Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:9][C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Yield: 91.5 %

Procedure:
Benzyl bromide (12.9 ml, 0.108 mol) was added to a suspension of 2-hydroxy-3,4-dimethoxybenzaldehyde (19 g, 0.104 mol) and potassium carbonate (14.41 g, 0.104 mol) in acetone (200 ml) and the reaction stirred at reflux for 3 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (150 ml) and dichloromethane (150 ml). The organic layer was filtered through silica, washing through with hexane and then ethyl acetate. Evaporation of the filtrate under reduced pressure gave a yellow gum. The crude product was purified on silica gel eluting with ethyl acetate:hexane (30:70 v/v) to give the subtitle compound (25.9 g, 88%). Rf 0.82 (ethyl acetate:hexane 1:1, v/v). MS m/z 273 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.[Cu]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
3.12 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved in 50 ml of absolute dimethylformamide and combined with 0.3 g of sodium hydride (80% strength in white oil). The mixture is stirred for 30 minutes and then 1.26 g of 2-chloropyrimidine in 25 ml of dimethylformamide is added dropwise thereto. The reaction mixture is combined with a pinch of powdered copper and stirred for one week under argon at room temperature. The solution is then poured into 300 ml of ice water, the product is extracted with ethyl acetate, the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from glacial acetic acid/ether, thus obtaining 2.87 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidylthio)imidazole, mp 86°.
Reaction SMILES: COC([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:6]1)=O.N.Cl>O1CCOCC1>[N+:17]([C:14]1[O:13][C:12]([C:7]2[C:8]([CH:10]=[O:11])=[CH:9][NH:5][N:6]=2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: COC(=O)n1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a suspension of 9.1 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4 -carboxaldehyde in 80 ml of dioxan add dropwise at 5° to 8° C 33.4 ml of concentrated ammonia solution. Stirr the resulting admixture for 15 minutes before acidifying it with 2N hydrochloric acid to a pH value of 2. Distill off the greater part of the dioxan in vacuo. Mix the residue with 100 ml of water. Draw off the precipitate and wash it with water to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde [melting point: 179° to 185° C] with a yield of 78%.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:24][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Br)c2CC1)NCCC3
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C
Reaction time: 13 h

Procedure:
To a solution of 460 mg of t-butyl 11-bromo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 9 ml of dioxane were added 1.6 ml of a 2 M aqueous potassium carbonate solution under an argon atmosphere, and subsequently 449 mg of trimethylboroxine and 70 mg of tetrakistriphenylphosphine palladium, followed by stirring at 90° C. for 13 hours. The reaction mixture was allowed to cool, filtered, and then concentrated under reduced pressure, the resulting residue was diluted with EtOAc, and the organic layer was washed with water and saturated brine. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 380 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(Cl)cc1Cl
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](c3ccc(Cl)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
(2S,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (67 mg, 0.18 mmol) (from example 51, step 3) was diluted with hydrogen bromide (33% in AcOH, 948 μl, 5.41 mmol) and stirred at ambient temperature for 24 h. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(2,4-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (36 mg, 64%). 1H NMR (600 MHz, dmso) δ 1.46-1.54 (m, 1H), 1.77-1.85 (m, 1H), 1.93-1.99 (m, 1H), 2.05-2.11 (m, 1H), 2.67 (dt, 1H), 2.86-2.92 (m, 1H), 3.18-3.22 (m, 1H), 3.98 (dd, 1H), 5.93 (d, 1H), 7.40 (dd, 1H), 7.53 (d, 1H), 7.66 (d, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0499
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:26]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>CN(C=O)C>[NH:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:26]([C:31]([NH:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 76 %

Procedure:
5.0 g (14.0 mmoles) of H-Asp(OtBu)-D-Phg-NH2.HCl, prepared as described in Example 1, Step 4, and 5.13 g (14.2 mmoles) of Z-Leu-OSu are dissolved in 60 ml of DMF, and 1.96 ml (14.0 mmoles) of triethylamine are added to the solution. Next day the reaction mixture is evaporated in vacuo, and the residue is triturated with water. The resulting crude product, weighing 7.32 g, is recrystallized from ethanol under decolourizing. 6.05 g (77.7%) of Z-Leu-Asp(OtBu)-D-Phg-NH2 are obtained; m.p.: 192°-194° C., Rf4 : 0.75. A sample of the product melts as 195°-196° C. after recrystallization from ethanol; [α9 D : -69.5° (c: 1.0, in dimethyl formamide).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]([CH2:17][C:18]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:7]=1)=[O:5])C.C1(C2C=CC=CC=2)C=CC=CC=1CN1C2C(=NC=CC=2)C(=O)C(C(O)=O)=C1>>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]([CH2:17][C:18]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2cccnc2c1=O
Agent: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Product: O=C(O)c1cn(CC2(c3ccccc3)CCCC2)c2cccnc2c1=O
Yield: 33.5 %

Procedure:
4-Oxo-1-(1-phenyl-cyclopentylmethyl)-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (10) (310 mg, 33.46%) was synthesized as an off white solid from 1 g of 4-oxo-1-(1-phenyl-cyclopentylmethyl)-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (9) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (7).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([CH3:27])=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])=[N:5][C:4]=1[C:30]([F:33])([F:32])[F:31])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([CH3:27])=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])=[N:5][C:4]=1[C:30]([F:33])([F:31])[F:32])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(C(F)(F)F)c(CC)[nH]3)[C@H](OC)C2)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C)s3)C[C@H]2OC)nc1C(F)(F)F
Yield: 86.7 %

Procedure:
Ethyl cis(±)-2-(4-{[(5-ethyl-4-trifluoromethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40f) (29.2 mg, 0.060 mmol) was dissolved in methanol (1 mL). The solution was subjected to the same operation as in Example (36g) using a 1 N aqueous sodium hydroxide solution (1.5 mL), to obtain 24.0 mg of the title compound as a white solid (87%).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)([CH3:4])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[H][H]>[Pt].C(OCC)(=O)C>[NH2:16][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:6]=1[NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1c(N)cnc2ccccc12

Procedure:
A mixture of 17.7 g (0.0722 mole) of N-(1,1-dimethylethyl)-3-nitro-4-quinolinamine, 350 mL of ethyl acetate, 20 g of magnesium sulfate and about one gram of platinum on charcoal was hydrogenated on a Paar apparatus. After hydrogen pressure stabilized, the mixture was filtered and the filtrate was evaporated to provide a solid residue of 3-amino-N-(1,1-dimethylethyl)-4-quinolinamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][NH:11][CH2:12]2.[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][NH:24][C:23]=12.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28]([N:11]3[CH2:10][CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12]3)=[O:29])=[CH:25][NH:24][C:23]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2cccc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 70 h
Yield: 75.3 %

Procedure:
To a 250 mL flask was added 5-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.250 g, 10.7 mmol) and 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.75 g, 9.19 mmol). The mixture was diluted with DMF (100 mL) and Hunig's Base (16.6 mL, 95 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4 g, 12.46 mmol) was added to the mixture. The mixture was stirred at rt for 70 h, quenched with water (50 mL) and the solvent removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the residue purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The residue still had impurities by 1H NMR so it was dissolved in dichloromethane (150 mL) and washed with sat. NaHCO3 (100 mL) then with sat. ammonium chloride (150 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the solution was concentrated under reduced pressure to give 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (3.40 g, 6.92 mmol, 75% yield) as a blue solid. The product still had some impurities by 1H NMR, but was used in the next step with no additional purification. LC/MS: m/z 489.14 (M+H)+, 1.169 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 10.89 (br. s., 1H) 8.62-8.80 (m, 1H) 7.64-7.95 (m, 3H) 6.98-7.49 (m, 5H) 4.66-4.99 (m, 2H) 3.60-3.87 (m, 5H) 2.87-3.12 (m, 2H).
Reaction SMILES: C(OC(C1C(CO)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C.[C:28]([O:32][C:33]([CH:35]1[CH:41]([CH2:42][S:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)(=[O:52])=[O:51])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([CH:35]1[CH:41]([CH2:42][S:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH:39]=[CH:38][CH2:37][N:36]1[S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)(=[O:52])=[O:51])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CSc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(CO)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)OC(C)(C)C)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester was synthesized from 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert butyl ester in the same manner as the procedures used for the preparation of 1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-azepane-2-carboxylic acid tert-butyl ester: MS (M+H)+ =490, (M+NH4)+ =507.
Reaction SMILES: [Br:1][C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42]C)=[O:41])[C:3]=1[CH3:49].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[Br:1][C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:7][CH2:8][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:36][CH2:37]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([OH:42])=[O:41])[C:3]=1[CH3:49]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1Br)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 47 %

Procedure:
Prepared in 47% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. Prepared in 47% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.18-8.13 (m, 2H), 8.09 (s, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 7.18 (d, J=5.5 Hz, 2H), 5.82 (br. s., 1H), 4.63 (br. s., 1H), 3.86-3.77 (m, 1H), 3.60-3.54 (m, J=11.4 Hz, 1H), 3.49-3.40 (m, 3H), 2.67 (d, J=8.8 Hz, 1H), 2.50 (s, 3H), 1.94-1.48 (m, 10H), 1.19 (s, 3H), 1.15 (s, 9H), 1.08 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 721.3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:14]([NH:21][CH2:4][C:3]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzaldehyde (3 g, 11.9 mmol), benzylamine (1.94 mL, 17.8 mmol), and sodium cyanoborohydride (1.12 g, 17.8 mmol) were combined in MeOH (30 mL). Acetic acid (1.02 mL, 17.8 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and H2O. The aqueous layer was separated and extracted twice with CH2Cl2, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine.
Reaction SMILES: N1C=CN2C=1C(C(N)=O)=NC=C2.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([C:25]1[C:26](=[O:50])[C:27]([O:42]CC2C=CC=CC=2)=[C:28]2[C:33](=[O:34])[N:32]3[CH2:35][C@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C@@H:31]3[CH2:30][N:29]2[CH:41]=1)=[O:24].[OH-].[NH4+]>[Pd].C(O)C>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([C:25]1[C:26](=[O:50])[C:27]([OH:42])=[C:28]2[C:33](=[O:34])[N:32]3[CH2:35][C@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C@@H:31]3[CH2:30][N:29]2[CH:41]=1)=[O:24]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Agent: [Pd]
Agent: NC(=O)c1nccn2ccnc12
Agent: [NH4+]
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Yield: 78.4 %

Procedure:
(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,′: 3,4]imidazo[1,2-d]pyrazine-8-carboxamide. A pressure reaction vessel was charged with (4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (950 g), 192 g of palladium on carbon (50% wet), ethanol (9.5 L) and concentrated ammonium hydroxide (124 mL). The mixture was degassed with nitrogen 3 times and then placed under 50 psi of hydrogen until the reaction was complete. The mixture was degassed again with nitrogen and then filtered through Celite. The cake was extracted with refluxing dichloromethane and then filtered again. The combined filtrates were concentrated to a small volume (4 L), azeotroped with ethanol (28.5 L) to a final volume of 9 L. The slurry was filtered and washed with ethanol and dried to produce (4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′: 3,4]imidazo[1,2-d]pyrazine-8-carboxamide (616 g, 78.4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (m, 1H), 8.42 (s, 1H), 7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m, 1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60 (m, 4H).
Reaction SMILES: CC1C=C(C=C(C)C=1O)C#N.[C:12]([O:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([C:27](=[NH:30])[NH:28][OH:29])=[CH:22][C:21]=1[CH2:31]C)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]1[C:21]([CH3:31])=[CH:22][C:23]([C:27](=[NH:30])[NH:28][OH:29])=[CH:24][C:25]=1[CH3:26])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Agent: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C

Procedure:
The title compound is prepared starting from 3,5-dimethyl-4-hydroxybenzonitrile following steps b), c), d), and g) of the preparation of 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester; LC-MS: tR=0.75 min, [M+1]+=293.09.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>O1CCCC1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: Cn1nnnc1CCCC(O)=S
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=S)CCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (2 g) is dissolved in dry tetrahydrofuran (30 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes. To the mixture is further added dropwise with stirring diethylamine (0.9 g) at room temperature, and the mixture is stirred for 2 hours. The mixture is concentrated under reduced pressure, and the resulting residue is purified by subjecting it to column chromatography (Kieselgel 60, made by Merck & Co.). By eluting with n-hexaneethyl acetate (1:1), there is obtained N,N-diethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (1.4 g), colorless liquid, nD17.5 =1.5227.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Methyl 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoate (2.0 g, 4.9 mol) was dissolved in methanol (30 mL). A solution of lithium hydroxide monohydrate (0.41 g, 9.8 mmol) in water (8 mL) was added and the mixture heated to reflux for 1 hour. After cooling to room temperature, the methanol was removed in vacuo, the residue diluted with water and acidified to about pH 2 using dilute hydrochloric acid solution. The mixture was extracted with EtOAc, the combined extracts dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel using CH2Cl2 /MeOH (95/5) as eluent to give 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoic acid (1.70 g, 88%).