Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C@H:28]3[CH2:30][O:29]3)[CH:21]=2)=[N:13]1>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:30][C@@H:28]([OH:29])[CH2:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[C:15]3[S:19][CH:18]=[CH:17][C:16]=3[N:12]([CH3:11])[N:13]=2)[CH:21]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cn1nc(-c2cccc(OC[C@H]3CO3)c2)c2sccc21
Solvent: CCO
Product: Cn1nc(-c2cccc(OC[C@H](O)CN3CCc4ccccc4C3)c2)c2sccc21

Procedure:
Add a solution of 1,2,3,4-tetrahydroisoquinoline (Aldrich Chemical Company) in absolute ethanol (0.0465 g, 0.200 M solution, 1.745 mL, 2.0 equiv.) to a reaction tube. Add absolute ethanol (3 mL) to the reaction tube and then add a solution of (R)-1-methyl-3-(3-oxiranylmethoxy-phenyl)-1H-thieno[3,2-c]pyrazole and absolute ethanol (example 8, 0.050 g, 0.200 M solution, 0.875 mL). Shake the reaction mixture under Argon at reflux temperature overnight in a Bohdan apparatus. Cool and concentrate to remove the solvent. Purify the residue by flash chromatography (5 g silica gel SepPak cartridge) eluting in step gradient fashion sequentially with 2% and 5% methanol in dichloromethane, and dichloromethane:methanol:ammonium hydroxide solution, 90:9:1. Combine and concentrate the desired fractions to give the title compound (0.0796 g), LC/MS (APCI, condition 3) m/e 420 (MH+), retention time 5.16 min.
Reaction SMILES: C(O[C:4](=O)[C@H:5]([C:24]1C=NC(C)=NC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)C.[OH-:32].[Na+].[CH2:34]([OH:36])[CH3:35]>>[CH3:16][C:17]1[N:23]=[CH:4][C:5]([C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:23]=2)[CH2:35][C:34]([OH:32])=[O:36])=[CH:24][N:18]=1
Reactant: CCOC(=O)[C@@H](CCCCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: Cc1ncc([C@@H](CCCCCCc2ccc3c(n2)NCCCC3)CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-14 (0.50 g, 1.36 mmol) in ethanol (10 mL) was added 1N NaOH (1.5 mL), and the mixture stirred at 50° C. for 30 minutes, then concentrated. The residue was chromatographed on silica gel (25:10:1:1 to 15:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 8-15 as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=O)[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:21](=[O:24])([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30].[I-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]3[CH2:18][C:17]([CH3:19])([CH2:16][C:8]4[CH:7]=[N:6][CH:18]=[CH:17][CH:16]=4)[C:21](=[O:24])[C:12]4[CH:11]=[C:10]([O:15][CH2:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH:9]=[C:8]([C:4]=2[CH:3]=1)[C:7]3=4
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)COc1cc2c3c(c1)c1cc(Br)ccc1n3CC(C)(Cc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and i-propyl bromoacetate (0.12 ml) and potassium iodide (1 grain) were added in succession, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (50 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate), and the crude purification product was washed with ether and recovered by filtration to obtain the title compound (220 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 140 °C

Procedure:
255 mg (0.533 mmol) of methyl 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carboxylate (Example 16A), 259 mg (0.799 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.56 ml (3.2 mmol) of N,N-diisopropylethylamine were initially charged in 4.5 ml of DMSO. The mixture was heated at 140° C. in a microwave for 45 min. The crude product was purified by means of preparative HPLC (method 10). 28 mg (8% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1c(F)cccc1F
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3c(F)cccc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,6-difluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.44-7.19 (10H, m), 6.93 (2H, t, J=9.0 Hz), 6.52 (1H, br.s), 3.39-3.37 (2H, m), 2.79-2.74 (2H, m), 2.29 (3H, s), 2.20 (3H, s).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(SCC(CC(=O)C)C(O)=S)(=O)C.[C:30]([O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(CCC(=O)C(C)C)C(=O)O
Agent: CC(=O)CC(CSC(C)=O)C(O)=S
Product: CC(=O)SCC(CCC(=O)C(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
By substituting 2-acetylthiomethyl-5-oxo-6-methylheptanoic acid for the 2-(acetylthiomethyl)-3-acetylthiopropanoic acid in the procedure of Example 2, 1-[2-acetylthiomethyl)-5-oxo-6-methylheptanoyl]-L-proline tert.butyl ester is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:25])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:36][O:37][CH3:38]>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:25][CH2:36][O:37][CH3:38])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)cc21
Reaction time: 2 h
Yield: 38.5 %

Procedure:
1-(3-{[Tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-7-methoxyquinoxalin-2(1H)-one (2.0 g, 5.49 mmol) was dissolved in dichloromethane (30 ml). N,N-Diisopropylethylamine (3.35 ml, 19.22 mmol) and chloromethylmethyl ether (1.04 ml, 13.73 mmol) were added to this solution under cooling on ice, and the mixture was stirred for 2 hours. N,N-Diisopropylethylamine (3.35 ml, 19.22 mmol) and chloromethylmethyl ether (1.04 ml, 13.73 mmol) were further added to the reaction solution and stirred for 14 hours, and the reaction solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 863 mg (39%) of the title compound in the form of a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21]N1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCC1CC[CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:68]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH:23]1[CH2:22][CH2:21][CH2:68][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:70]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(5-bromopentyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.28 min; MH+ 525
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[NH:9][C:10]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[C:11]2[C:15]([N:16]=1)=[N:14][CH:13]=[N:12]2.O>C(O)(C(F)(F)F)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:10]1[NH:9][C:8]([NH2:7])=[N:16][C:15]2[C:11]=1[N:12]=[CH:13][N:14]=2
Reactant: COc1ccc(CNc2nc3ncnc-3c(-c3ccco3)[nH]2)cc1OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Yield: 67.8 %

Procedure:
A solution of N-(3,4-dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine (194 mg, 0.55 mmol) in TFA (1 mL) was heated at 60° C. for 30 min, poured into water, extracted with EtOAc and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 5% MeOH in EtOAc). The resulting yellow solid was dissolved in MeOH, treated with HCl (1-M in Et2O) and filtered to give the title compound (75 mg, 57%) as a yellow solid.
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:16]2[NH2+:15][C:14]3[C:9](=[CH:10][C:11]([Br:17])=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5](Br)[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][O:26][CH3:27]>C(Cl)(Cl)Cl>[Br-:17].[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][CH3:27])[C:5]1[CH:4]=[C:3]([CH3:2])[C:16]2[C:7]([CH:6]=1)=[S+:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([N:23]([CH2:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:21][O:20][CH3:19])[CH:10]=1)[N:15]=2
Reactant: Cc1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Reactant: COCCNCCOC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: COCCN(CCOC)c1ccc2nc3c(C)cc(N(CCOC)CCOC)cc3[s+]c2c1
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 1-methyl-3,7-dibromophenothiazinium bromide (315 mg, 0.7 mmol) in chloroform (15 mL) kept under argon, bis(2-methoxyethyl)amine (0.52 mL, 3.5 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (30 mL, 1% v/v) and then twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum (93 mg, 24% yield). The desired final product was purified by flash chromatography.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16]>C(O)C.O>[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: CC1(O)CCC(=O)C1(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(O)CCC(=NO)C1(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Sodium acetate (7.57 g, 92 mmol) and hydroxylamine hydrochloride (6.01 g, 87 mmol) were added to a solution of 3-hydroxy-2,2,3-trimethylcyclopentanone (8.20 g, 57.7 mmol, from Step 1) in ethanol (80 mL) and water (16 mL). The resultant mixture was heated to 80° C. for 15 h, then cooled to room temperature. After removal of ethanol in vacuo, the aqueous residue was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to give crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g). 1H NMR (400 MHz, methanol-d4) δ ppm 2.29-2.80 (2 H, m), 1.63-1.94 (2 H, m), 1.22 (3 H, s), 1.08 (3 H, s), 0.99 (3 H, s).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-Boc-L-valine (3.72 g, 17.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.84 g, 18.86 mmol) were dissolved in anhydrous methylene chloride (50 mL) under nitrogen. Triethylamine (2.09 g, 20.64 mmol) was added to the mixture, followed by dropwise addition of diethyl cyanophosphonate (3.09 g, 18.92 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was then diluted with methylene chloride (150 mL) and washed with water (100 mL). The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was carried forward without further purification. 1H NMR (CDCl3): 5.28 (d, 1H), 4.61 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 2.09-1.85 (m, 1H), 1.43 (s, 9H), 0.99 (d, 3H), 0.90 ppm (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].[Li+].[OH-].CO.O.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=[O:28])[S:26][C:19]=23)=[CH:31][CH:32]=1)=[O:11]
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Temperature: 50 °C

Procedure:
To a stirred suspension of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate (50 mg, 0.11 mmol) in MeOH (3 ml), was added 0.4M LiOH/MeOH solution (10 ml, 4.0 mmol). The mixture was heated at 50° C. for 7 hours, and poured into 100 ml of water. 1M HCl was added until pH=4. The resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as light grey solid. Yield: 40 mg, 83%.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C[OH:21]>>[C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1C(CO)CC1OC(=O)c1ccccc1
Reactant: CO
Solvent: ClCCl
Product: O=C(OC1CC(CO)C1=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 2.09 g (9.5 mmol) of 1-benzoyloxy-3-hydroxymethyl-2-methylenecyclobutane from Step G, 112 mL of methylene chloride and 28 mL of methanol was cooled to -78° C. under a nitrogen atmosphere. Ozone was bubbled through the mixture for 10 minutes, until a persistent blue color was observed. Excess ozone was flushed out with nitrogen, 9 mL of dimethyl sulfide was added and the reaction mixture stirred for 0.5 h at -78° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 0.5 h at ambient temperature and evaporated under reduced pressure to a syrup. The syrup (2.5 g) was dissolved to ~2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5 psi with 100 mL of methylene chloride, followed by 250 mL of 1% methanol in methylene chloride and 250 mL of 2% methanol in methylene chloride to give 1.79 g (86% yield) of the title compound; MS DCI-NH3M/Z: 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](N)=[O:8])[C:5]=1C([O-])=O)([O-:3])=[O:2].[NH4+:16].Cl[O-:18].[Na+].[OH-].[Na+].Cl>O>[NH2:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:8])=[O:18]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1C(=O)[O-]
Reactant: [O-]Cl
Reactant: [NH4+]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
22 g (105.2 mmol) of ammonium 3-nitrophthalamidate (1a) were treated with stirring with 165 ml of sodium hypochlorite solution. After 5 minutes, a solution of 8.8 g of sodium hydroxide in 22 ml of water was added and the mixture was then stirred at 70° C. for 1 h. The suspension was poured into 500 ml of water with stirring. The resulting clear solution was acidified with concentrated HCl. The precipitate was filtered off and dried in a desiccator. Yield: 9.68 g (51%).
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]=[O:14])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.CC1C2C=[C:22]3[O:25][CH2:26]C(=O)CO[C:21]3=CC=2CC1>>[CH3:10][C:8]1([CH3:9])[C:3]2[CH:2]=[C:1]3[O:11][CH2:12][C:13](=[O:14])[CH2:26][O:25][C:22]3=[CH:21][C:5]=2[CH2:6][CH2:7]1
Reactant: CC(C)=CCCC(C)CCOCC=O
Reactant: CC1CCc2cc3c(cc21)OCC(=O)CO3
Product: CC1(C)CCc2cc3c(cc21)OCC(=O)CO3

Procedure:
Odor: Marine-aldehyde-like, floral-rosy odor with nuances of citronelloxyacetaldehyde [(3,7-dimethyl-6-octenyl)oxyacetaldehyde].—IR (film): ν=1322/1253/1281/1350 cm−1 (ν ring), 1040/1067 cm−1 (ν C—O—C), 1484/1438 cm−1 (ν C═C, Ar), 1736 cm−1 (ν C═O). 1H-NMR (CDCl3): δ=1.22 (s, 6H, 1-Me2), 1.92 (t, J=7.2 Hz, 2H, 2-H2), 2.79 (t, J=7.2 Hz, 2H, 3-H2), 4.67 (d, J=2.8 Hz, 4H, 6-, 8-H2), 6.75 (s, 1H, 4-H), 6.81 (s, 1H, 10-H).—13C-NMR (CDCl3): δ=28.43 (2q, 1-Me2), 29.29 (t, C-3), 41.68 (t, C-2), 43.61 (s, C-1), 75.47/75.51 (2t, C-6,-8), 113.99 (d, C-10), 116.31 (d, C-4), 138.98 (s, C-3a), 146.83/147.22 (2s, C-4a, -9a), 148.30 (s, C-10a), 205.06 (s, C-7).—MS (EI): m/z (%)=133 (33) [C9H9O+], 145 (6) [C11H13+], 161 (7) [M+—CH3—2CO], 189 (2) [M+-CH3—CO], 217 (100) [M+-CH3], 232 (30) [M+].
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([Cl:21])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[Cl:21][C:12]1[CH:11]=[C:10]([C:9]2[O:22][C:2]3[CH:3]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:35])[CH3:26])[N:5]=[CH:6][C:7]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)c(Cl)c2)cn1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2cn1
Temperature: 160 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((3-chloro-4-(cyclopropylmethoxy)benzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (1.02 g), potassium carbonate (0.552 g) and copper(I) iodide (38.0 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and to the obtained residue was added 2 M hydrogen chloride/methanol (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (92.4 mg). 1H NMR (300 MHz, CDCl3) δ 0.38-0.48 (2H, m), 0.64-0.77 (2H, m), 1.30 (3H, d, J=6.4 Hz), 1.33-1.44 (1H, m), 1.97 (3H, s), 3.99 (2H, d, J=6.8 Hz), 4.25-4.51 (3H, m), 6.01 (1H, d, J=6.0 Hz), 6.91 (1H, s), 7.02 (1H, d, J=8.7 Hz), 8.06 (1H, dd, J=8.7, 1.9 Hz), 8.24 (1H, d, J=2.3 Hz), 8.53 (1H, s).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)=[C:2]=[S:3]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[N:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=1)=[C:2]=[S:3]
Reactant: O=C(O)c1ccc(N=C=S)cc1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(=O)c2cc(N=C=S)ccc21
Temperature: 25 °C

Procedure:
The 4-isothiocyanatophthalic acid thus obtained was immediately heated to reflux in a mixture of trifluoroacetic anhydride and methylene chloride for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Recrystallization of the resultant solid from 30 mL of carbon tetrachloride afforded 4-isothiocyanatophthalic anhydride as brownish-purple crystals in a yield of 2.3778 g, (77 percent of theoretical). The title compound melted at 106°-108° C.; 1H NMR (300 MHz, acetone-d6) d, 8.15 (d, J=8.1 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.97 (dd, J=8.1, 1.7 Hz, 1H); 13C NMR (75 MHz, acetone-d6) d 163.3, 162.6, 139.8, 134.8, 134.6, 130.6, 128.2, 123.5, 111.6; IR (CHCl3) 2010 (br), 1840, 1740 cm-1; MS m/e 205, 161, 133 (base), 74.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13]C)=[O:12].CO.[OH-].[Na+]>O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 5B (2.38 g) and methanol (20 ml) was added to a stirred solution of sodium hydroxide (1.68 g) in water (20 ml). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was cooled to 5° C. and acidified with concentrated HCI (3.5 ml). The resulting suspension was stirred at 5° C. for 30 minutes. The solid was collected by filtration, washed with water, then dried in vacuo at 35-40° C. to give the free acid (1.45 g, 65 %).