Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[F:34])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=3[F:34])[CH2:26][CH2:27]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCCC3)CC2)c1

Procedure:
Example 133 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=6.4, 8.5 Hz), 7.44–7.38 (m, 2H), 7.35–7.30 (m, 1H), 7.13 (dd, 1H, J=8.5, 3.0 Hz), 7.00–6.91 (m, 2H), 6.05–5.99 (m, 1H), 3.30 (q, 2H, J=5.7 Hz), 2.92–2.86 (m, 2H), 2.80–2.71 (m, 1H), 2.52 (septet, 1H, J=6.7 Hz), 2.34 (t, 2H, J=5.7 Hz), 2.30–2.24 (m, 3H), 2.13–2.05 (m, 2H), 2.00–1.92 (m, 2H), 1.86–1.69 (m, 4H), 1.66–1.43 (m, 7H), 1.71 (d, 6H, J=6.7 Hz); ESMS m/e: 560.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 60 °C

Procedure:
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture heated to 60° C. SOCl2 (1.4 eq) is added via addition funnel. The toluene and SOCl2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(OC(C)(C)C)=O)=[C:21]([F:33])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].Cl>CO.O1CCOCC1>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([F:33])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(-c4sccc4C(N)=O)n[nH]c3c2F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1ccsc1-c1n[nH]c2c(F)c(-c3ccc(N)c(F)c3)ccc12
Temperature: 40 °C
Yield: 127 %

Procedure:
A solution of 0.99 g of (7-fluoro-6-{3-fluoro-4-tert-butyloxycarbonylaminophenyl}-1H -indazol-3-yl)thiophene-3-carboxamide in 30 mL of methanol is admixed at ambient temperature with 2.63 mL of a 4N solution of hydrochloric acid in dioxane. The reaction mixture is heated at 40° C. for 4 h and then concentrated to dryness under reduced pressure. The solid obtained is triturated in isopropyl ether and isolated by filtration. Drying under vacuum gives 0.99 g of (7-fluoro-6-{3-fluoro-4-aminophenyl}-1H-indazol-3-yl)thiophene-3-carboxamide in the form of a yellow solid, whose characteristics are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:16]([CH3:18])[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)I
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1cccc(Br)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
3-Bromobenzenethiol (1 g, 5.3 mmol) was added to acetone (25 mL). Next was added potassium carbonate (1.46 g, 10.58 mmol) and 2-iodopropane (1.17 g, 6.88 mmol). This was refluxed for 5 h. Reaction was then cooled to rt and filtered through a pad of Celite. The organic was then concentrated in vacuo and taken up in ether at which time a white precipitate crashed out. The organic was then re-filtered through the same celite plug and concentrated in vacuo to provide 1.14 g (93.17%) of 1-bromo-3-isopropylsulfanyl-benzene as an oil. 1H-NMR (methylene chloride-d2) δ 7.54 (s, 1H), 7.37-1.31 (m, 2H), 7.18 (t, J-7.9 Hz, 1H), 3.50-3.36 (m, 1H), 1.31 (d, J=6.1 Hz, 6H); LC-MS RT: 4.15, [M+H]+: 233.2.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I>COCCOC>[CH3:15][C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: O=C1CCCC1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2ccccc2)CCCC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a slurry of 60% NaH (125 mg, 3.12 mmol) in DME (3571 μL) at 0° C. was added 2-phenylcyclopentanone (500 mg, 3.12 mmol). After stirring for 1 h, MeI (898 μL, 14.36 mmol) was added, and the solution heated to reflux for 2 h. The reaction was poured onto ice and extracted 3 times into Et2O. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Applied to Silica gel and eluted with an EtOAc/Hex gradient to afford 2-methyl-2-phenylcyclopentanone (401.7 mg, 2.305 mmol, 73.9% yield). LC-MS (M+H)+=175.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.37 (4H, m), 7.20-7.24 (1H, m), 2.54 (1H, dt, J=12.51, 6.26 Hz), 2.34 (2H, t, J=7.63 Hz), 1.82-2.05 (3H, m), 1.38 (3H, s).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)(=[O:20])=[O:21]
Reactant: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 105 °C
Yield: 52.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-methyl-4-(piperazin-1-yl)benzenesulfonamide (116 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (2:1, 6 mL) and dried in vacuum to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide (110 mg, 0.241 mmol, 52.8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.04 (m, 3H) 2.15-2.27 (m, 1H) 2.38 (d, J=4.80 Hz, 3H) 2.51 (d, J=4.29 Hz, 4H) 3.32 (br. s., 4H) 3.38-3.49 (m, 3H) 3.57-3.69 (m, 1H) 3.97-4.07 (m, 1H) 7.02 (d, J=1.52 Hz, 1H) 7.07 (d, J=9.09 Hz, 2H) 7.15 (q, J=4.72 Hz, 1H) 7.59 (d, J=8.84 Hz, 2H) 7.66 (d, J=1.77 Hz, 1H) 10.48 (s, 1H). [M+H] calc'd for C24H29ClN6O2, 457; found, 457.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N+:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:40]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (380 mg, 1 mmol) was mixed with K2CO3 (280 mg, 2 mmol), 3-nitro-phenylboronic acid (334 mg, 2 mmol), Pd(Ph3)4 (115 mg, 0.1 mmol), 4 mL of 1,2-dimethoxyethane and 5 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 3 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 310 mg (88% yield) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH2:7][CH2:6]2.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
To a solution of 3,4-dihydro-6-methoxy-l(2H)-isoquinolinone (852 mg, 4.81 mmol, prepared according to J. Chem. Soc., 1969, p 183) in THF (45 mL) at −78° C. was added 0.5M potassium hexamethyidisilazide (10.6 mL, 5.28 mmol) dropwise and the reaction mixture stirred at −78° C. for 5 minutes. The reaction mixture was warmed to 0° C. in a ice/water bath and ethyl bromoacetate (1.20 g, 7.21 mmol) was added dropwise and the mixture stirred at that temperature for 1 hour, and then at room temperature for 2 hours. The reaction mixture was quenched by addition of sat. NaHCO3, diluted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 and then brine. It was dried (MgSO4) and concentrated in vacuo to afford the title compound (1.1 g, 86%) as a yellow solid. Molecular weight (MS): 263.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:43][C:44]([CH3:55])([CH3:54])[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:55][C:44]([NH:43][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:22])([CH3:54])[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52]
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mmol, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added tert-butyl 2-amino-2-methylpropylcarbamate (128 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude tert-butyl 2-methyl-2-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propylcarbamate (100 mg, 63.4%) as a pale yellow solid. MS: (M+H)+=463.2.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[O:3]1>C(O)(=O)C.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13](=[O:14])[NH:15][C:16]2=[O:17])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Temperature: 95 °C
Yield: 77.3 %

Procedure:
A suspension of 51 g (0.105 m) of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine in 500 ml of acetic acid and 120 ml of water is heated at 95° C. for 90 minutes. The solution thus obtained is concentrated under vacuum and the residue is taken up with 2 l of ethyl acetate, then is concentrated to a small volume and, after 15 hours at room temperature, the precipitate is filtered, washed with ethyl acetate and dried to give 35.6 g of 5′-deoxy-5′-iodo-5-fluoro uridine. M.p.=174.5÷175.5° C., purity (HPLC)=99.74% [α]D=+8.96° (c=1.00, CH3OH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 85.2 %

Procedure:
To a solution of 2-bromo-5-nitropyridine (LXXI) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95° C. for 1 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane→5:95 EtOAc:hexane) to give 5-nitro-2-phenylpyridine (LXXIII) as off-white needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for C11H8N2O2 m/z 200.9 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[CH3:12][O:13][C:14]([C:16]1[C:17]([CH:26]([CH3:28])[CH3:27])=[C:18]2[N:23]([CH:24]=1)[N:22]=[CH:21][N:20]=[C:19]2Cl)=[O:15].Cl>>[CH3:12][O:13][C:14]([C:16]1[C:17]([CH:26]([CH3:28])[CH3:27])=[C:18]2[N:23]([CH:24]=1)[N:22]=[CH:21][N:20]=[C:19]2[N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)=[O:15]
Reactant: COC(=O)c1cn2ncnc(Cl)c2c1C(C)C
Reactant: CNc1cnc2[nH]ccc2c1
Agent: Cl
Product: COC(=O)c1cn2ncnc(N(C)c3cnc4[nH]ccc4c3)c2c1C(C)C
Yield: 25 %

Procedure:
The title compound was prepared in a manner similar to the preparation of Example 24 by using methyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine and 4-chloro-5-isopropylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester. (25% yield). LCMS; m/z 365 (M+H+). Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 8.22 (1H, s.), 8.00 (1H, s), 7.75 (1H, s), 7.50 (1H, s), 6.40 (1H, s.), 3.70 (3H, s), 3.26 (1H, m), 2.51 (3H, s), 0.54 (6H, d, J=7.3 Hz).
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[CH:12][C:11]=3[N:20]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:26].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N+:13]([O-:26])=[CH:12][C:11]=3[N:20]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)[C@H]1COCc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1.25 h
Yield: 100.1 %

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (1.13 g, 4.23 mmol) was dissolved in 40 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (MCPBA) (1.13 g, 77% max). After stirring for 75 minutes, the reaction was treated with 20 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.20 g) as a crusty, off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH:8]=O)=[CH:3][CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=C(Cl)[N:12]=1>>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:12]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccncc1
Product: Cn1cnc2c(Nc3ccncc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-pyridin-4-yl-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.Cl>CO.O1CCCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][C:9]=1[O:19][CH3:20]
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1CC(O)CO)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 117 %

Procedure:
109 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 4 ml of methanol-tetrahydrofuran (1:1). While cooling on ice, 1 ml of 2 N hydrochloric acid was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, so as to obtain 110 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one. This compound was directly used in the following reaction without further purification.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[N:20]O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N12CCCN=C1CCCCC2.O>ClCCl>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]#[N:20])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: ON=C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: N#C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde oxime (37.4 mg, 0.132 mmol) in dichloromethane (3 mL) was mixed with trifluoromethanesulfonic anhydride (24.0 μL, 0.145 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (43.0 μL, 0.289 mmol) and stirred at room temperature for 18 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2 (v/v)) and washed with hexane/ethyl acetate (5/1 (v/v)) to give the title compound as a colorless solid (20.7 mg, yield 59%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Si:25]([O:42][CH2:43][C@H:44]1[O:48][CH:47](CC([O-])=O)[C@H:46]([C:53]([F:56])([CH3:55])[CH3:54])[CH2:45]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([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[Si](OS(C(F)(F)F)(=O)=O)(C)C>>[NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:47]3[C@H:46]([C:53]([F:56])([CH3:55])[CH3:54])[CH2:45][C@@H:44]([CH2:43][O:42][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:48]3)[C:6]=2[N:7]=1
Reactant: CC(C)(F)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1CC(=O)[O-]
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: CC(C)(F)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 75 °C
Yield: 44.4 %

Procedure:
A mixture of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (162 mg, 0.87 mmol) and bis(trimethylsilyl)acetamide (527 mg, 2.61 mmol) was heated with stirring at 75° C. under argon until the mixture became clear. The mixture was cooled to room temperature. To the previous reaction mixture, [(3R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-fluoro-1-methyl-ethyl)tetrahydrofuran-2-yl]acetate (compound 40g, 280 mg, 1.02 mmol) and trimethylsilyltrifluoromethanesulfonate (290 mg, 1.31 mmol) were introduced. The resulting mixture was heated at 75° C. under argon for 3 hours. Then the resulting mixture was concentrated in vacuo to remove the solvent and the residue was purified by column chromatography on silica gel (eluting with 0-5% methanol in DCM) to afford 225 mg of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-fluoro-1-methyl-ethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 40h) as a brown solid. MS obsd. (ESI+) [(M+H)+]: 583.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(C(C)(C)C)cc2)C[C@H](C)N1
Temperature: 100 °C
Yield: 37.3 %

Procedure:
To a solution of cis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) was added 4-(tert-butyl)bromobenzene (1.86 g, 8.7 mmol), followed by BINAP (0.81 g, 1.3 mmol) and 1-BuONa (1.5 g, 15.6 mmol) in one portion each. The resulting mixture was degassed twice. To the mixture was added Pd2(dba)3 (0.79 g, 0.87 mmol) in one portion and the mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×100 mL), washed with water (1×100 mL), and brine (1×50 mL), dried over Na2SO4 and concentarted in vacuo. The residue was purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 0.8 g 1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H), 3.08-3.00 (m, 2H), 2.33-2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13 (d, 6H).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](O)=O.O[CH:17]([CH2:22][CH2:23][CH2:24]COC1C=CC=CC=1)[CH2:18][C:19]([OH:21])=[O:20].OC(CCCCCCOC1C=CC=CC=1)CC(O)=O>>[O:9]([CH2:8][CH2:7][CH2:2][CH2:3][CH2:4][CH2:24][CH2:23][CH2:22][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CC(O)CCOc1ccccc1
Reactant: O=C(O)CC(O)CCCCOc1ccccc1
Agent: O=C(O)CC(O)CCCCCCOc1ccccc1
Product: O=C(O)CCCCCCCCCCOc1ccccc1

Procedure:
Result indicates that PHA copolymer containing three units of 3-hydroxy-5-phenoxyvaleric acid (3HPxV), 3-hydroxy-7-phenoxyheptanoic acid (3HPxHp) and 3-hydroxy-9-phenoxynonanoic acid (3HPxN) can be produced by the strain YN2 with a substrate 11-phenoxyundecanoic acid.