Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:13]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]=[N+:27]=[N-:28])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[N:11][N:28]=[N:27]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Product: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 84 %

Procedure:
A sealed tube was charged with p-toluenesulfonyl cyanide (5.0 g, 22.1 mmol) and (S)-Boc-2-azido methyl pyrrolidine (1) [Black, J.; Brown, A. D.; Erizabet C. L.; Smith, J. D,; Mckelloy, A. B. 2000 JP2000063380/] (4.0 g, 22.1 mmol). The mixture was stirred at 80° C. for 40 hrs. The crude product was purified on flash silica gel column with (Hexane:EtOAc=1:1) to furnish 2 (7.6 g, 84%) as colorless foam. [α]D −11.7 (c 0.64, CHCl3). 1H NMR (400 MHz, CD3OD, −20° C., rotamers 6:4): δ 1.20 & 1.35 (s, 9H), 1.83 & 2.01 (m, 4H), 2.50 (s, 3H) 3.40 & 3.45 (m, 2H), 4.40 & 4.43 (m, 1H), 4.71 & 4.82 (m, 2H), 7.50 & 7.70 (d, J=8 Hz, 2H), 8.00 & 8.40 (d, J=8 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 22.0, 23.7, 28.4, 46.5, 52.1, 56.1, 76.9, 80.6, 129.4, 134.4, 147.4, 154.4, 154.8, 155.5; IR (film): 2976, 1693, 1392, 815, 704 cm−1; MS: (ESI) [M+1]+ 408.2.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1.[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)[CH:31]=[C:30](Cl)[N:29]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)[CH:31]=[C:30]([O:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[N:14]=3)=[CH:16][CH:17]=2)[C:22]([F:23])([F:24])[F:25])[N:29]=1
Reactant: COc1cccc(-c2ccc(C(O)C(F)(F)F)cc2)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)n1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
Cs2CO3 (375 mg, 1 mmol) was added to a solution of 1-[4-(6-methoxy-pyridine-2-yl)-phenyl]-2,2,2-trifluoro-ethanol (67 mg, 0.2 mmol) in 10 ml of anhydrous 1,4-dioxane. The mixture was stirred for 5 min, then was added (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (78 mg, 0.2 mmol), and the mixture was heated at 110° C. overnight. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 112 mg (S)-3-[4-(2-Amino-6-{2,2,2-trifluoro-1-[4-(6-methoxy-pyridin-2-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (yield: 88%).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([OH:23])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([O:23][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(O)c2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2cccc3oc(SCc4ccc(C(C)(C)C)cc4)c(C)c(=O)c23)cc1
Reaction time: 8 h

Procedure:
2-(4-tert-butylbenzylmercapto)-3-methyl-5-hydroxy chromen-4-one (5 g, 14.1 mmol) is dissolved in pyridine in a 25 mL round bottom flask and p-toluenesulfonyl chloride (15 mmol) is added to it. The reaction mixture is stirred for 8 hours. Water is then added to the flask and the contents are poured into a separatory funnel. Ethyl acetate is added and the layers are separated. The organic layer is then washed with water and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (hexanes:ethyl acetate) to afford the above product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: CCO
Product: CCOC(=O)CCCCCCCCCBr
Reaction time: 3.5 h
Yield: 98.6 %

Procedure:
To this end, the 180.5 g of 10-bromodecanoic acid from Step II was added to the 11 reactor (described above) along with 645 g of absolute ethanol. The mixture was heated and stirred for about 3.5 h. GC analysis confirmed that reaction was completed when 10-bromodecanoic acid could not be detected. Next, excess ethanol and residual water were removed through evaporation leaving 197.8 g of 94.9% pure ethyl 10-bromodecanoate residue. 150 g MTBE was added to the ethyl 10-bromodecanoate residue which then was washed repeatedly with 10% sodium carbonate solution followed by water. The mixture was phase separated to obtain 340.7 g of a mixture of ethyl 10-bromodecanoate and MTBE. According to GC analysis the yield from Steps II and III was 89.7%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][N:5]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[Cl-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[O:8][C:4]([CH3:3])=[N:5][N:6]=1
Reactant: BrCC1CO1
Reactant: Cc1nnc(-c2ccccc2O)o1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(-c2ccccc2OCC2CO2)o1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
1.6 g of sodium hydride, in the form of a 55% strength suspension in paraffin oil (0.036 mole) are introduced into 70 ml of anhydrous tetrahydrofuran and 6.3 g (0.036 mole) of ortho-(5-methyl-1,3,4-oxadiazol-2-yl)-phenol, dissolved in 50 ml of tetrahydrofuran, are added dropwise. 5 g (0.036 mole) of epibromohydrin are then introduced dropwise, 10 ml of hexamethylphosphorotriamide are added to the reaction mixture, and the whole is stirred for 32 hours at room temperature. Thereafter, the reaction mixture is poured into 500 ml of aqueous sodium chloride solution and repeatedly extracted by shaking with diethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil. This crystallizes on triturating with a toluene/hexane mixture. 5.5 g (66% of theory) of colorless crystals are obtained; melting point 38°-40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>COC1C=CC(O)=CC=1.N1C=CC=CC=1>[OH:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: Nc1cccc2c(O)cccc12
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1cccc2c(O)cccc12
Temperature: -10 °C
Yield: 87.8 %

Procedure:
227 g of 5-amino-α-naphthol, 1 g of hydroquinone monomethyl ether and 2 litres of pyridine were mixed and cooled to -10° C. by using a freezing medium, and then 110 g of methacrylic acid chloride was added dropwise to the mixture with stirring. After said dropwise addition ended, the solution was stirred at 0°-3° C. for 2 hours, followed by additional 2-hour stirring at 25° C. The reaction solution was poured into 20 litres of ice water. The resultantly formed precipitate was filtered, washed with water and dried. The resulting solids were added into 2 litres of a methanol aqueous 5% sodium carbonate (1/1) mixed solvent, and stirred at 40° C. for 30 minutes and the solution was poured into 4 litres of 5% hydrochloric acid. A large amount of precipitate was formed. This precipitate was suction filtered and recrystallized from ethanol to give 210 g of N-(5-hydroxy-α-naphthyl)methacrylamide having a melting point of 223°-224° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([OH:5])=O.Cl.[CH3:37][O:38][NH2:39]>>[OH:1][CH:2]([C:3]([NH:39][O:38][CH3:37])=[O:5])[CH:6]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:25]1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CON
Reactant: COc1ccc(CC(NC(=O)c2cccnc2-n2ccc(-c3ccccc3)n2)C(O)C(=O)O)cc1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccc(OC)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-(4-methoxyphenyl)-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 502.2
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:18]([O:25][CH2:26][CH2:27][OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CCCCCC>[CH2:18]([O:25][CH2:26][CH2:27][O:28][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCOCc1ccccc1
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1c2ccccc2c(OCCOCc2ccccc2)c2ccccc12
Yield: 29.5 %

Procedure:
Using the procedure outlined in Example 2A, 10-chloroanthracene-9-carbaldehyde (Aldrich) and 2-benzyloxyethanol (Aldrich) gave a 29.5% yield of 10-[2-(benzyloxy)ethoxy]anthracene-9-carbaldehyde, mp 68°-69°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([C@H:10]1[CH2:14][N:13]([CH2:15][CH3:16])[C@H:12]([C:17](OCC)=[O:18])[CH2:11]1)=[N+]=[N-].[OH-].[Na+]>O1CCCC1>[NH2:7][C@H:10]1[CH2:14][N:13]([CH2:15][CH3:16])[C@H:12]([CH2:17][OH:18])[CH2:11]1
Reactant: CCOC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1C[C@H](N)C[C@H]1CO
Reaction time: 1 h

Procedure:
To a suspension of 0.99 g of lithium aluminium hydride in 15 ml of tetrahydrofuran, a solution of 3.03 g of (2S,4R)-4-azido 2-ethoxycarbonyl-N-ethyl pyrrolidine in 10 ml of tetrahydrofuran was dropwise added while cooling and the combined was stirred for 1 hour. Sirring was continued at room temperature for additional 2 hours, and then a mixture of 4.7 ml of aqueous 1N-NaOH solution and 33 ml of tetrahydrofuran was added to decompose excess amount of lithium aluminium hydride. After filtrating the mixture to remove undissolved substance, the filtrate was concentrated under reduced pressure to obtain (2S,4R)-4-amino-N-ethyl-2-hydroxymethyl pyrrolidine as an oily product. Yield 1.33 g.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:20][CH:21]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To an ice-bath cooled mixture of phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 3, 3.0 g) and 1 mL of CH2Cl2 was added drop-wise 3.0 mL of chlorosulfonic acid (5.2 g, 5.0 eq). After the addition of the chlorosulfonic acid was complete the ice bath was removed. The mixture was continued to stir at room temperature for 3 h. Thereafter the thick syrupy mixture was poured onto the crushed ice with vigorous stirring. White precipitates were collected by filtration, were washed with methanol and cold benzene, and dried overnight under high vacuum to yield 3.4 g (87%) of Intermediate 4 as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[OH:10].[C:11](O)(=[O:13])C>>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[OH:10])[CH:11]=[O:13]
Reactant: CC(=O)O
Reactant: CCc1cccc(Br)c1O
Product: CCc1cc(C=O)cc(Br)c1O
Yield: 46 %

Procedure:
A solution of 2-bromo-6-ethylphenol 1 (3.8 g, 18.8 mmol) hexamethylene tetraamine (10.6 g, 75.4 mmol), and acetic acid (120 mL) was heated at reflux for 12 h. Most of the solvent was removed under reduced pressure, and the residue was poured into water (500 nL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 until gas evolution ceased. The organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (SiO2, gradient elution 5 to 10% ethyl acetate/hexanes) to yield 2.0 g (46%) of 3-bromo-5-ethyl-4-hydroxybenzaldehyde 2 as a colorless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:34][C:14]4=[C:15]([NH2:33])[N:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26]C6CCCCO6)[CH:23]=5)=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl>CO>[NH2:33][C:15]1[N:16]=[CH:17][C:18]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH2:25][OH:26])[CH:23]=2)=[C:13]2[CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:34][C:14]=12
Reactant: Nc1ncc(-c2cnn(CCOC3CCCCO3)c2)c2cc(-c3cccc4cnccc34)oc12
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2cnn(CCO)c2)c2cc(-c3cccc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
2-(isoquinolin-5-yl)-4-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}furo[2,3-c]pyridin-7-amine (20.0 mg, 0.0439 mmol) was dissolved in MeOH (0.5 mL) and HCl (4 M in 1,4-dioxane, 0.50 mL, 2.0 mmol) was added. The reaction stirred at RT for 16 h. The reaction was concentrated in vacuo to a solid. Purification by flash chromatography (0 to 10% 7 N NH3/MeOH:EtOAc) afforded 1.6 mg (10%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 9.36 (s, 1H), 8.60 (d, J=6.06 Hz, 1H), 8.52 (d, J=6.32 Hz, 1H), 8.38 (dd, J=7.33, 1.26 Hz, 1H), 8.27 (d, J=8.34 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J=1.01 Hz, 2H), 7.82-7.89 (m, 1H), 7.55 (s, 1H), 4.32-4.38 (m, 2H), 3.97 (t, 2H); MS (ESI): 372.14 [M+H]+; HPLC tR=0.82 min (TOF: polar—3 min).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:30](=[NH:39])OCC1C=CC=CC=1>O>[CH:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])=[NH:39]
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reactant: N=COCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C/C(=C\[C@@H]1CCCN1C=N)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
A solution of (5R,6S)-6-{(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.48 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and benzyl formimidate hydrochloride (2.7 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion Hp-20" (50 ml) eluting successively with water and 3% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(E)-2-{(2S)-1-formimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylic acid (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:11])[CH2:5][CH:6](OC)[O:7]C.Cl>C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:11])[CH2:5][CH:6]=[O:7]
Reactant: COC(=O)C(C)(CC(OC)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
A mixture of 6 g (19 mmol) 2-(3,4-dichloro-phenyl)-4,4-dimethoxy-2-methyl-butyric acid methyl ester and 28 mL 2N HCl aq. in 60 mL THF and 60 mL water was stirred at room temperature for 20 h. The mixture was extracted with diethyl ether. The combined organic phases were washed with sat. NaCl aq., dried with Na2SO4 and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and hexane. The product containing fractions were evaporated to yield 3 g (58%) of the title compound as light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:7][C:8]1[C:9]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[CH:12][CH:13]=1)=O)[CH3:2]>C1(C)C=CC=CC=1>[CH:15]1([N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[N:7]=[C:5]2[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=O)Nc1cccnc1NC1CCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2cccnc2n1C1CCCC1

Procedure:
A solution of crude ethyl {[2-(cyclopentylamino)pyridin-3-yl]amino}(oxo)acetate (C6) (from the previous step, 2 g) in toluene (100 mL) was stirred at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified using silica gel chromatography (Gradient: 9% to 50% ethyl acetate in petroleum ether) to provide the product as a brown solid. Yield: 0.70 g, 2.7 mmol, 27% over 2 steps. 1H NMR (400 MHz, CD3OD) δ 8.53 (dd, J=4.6, 1.4 Hz, 1H), 8.14 (dd, J=8.2, 1.4 Hz, 1H), 7.40 (dd, J=8.2, 4.7 Hz, 1H), 5.79-5.89 (m, 1H), 4.51 (q, J=7.1 Hz, 2H), 2.48-2.61 (m, 2H), 2.07-2.20 (m, 4H), 1.70-1.83 (m, 2H), 1.46 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:24]([CH3:25])[S:26][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Solvent: CO
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)sc1CC2
Yield: 34 %

Procedure:
To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.78 mmol) in 10 mL CH3OH is added thioacetamide (1.55 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. The brown oil is chromatographed using EtOAc 1: hexane 1, followed by 5% MeOH in CH2Cl2 as mobile phases to yield 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (34%). 1H NMR (DMSO-d6) 1.27 (t, 3H), 2.60 (s, 3H), 2.78(t, 2H), 2.96 (t, 2H), 4.19 (q, 2H), 7.21 (s, 1H), 11.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([O:11]C)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (8.9 g, 37 mmol, from Oakwood) in methylene chloride (200 mL) was added 1.0 M boron tribromide in methylene chloride (38.4 mL, 38.4 mmol) at −78° C. After stirring at −78° C. for 10 minutes, the reaction was allowed to warm up to 0° C., quenched with water at 0° C., and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. After evaporating to dryness under reduced pressure, the residue was used directly in next step (8.2 g, 98%). LCMS calculated for C9H9ClNO4 (M+H)+: m/z=230.0. found: 230.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16][C:15]=1[NH2:21].CCN(CC)CC>O=S(Cl)Cl>[NH2:21][C:15]1[N:16]=[CH:17][C:18]([NH:20][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:19][N:14]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1cnc(N)nc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methyl-5-nitrobenzoic acid (659 mg, 3.64 mmol) was heated to reflux in SOCl2 (6 mL) for 1 h. After cooling to room temperature and concentrating to dryness, the crude acid chloride was taken up in CH2Cl2 (25 mL). Pyrimidine-2,5-diamine 7 (400 mg, 3.64 mmol) was added to the solution and the mixture was allowed to stir at rt over night. The mixture became a thick white suspension. NEt3 (700 □L, 4.73 mmol) was added. After 2 h, a thick-white suspension remained. The mixture was filtered through a Buchner funnel and washed with copious amounts of CH2Cl2 to remove NEt3HCl salt, affording N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>>[CH:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Product: COc1cc2c(cc1C)C(C(C)C)=CCC2(C)C
Yield: 52.2 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30) (1.5 g, 6.9 mmol) was reacted with a solution of 2 M isopropylmagnesiumchloride (17 mL, 34.5 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.88 g (53%) of the title product as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([F:16])[C@@:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:17])[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd].[H][H]>[C:22]([O:21][C:19]([NH:18][C@@:13]1([CH3:17])[CH:14]([F:16])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@]1(C)CNCC1F

Procedure:
To a solution of (3R)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)-4-fluoro-3-methylpyrrolidine (isomer B) (304 mg, 0.863 mmol) in ethanol (12 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 30.0 mg), and the suspension was stirred for 2 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 182 mg (97%) of the crude target compound (isomer B) as a colorless transparent syrup substance.