc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC=Cc1ncnc2c1ncn2Cc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 9-benzyl-6-iodopurine (7) (1.00 g, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (0.208 g, 0.02 mmol) and ethoxyvinyl(tributyl)tin (2.07 g, 3.8 mmol) in dry DMF (4 mL) was heated under N2 at 100° C. for 6 h. TLC indicated completion of reaction. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The solvent (EtOAc) was distilled off and the residue obtained purified by flash chromatography. Yield 0.393 g, (47%). Mp 114-115° C. 1H NMR (CDCl3): δ 1.55 (t, 3H, CH3, J=7.5 Hz), 4.13 (q, 2H, CH2, J=13.7 Hz), 4.99 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 6.16 (d, 1H, CH, J=3 Hz), 7.30-7.38 (m, 5H, Ar—H), 8.09 (s, 1H, purine C8—H), 9.07 (s, 1H, purine C2—H). 3C NMR (CDCl3): δ 14.3, 47.3, 63.7, 94.7, 127.8, 127.8, 128.6, 129.1, 129.2, 130.3, 135.0, 144.4, 152.1, 152.3, 152.4, 155.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15](I)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(COC)OC.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH:29]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(C(=O)O)CC3)cc12
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a suspension of Example 61A (300 mg, 0.813 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (342 mg, 1.219 mmol) in 10 mL dimethoxyethane/ethanol/water (7:2:3) was added sodium carbonate (345 mg, 3.25 mmol) and dichlorobis(triphenylphosphine) palladium(II) (17.09 mg, 0.024 mmol). The reaction was stirred at 90° C. for 12 hours, then cooled, and extracted with ethyl acetate. The combined organic fractions were washed with saturated sodium bicarbonate (2×), water, and brine, dried over magnesium sulfate and concentrated. The crude material was triturated with ethyl acetate, and the solid was collected by filtration. The solid was dissolved in 15 mL dioxane, treated with 6 M sodium hydroxide (1.355 ml, 8.13 mmol) and stirred at 90° C. for 12 hours. Most of the solvent was removed, and the residue was diluted with 30 mL water. The aqueous mixture was extracted with ethyl acetate (2×), and the organic fractions were discarded. The aqueous layer was made neutral (˜pH 7) with 1 M HCl. The solid was collected by filtration and dried under high-vacuum to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 1H) 8.75 (s, 1H) 7.28-7.39 (m, 2H) 7.15-7.26 (m, 1H) 6.60 (s, 1H) 6.24 (s, 1H) 3.69-3.85 (m, 3H) 2.26-2.47 (m, 4H) 1.93-2.10 (m, 1H) 1.54-1.77 (m, 1H) MS (ESI+) m/z 368.2 (M+H)+.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].Cl>C1COCC1>[CH:2]1([C:13](=[O:14])[C:12]([O:11][CH2:9][CH3:10])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium turnings (2.20 g, 90.32 mmol) in THF (100 mL) was added cyclohexyl bromide (9.27 mL, 75.27 mmol). The mixture was sonicated (note 1) for 30 min, the supernatant liquid was decanted into an addition funnel and added to a solution of diethyloxalate (22.0 g, 146.14 mmol) in THF (240 mL) at −10° C. over one hour. After 30 minutes, 10% HCl (75 mL) was added the mixture was and stirred 15 minutes. Layers were separated and the aqueous layer was extracted with Et2O (100 mL). Combined organics were washed (brine), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.15-1.40 (m, 5H) 1.56-1.94 (m, 8H) 2.97-3.05 (m, 1H) 4.30 (q, J=7.32 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH3:8][N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[N:10]1.Br[C:24]1[C:25]([F:42])=[C:26]([CH:39]=[CH:40][CH:41]=1)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(#N)C>[F:42][C:25]1[C:24]([C:12]2[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=2)=[CH:41][CH:40]=[CH:39][C:26]=1[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2F)cn1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Pd-118 (104 mg) was dissolved in acetonitrile (10 mL) and stirred for 5 min before addition of potassium carbonate (2.364 g), water (10 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.305 g). The mixture was stirred for a further 5 min then tert-butyl 3-(3-bromo-2-fluorophenethoxy)propanoate [Example 16, Step iii)] (1.98 g) added and the reaction was heated at the heating block (80° C.) for 2 h. The mixture was cooled and extracted into ethyl acetate (150 mL). Organic was separated, dried (MgSO4) solvents evaporated to give a brown oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in isohexane to afford the subtitled compound (1.480 g) as a gum. MS [M+H-C4H9]+=293 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.39 (td, J=2.5 and 7.3 Hz, 1H), 7.13-7.01 (m, 2H), 3.96 (s, 3H), 3.74-3.64 (m, 4H), 2.96 (t, J=6.8 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[C:5]#[N:6].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21].COC(=O)C1C=CC(NC2CC3N(C)C(CC3)C2)=C(O)C=1.F[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:50]=1[N+]([O-])=O.FC1C=CC=CC=1[N+]([O-])=O>>[CH3:56][O:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:49]2[C:50]=1[O:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N:10]2[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: CN1C2CCC1CC(Nc1ccc(C#N)cc1O)C2
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Agent: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Agent: O=[N+]([O-])c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(C#N)ccc1N2C1CC2CCC(C1)N2C

Procedure:
Using an adaptation of Procedure 2, substituting the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile, 2p for the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a, and 1-fluoro-3-methoxy-2-nitrobenzene, 1e for 2-fluoronitrobenzene, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile, 3p was obtained as TFA salt and as a mixture of endo and exo isomers after purification via reverse phase HPLC (eluent gradient: 20% to 45% CH3CN in water containing 0.1% TFA). MS m/z=362 (M+1).
Reaction SMILES: [Na].COC([C:6]1[C:7]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:9]=[CH:10][N:11]=1)=O.[CH3:22][OH:23]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:7]3[C:6]([O:23][CH3:22])=[N:11][CH:10]=[CH:9][N:8]3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: CO
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Na]
Product: COc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 50 °C

Procedure:
A mixture of MeOH (18 mL) and sodium (1.1 g, 48 mmol) was stirred at ambient temperature until the sodium was consumed then 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 1.0 g, 4 mmol) was added. The mixture was heated at about 50° C. for about 1 h. The mixture was cooled to ambient temperature and filtered. The beige solid isolated was carried on crude. (0.98 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 244.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:9][CH:8]=1.[NH3:19]>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:19])=[O:16])=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(Cc1ccncc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(Cc1ccncc1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Oxalyl chloride (154 mg, 1.21 mmol) was added to a stirred solution of 2-((pyridin-4-yl)methyl)propanoic acid (100 mg, 0.61 mmol) in DCM (5 ml) at 0° C. under an atmosphere of nitrogen and stirred for 1.5 h at room temperature. The reaction mixture was concentrated under reduced pressure to give the crude acid chloride. Aqueous ammonia (5 ml) was added to the above acid chloride solution at 0° C. and stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 92.0 mg (92.9%) of 2-((pyridin-4-yl)methyl)propanamide as a pale brown solid.
Reaction SMILES: [N:1](=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)[OH:2].[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>CCOCC>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([O:2][N:1]=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)=[O:14]
Reactant: O=C=NCCCl
Reactant: CC1OCSC1=NO
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: CC1OCSC1=NOC(=O)NCCCl

Procedure:
4-Oximino-5-methyl-1,3-oxathiolane was caused to react with 2-chloroethylisocyanate in the presence of dibutyltin diacetate in ether. The reaction mixture was worked up and recrystallized in the manner described in Example I. The product had a mp 88.5°-90.5°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[OH-].[NH4+:17]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CC1CC(=O)c2ccc(F)cc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)CC1CC(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride (prepared from 0.024 mol of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid) in dichloromethane (150 ml) was cooled to 0° C. and stirred rapidly while 50 ml of ammonium hydroxide, 28-30%, was added. The resulting mixture was allowed to warm to room temperature and stirring was continued for 18 hr. The volatiles from this mixture was removed by spin evaporation in vacuo and the residue was dissolved in dichloromethane (250 ml) and washed with water (3×50 ml). The dichloromethane phase was then slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica was then applied to a column of Silica Gel 60 (51×400 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97) to give, after recrystallization from methanol, 2.4 g (48%) of 2-(6-fluoro-3-oxo-1-indanyl)acetamide as a yellow solid: m.p., 150-152° C.:
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10](C)/[C:7](=N\O)/[C@H](C)[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52].S([O-])(O)=O.[Na+].[C:59](=O)([O-])[O-].[Na+].[Na+].[CH2:65]([OH:67])[CH3:66]>O>[CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:43])[CH3:44])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:7])[C:65](=[O:67])[C@H:66]([CH3:59])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52]
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3 g of 6-0-methylerythromycin A 9-oxime and 3.27 g of sodium hydrogen sulfite were dissolved in a mixture of 30 ml of ethanol and 30 ml of water, and the solution was refluxed with stirring for 6 hours. The solution was cooled to room temperature, 60 ml of water was added, and the pH of the solution was adjusted to more than 10 with a saturated aqueous sodium carbonate solution. The precipitate which formed was collected by filtration, washed throughly with water and recrystallized from ethanol to give 2.01 g of 6-0-methylerythromycin A. m.p. 223°-225° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
A mixture of 4-iodoaniline (20.00 g, 90.0 mmol, 1.0 equiv) triethylamine (38.4 ml, 274 mmol, 3.0 equiv) and CH2Cl2 (200 ml) was cooled to 0° C. Acetic anhydride (26.0 ml, 270 mmol, 3.0 equiv) was added drop wise. The reaction mixture was stirred at 0° C. for 10 min, and at rt for 2 h. The volatile materials were removed under vacuum, and the solid residue was dissolved in 30 ml of hot CH2Cl2. The solution was left to stand in a freezer for 72 h. The separated solid was filtered out and dried under vacuum to give N-(4-iodophenyl)acetamide (20.35 g, 86.6%). 1H NMR (CDCl3) δ 7.58–7.28 (d, 2H), 7.25–7.23 (d, 2H), 2.15 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[N:9]=[CH:8][CH:7]=1.[NH4+].[Cl-]>CN(C=O)C.O>[N:1]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[N:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c2c(Cl)ccnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c(N=[N+]=[N-])ccnc12
Temperature: 90 °C
Yield: 84.5 %

Procedure:
16.7 g of NaN3 are added to a solution of 10 g (44.7 mmol) of 4-chloro-5,8-dimethoxyquinoline in a DMF/H2O mixture (160 mL/60 mL). The reaction medium is heated at 90° C. for 2 h 30 min. After cooling, the mixture is hydrolyzed with 500 mL of saturated NH4Cl solution and is extracted with CHCl3 (3 times 150 mL) After drying over MgSO4, the organic phases are concentrated on a rotary evaporator and the DMF is then removed under vacuum (2 mmHg). 8.7 g of azide are obtained in the form of a brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C=CC(C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 4-t-butoxycarbonylaminocyclopent-2-enecarboxylic acid (1 g, 4.4 mmol) dissolved in THF (100 ml) and added with borane-THF (4.5 ml, 4.5 mmol) at 0° C. and stirred overnight at r.t. The reaction mixture was poured into ice-cold water (100 ml) and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate and evaporated to obtain the title compound (655 mg, 69%). ESMS: 214 (M+1)+, 236 (M+23)+, 248 (M+35)−, 272 (M+59)−.