Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCOCC>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[O:29][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(Oc3cc(C)ccc3C)cc2OC1C(F)(F)F
Temperature: 110 °C

Procedure:
To 0.200 g (0.689 mmole) of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 2.5 mL of DMF was added 0.118 g (0.946 mmol) of 2,5-dimethyl phenol to the vessel followed by 0.131 g (0.946 mmole) of potassium carbonate. The suspension was prepared in a capped vial and placed in a J-KEM heating block equipped with shaker, condenser and nitrogen atmosphere. The block was heated to 110° C. for 20hrs. For work up, 10 mL of H2O and 5 mL of ether was added to the mixture. The organic layer was separated and then the aqueous was extracted 3 times with ether. The product was then run through a pre-packed silica gel plug (20 mL, 5 g capacity) and the silica column washed with 4×5 mL aliquots of ether. Concentration of the solution afforded the product with was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][C:11]=1[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][C:11]=1[F:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
Add manganese dioxide (4.4 g, 50.6 mmol) to a solution of N-(tert-butoxycarbonyl)-2-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine (1.1 g, 3.38 mmol) in anhydrous 1,4-dioxane (45 mL) at room temperature. Heat the reaction mixture at 70° C. overnight. Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as an oil (980 mg, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>C(Cl)Cl>[N:66]1[CH:67]=[CH:68][CH:69]=[C:64]([NH:63][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[NH:17]2)=[O:37])[CH:65]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccnc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccnc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a colorless solution. DIPEA (240 μl, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. 3-Amino-pyridine (38.9 mg, 413 μmol, Eq: 1.2) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 2% to 5% MeOH in DCM) to give a white solid as the product. 185 mg. MS (ES+) m/z Calcd: [(M+H)+]: 543. found: 543.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)=[CH:21][C:20]([O:29][CH3:30])=[C:19]([OH:31])[C:18]=2[N+:32]([O-:34])=[O:33])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>Br.C(O)(=O)C>[OH:31][C:19]1[C:18]([N+:32]([O-:34])=[O:33])=[C:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[O:16])[C:22]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[CH:21][C:20]=1[O:29][CH3:30]
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(-c2noc(C)n2)c(C(=O)c2ccc(O)cc2)c([N+](=O)[O-])c1O
Yield: 97.5 %

Procedure:
A mixture of (4-benzyloxyphenyl)-[3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]methanone (reference example 22-42) (395 mg) and a 25% hydrogen bromide-acetic acid solution (10 mL) was stirred at 45° C. for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (310 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH:17]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:18][C:19](OC)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>CCCCCC>[C:11]1([CH:17]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:18][CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooled to −78° C. under a nitrogen atmosphere. The reaction was stirred for 1 h at −78° C. and was allowed to warm to room temperature for 4 hrs. The reaction was quenched with methanol (100 μL), and saturated ammonium chloride (100 μL), and then taken up in ethyl acetate dried over MgSO4 and filtered. The filtrate was concentrated to give 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (130 mg, 92%) as an oil. m/z=450 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[N+](C1C=CC([O:37][C:38]([NH:40][C@H:41]([CH2:48][N:49]([CH3:59])[C:50]([O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:51])[CH2:42][O:43][Si](C)(C)C)=O)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:38]([NH:40][C@H:41]([CH2:48][N:49]([CH3:59])[C:50]([O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:51])[CH2:42][OH:43])=[O:37])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CN(C[C@H](CO[Si](C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (19.9 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added the solution of (2R)-2-(p-nitrophenoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propane (0.05 mmol), followed by DIEA (26 μL, 0.15 mmol). The resulting yellow solution was stirred at rt for 30 min. CH2Cl2 was removed in vacuo and the residue was redissolved in acetonitrile, and purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (10.0 mg, 30%). MS m/z 672 (M+H+).
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].S(=O)(=O)(O)O.O.[F:19][CH:20]([CH3:28])[C:21](=O)[CH2:22][C:23](OC)=[O:24]>CO>[F:19][CH:20]([C:21]1[N:12]=[CH:10][NH:11][C:23](=[O:24])[CH:22]=1)[CH3:28]
Reactant: COC(=O)CC(=O)C(C)F
Reactant: N=CN
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(F)c1cc(=O)[nH]cn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution in which 9.33 g of methyl 4-fluoro-3-oxopentanoate had been dissolved in 115 ml of methanol were successively added 36.5 g of a 28% sodium methoxide methanol solution and 9.84 g of formamidine acetate at room temperature, and the mixture was stirred at 40° C. for 12 hours. To the mixture was further added 0.66 g of formamidine acetate and after stirring the mixture at 50° C. for 2 hours, the mixture was cooled to 10° C. or lower. After cooling, a mixture of 9.51 g of conc. sulfuric acid and 8.5 g of water was added to the reaction mixture. After stirring the mixture at 50° C. for 30 minutes, insolubles were removed by filtration and the filtrate was quantitated by the liquid chromatography internal standard method. As a result, 7.99 g of 6-(1-fluoroethyl)-4-pyrimidone was found to be formed (yield: 89.2%). The filtrate was concentrated under reduced pressure and the concentrated solution was recrystallized from 40 ml of 2-propanol to obtain 5.82 g of 6-(1-fluoroethyl)-4-pyrimidone.
Reaction SMILES: C(N(CC)C(=O)OC[N:7]1[CH:11]=[C:10]([C:12]2[C:23](=[O:24])[N:22]([CH:25]([CH3:27])[CH3:26])[C:15]3[N:16]=[C:17]([NH2:21])[N:18]=[C:19]([CH3:20])[C:14]=3[CH:13]=2)[N:9]=[N:8]1)C.[OH-].[Na+]>CO>[NH2:21][C:17]1[N:18]=[C:19]([CH3:20])[C:14]2[CH:13]=[C:12]([C:10]3[N:9]=[N:8][NH:7][CH:11]=3)[C:23](=[O:24])[N:22]([CH:25]([CH3:26])[CH3:27])[C:15]=2[N:16]=1
Reactant: CCN(CC)C(=O)OCn1cc(-c2cc3c(C)nc(N)nc3n(C(C)C)c2=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N)nc2c1cc(-c1c[nH]nn1)c(=O)n2C(C)C
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a solution of (4-(2-amino-8-isopropyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-1H-1,2,3-triazol-1-yl)methyl diethylcarbamate (38 mg, 0.092 mmol) in MeOH (0.5 mL) was added aqueous NaOH (1.0 M, 0.20 mL, 0.20 mmol) and the reaction mixture was stirred at 85° C. for 2 day. There is about 90% conversion from LCMS. Solvent was evaporated and the residue was purified by flash chromatography eluting with MeOH/CHCl3 (0-5%) to give the title (8 mg, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=3)=[CH:4][CH:3]=1>CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2COc3cc(O)ccc3C2)cc1
Reaction time: 6 h

Procedure:
To a solution of 3-(4-hydroxy-phenyl)-2H-chromen-7-ol (P7) (0.241 g, 1 mmol) in MeOH was added 10% Pd—C (0.050 g). This reaction mixture was hydrogenated at room temperature under 2 atm (30 psi) of H2 pressure for ca. 6 hours. After the disappearance of starting material (TLC), the catalyst was filtered through a pad of celite. The celite-pad was washed with 10 mL of THF then 2×10 mL of MeOH. The solution was filtered once more through filter paper and evaporated to obtain the brownish solid residue which was chromatographed over silica gel using CH2Cl2:MeOH (6:1) to get (0.169 g, 70%) reddish white solid P8. 1H NMR (600 MHz, Acetone-d6) δ,7.08 (d, 2H, J=8.4 Hz, Ar—H2′/H6′), 6.82 (d, 1H, J=7.8 Hz, Ar—H5), 6.80 (d, 2H, J=8.4 Hz, Ar—H3′/H5′), 6.35, (dd, 1H, 2J=7.8 Hz, 3J=2.4 Hz), 6.27 (d, 1H, 3J=2.4 Hz), 4.15 (m, 1H, O—CH), 3.88 (t, 1H, J=10.8 Hz, O—CH), 3.0 (m, 1H, 3-CH), 2.9 (m, 2 H, 4-CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reaction time: 3 h

Procedure:
The title compound was prepared according to Procedure D as follows. The 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (12.58 g, 24.7 mmol) was added to a solution of 2-methanesulphonyl-ethylamine (4.55 g, 37.0 mmol) and triethylamine (2.0 ml, 27.2 mmol) in 125 ml of tetrahydrofuran and 125 ml of methanol. After stirring 3 hours, the solution was cooled in an ice bath and sodium borohydride (2.42 g, 64.0 mmol) was added in five portions over a 20 minute period. The reaction mixture was stirred overnight at room temperature and then quenched with the dropwise addition of 250 ml of water. The solution was concentrated in vacuo to remove the organic solvents and the residual oily solution was extracted with 1 l of ethyl acetate. The organic solution was washed with 1M sodium hydroxide and brine and then dried with sodium sulfate. The solution was concentrated in vacuo to a very small volume and solid crystallized out. The suspension was filtered with a small volume of ethyl acetate, washed with ether and dried in a vacuum oven at 65 C to give 10.0 g (70%) of free base as an off white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]([C:4]1[C:5]([F:11])=[CH:6][CH:7]=[CH:8][C:9]=1[F:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40.6 g of 2,6-difluoroacetophenone are placed in 120 ml of chloroform, and 0.1 g of aluminium chloride is added. Then, at 0° C., 37 g of bromine in 240 ml of chloroform are added dropwise and stirring is carried out at 0° C. for 1 h. The reaction mixture is then heated to room temperature and is concentrated using a rotary evaporator. The residue is distilled over a Vigreux column. In this way 2-bromo-1-(2,6-difluorophenyl)-ethanone having a boiling point of 101-11° C. at 9 mbar is obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[S:22]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(=O)C1CCNC(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCNC(=S)C1
Yield: 49.3 %

Procedure:
To a solution of ethyl 2-oxopiperidine-4-carboxylate (10.76 g, 62.85 mmol) in toluene (120 mL) was added the Lawesson's reagent (25.42 g, 62.85 mmol) under a nitrogen atmosphere. The mixture was heated to reflux for 2 h. Removed the solvent under reduced pressure and the residue was purified by silica gel column chromatography (DCM/EA=20/1) to afford ethyl 2-thioxopiperidine-4-carboxylate (5.8 g, yield 49.3%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].N#N>O>[CH3:16][O:15][C:13](=[O:14])[CH:12]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:11]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)c1ccccc1Br
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccccc1C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a rapidly stirred cold suspension (0° C.) of 2-bromobenzoic acid (30.0 g, 149.32 mmol), cuprous bromide (2.14 g, 14.93 mmol) and dimethyl malonate (300 mL) was added NaH (80% in mineral oil, 10.75 g, 358.37 mmol) over a 30 minute period, while a stream of dry N2 was passed over the mixture. After the addition of the NaH had been completed, the mixture was stirred for 10 minutes at room temperature and 30 minutes at 70° C. (external oil bath temperature). At this point, the suspension had turned to a solid mass, which was dissolved in H2O (1000 mL). The aqueous layer was extracted with diethyl ether (3×500 mL) and was acidified with HCl (2N). The mixture was extracted with EtOAc and dried over MgSO4. Evaporation gave an off-white solid which was recrystallized from Et2O/hexane (-20° C.) to give a white solid (34.2 g, 90.9%).
Reaction SMILES: [CH3:1][C:2]([CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][C:4]([O:6]CC)=[O:5].[OH-].[K+].Cl>C(O)(C)C>[CH3:1][C:2]([CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CCCC(C)CCC=C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCCC(C)CCCC(C)=CC=CC(C)=CC(=O)O
Temperature: 0 °C

Procedure:
8.0 g. of the ethyl 3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoate obtained in the previous. Example 1 was added to a solution of 3.2 g. of potassium hydroxide in 20 ml. of isopropyl alcohol, and the mixture was stirred at 50° C. for 1 hour. The reaction liquid was then poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 50 ml. of diethyl ether. The ether phase was washed with water, dried over magnesium sulfate, and concentrated to give 7. g. of an oil. The oil was dissolved in 40 ml. of n-hexane and crystallized at -20° C. to give 3.1 g. of the desired product as white crystals.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+]>COCCO>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[S:7][C:6](=[O:17])[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])=[C:14]2[OH:15]
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2sc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)ccc2sc1=O)C(=O)O
Yield: 41.2 %

Procedure:
A mixture of 6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 58(b)) (100 mg, 0.37 mmol), L-alanine (165 mg, 1.85 mmol) and NaOMe (80 mg, 1.48 mmol) in 2-methoxyethanol (5.2 mL) was microwaved at 150° C. for 2 h and concentrated. Residue was dissolved in water (60 mL). Insoluble solid was filtered off. The Aqueous filtrate was acidified using 1 N HCl solution to pH=3-4. Precipitate was collected and dried. It was then triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound (50 mg). MS ESI(−) m/e: 325.93 (M−1).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[NH2:9][C:10]1[C:19]([I:7])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1
Reactant: COC(=O)c1ccc(N)nc1C
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(N)nc1C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium periodate (4.05 g, 18.9 mmol) and iodine (9.62 g, 37.9 mmol) were added to a solution of methyl 6-amino-2-methylnicotinate (8.40 g, 50.5 mmol) in DMF (45 ml), and the mixture was then stirred at 50° C. for 1.5 hours. The reaction mixture was added to a cold solution of 250 ml of saturated sodium thiosulphate solution in 150 ml of water. The solid formed was filtered off with suction, washed with water and dried. This gave 13.4 mg (88.9% of theory) of methyl 6-amino-5-iodo-2-methylnicotinate. HPLC-MS: log P=1.55; mass (m/z): 293.0 (M+H)+; 1H-NMR (D6DMSO) 2.50 (s, 3H), 3.74 (s, 3H), 6.81 (br. s, 1H), 8.25 (s, 1H).
Reaction SMILES: CO.C[O:4][C:5]([CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])=O.[BH4-].[Na+].COCCOC>O>[OH:4][CH2:5][CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: C=CCC(CCCC#N)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: C=CCC(CO)CCCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (4136 ml) is added dropwise over about 3 h to a mixture of 2054 g of 5-methoxycarbonyl-oct-7-enenitrile, 1286 g of sodium borohydride and 20.5 l of 1,2-dimethoxyethane heated at 75°. The reaction mixture is heated at 95° for 3.5 h, stirred at room temperature overnight, and cooled to 8° in an ice bath. Water (21.0 l) is added slowly, the mixture is again stirred for 1.5 h at room temperature, and then extracted with ethyl acetate (2×20 l). The combined extract is washed with brine, dried over sodium sulfate and evaporated to dryness at 65°-70°/3 mm Hg (=4.00 mbar). The residue is distilled to yield 6-hydroxy-5-(2-propenyl)-hexanenitrile, b.p. 113°-116°/0.8 mm Hg (=1.07 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([I:8])=[N:6][CH:7]=1.[CH3:10]N(C=O)C.[H-].[Na+].CI>[NH4+].[Cl-].O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)cnc1I
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(Br)cnc1I
Temperature: 0 °C
Yield: 78.3 %

Procedure:
To a stirred solution of 5-bromo-2-iodopyridin-3-ol (2.17 g, 7.2 mmol) in DMF (10.00 mL, 129 mmol) was added NaH (0.32 g, 8.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. and MeI was added at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with NH4Cl(aq) and water (10 mL each) at 0° C., and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography ((5%→50% EtOAc in hexane) to obtain 5-bromo-2-iodo-3-methoxypyridine as an off-white solid (1.77 g, 78% yield) m/z (%): 314.2 (100%, M++H).