Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:55][C:56]1(C)[CH2:60]C(=O)[O:58][C:57]1=[O:62]>C(OCC)(=O)C>[CH3:55][C:56]([CH3:60])([CH2:2][C:1](=[O:3])[O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])[C:57]([OH:62])=[O:58]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-(morpholinomethyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 23, 0.15 g, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 1H); 2.77-3.58 (m, 11H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: [M+1] 750 (100%); HPLC: 98.08%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20].CCN(CC)CC.S(Cl)(Cl)(=O)=O>C1COCC1>[C:19]([C:21]1[CH:22]=[C:23]([S:27]([N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:17]=[C:16]([Cl:18])[CH:15]=2)[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (1.40 g, 4.91 mmol) in THF (15 mL) was added 3-cyanobenzene-1-sulfonyl chloride (0.9 g, 4.46 mmol) and Et3N (1.22 mL, 8.93 mmol) at rt for 2 h. Additional sulfonyl chloride (0.35 g) and Et3N (0.5 mL) were added. The reaction mixture was stirred at rt for 15 h. The mixture was concentrated and the residue was diluted with ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with brine, saturated aq NaHCO3 solution, dried over MgSO4, and concentrated to give a glassy material which was purified by flash silica gel column chromatography on silica gel (ISCO. Column: 24 g. Eluent: A: hexane. B: ethyl acetate. Condition: A to 25% of B (50 min gradient) to obtain the desired product as a white solid (1.8 g, 81%). 1H NMR (CDCl3): δ 8.08-8.02 (m, 2H), 7.93-7.90 (m, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.25-7.24 (m, 1H), 7.13-7.09 (m, 2H), 6.98 (t, J=8.0 Hz, 2H), 6.90 (d, J=4.0 Hz, 2H), 4.38 (s, 2H), 4.30 (s, 2H); MS (ESI): [M−H]−=506.9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>COCCOC.O>[Cl:1][C:2]1[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4]
Reactant: OB(O)C1CC1
Reactant: Cc1c(Br)cc(Cl)c(N)c1F
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C2CC2)cc(Cl)c(N)c1F
Temperature: 25 °C

Procedure:
2-Chloro-4-bromo-5-methyl-6-fluoroaniline (6.5 g, 27 mmol), cyclopropylboronic acid (2.8 g, 33 mmol), tetrakis (triphenylphosphine)palladium (0) (1.4 g, 1.3 mmol), potassium phosphate (20.2 g, 95 mmol) and tricyclohexylphosphine (0.77 g, 2.7 mmol) are combined and stirred in 200 mL of a 4:1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10×). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (250 mL) and water (250 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (8% CH2Cl2/hexanes) to give 2-chloro-4-cyclopropyl-5-methyl-6-fluoroaniline as a tan oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[NH2:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Br:56][C:57]1[CH:65]=[C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])[CH:63]=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C)C=O>[CH3:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:17][CH3:18])([O:19][CH3:20])=[O:16])[NH:14][C:59](=[O:60])[C:58]1[CH:62]=[CH:63][C:64]([C:66]([NH:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[CH:71]=2)=[O:67])=[CH:65][C:57]=1[Br:56]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Br)c1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisopropylethylamine (1.81 g, 14 mmol) was added to a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (5.00 g, 15.1 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.20 g, 13.7 mmol), 1-hydroxybenzotriazole (1.85 g, 13.7 mmol) and 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid (Example 79; 4.80 g, 13.7 mmol) in N,N-dimethylformamide (50 mL). After the reaction was stirred for 4 h at 25° C., the volatiles were removed in vacuo. A solution of the residue in ethyl acetate (200 mL) was washed with 1N hydrochloric acid solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the resulting residue was flash chromatographed over silica gel (ethyl acetate-3% methanol in ethyl acetate) to give rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (5.50 g, 76% yield) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCC(=O)Cl
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)NC1=NC(=O)C2=CC=NC2=N1
Temperature: 85 °C
Yield: 80.1 %

Procedure:
2-Aminopyrrolo(2,3-d)pyrimidin-4-one (6.0 g) is suspendeed in pyridine (80 ml) and, with stirring on an ice bath, n-octanoyl chloride (22.8 g) is added. The reaction mixture is warmed at 85° C. for 30 minutes and the solvent is distilled off under reduced pressure. Dilute hydrochloric acid is added to the residue and the mixture is extracted with chloroform. The extracts are combined and concentrated to dryness. The residue is dissolved in 8% (W/V) alcoholic ammonia (50 ml) and the solution is allowed to stand at room temperature to give the above-identified compound (8.9 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.Cl[C:13]1[C:22]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=2)[N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[C:22]([N:23]([CH:24]([CH3:26])[CH3:25])[CH3:27])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:14]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of (4-fluoro-2-methylphenyl)boronic acid (158 mg, 1.03 mmol) in dioxane (5.0 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol), K3PO4 (215 mg, 1.01 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol), and the reaction was stirred for 1 hour at 95° C. under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to provide a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (53.0 mg, 42%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:11]1[CH2:15][CH:14]([C:16](N2CCCC2)=[O:17])[CH2:13][C:12]1=[O:23])([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=[O:34])(C)(C)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:11]1[C:12](=[O:23])[CH2:13][CH:14]([C:16]([OH:17])=[O:34])[CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: CC(C)(C)C1CCCCC1N1CC(C(=O)N2CCCC2)CC1=O
Product: CC(C)(C)C1CCCCC1N1CC(C(=O)O)CC1=O

Procedure:
1-(2-tert-Butyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one was similarly prepared as described in Examples I, II, and VI. 2-tert-Butylcyclohexanone (commercially available at Alfa Aesar GmbH & Co. KG) was used to obtain 1-(2-tert-butyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (1 g, 3.74 mmol), which was subsequently used to provide 1-(2-tert-butyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one (1.1 g, 3.2 mmol).
Reaction SMILES: C(#N)C.O.C([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([Br:20])=[CH:18][CH:19]=2)[C:10]1=[O:22])(=O)C>ClCCl>[Br:20][C:17]1[N:16]=[C:15]([CH3:21])[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([OH:8])[C:10]2=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)OC1CCN(c2ccc(Br)nc2C)C1=O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Br)ccc1N1CC[C@@H](O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
To a jacketed 5.0 liter glass reactor was added 2.150 liter of acetonitrile and 250 mL of water (10%, 27.78 moles, ˜87 molar equivalent to acetate). The temperature was set to 25° C. Then, to the same reactor was added 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (50 g, 0.160 moles, 20 g/L), followed by 100 mL of acetonitrile The reaction mixture was stirred for 10 min at 90 rpm until complete dissolution. To the reaction mixture added 12.5 g of Novozym 435 (Enzyme to substrate 1:4) with continuous stirring under same reaction conditions. The temperature of the reaction was maintained at 25° C. during the course of the reaction. The reaction was stopped after 28 h, and the Novozym 435 was filtered. The reaction mixture was concentrated to dryness 30° C. to yield a viscous brownish liquid. The reaction mixture was taken out in 75 ml dichloromethane and stirred it at room temperature for 1 h. To the reaction mixture was added 100 g of silica gel, and slurry was then allowed to dry under pressure. A Column was packed with ˜400 g of silica gel in heptanes and slurry was loaded into column with heptane. The column was run using 50% ethyl acetate-heptane until all the undesired chiral acetate was recovered. After the removal of acetate, the column was eluted with pure ethyl acetate and the (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one containing fractions were combined. The mixture was concentrated down to 50 mL under pressure at 20° C., stirred for 30 min, filtered, and washed with heptane. 16.042 g of (R)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one was obtained, as off-white solid, AP 99.4, ee 99.9% in 37% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Yield: 97.6 %

Procedure:
(S)-1-Benzyl-3-hydroxypyrrolidine (1003.5 g, 5.66 mol) was dissolved in toluene (12 L) and the solution stirred and cooled to 0°-5° C. Triethylamine (680 g, 6.67 mol) was added followed by methanesulfonyl chloride (760 g, 6.63 mol) over a 4 hour period. A slurry formed after 30 minutes. The mixture was allowed to stir an additional 1.5 hours and 7% sodium bicarbonate (12 L) was added to the reaction mixture and the organic layer separated. The aqueous layer was extracted with toluene (4 L and 2 L) and the combined organic layers washed with saturated sodium bicarbonate (3×6 n) , dried over MgSO4 and concentrated under reduced pressure to give (S)-1-benzyl-3-mesyloxy-pyrrolidine as a yellow oil (1.41 kg, 98%): 1HNMR (CDCl3, 200 MHz): δ2.0-2.6 (m, 4H), 2.85 (d, 2H, J=5), 2.97 (δ , 3H), 3.65 (AB, 2H, J=3), 5.20 (m, 1H), 7.3 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:34])[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[O:4][N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1CSCCc1ccccc1

Procedure:
1-[4′-(3-Methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.2 g, 0.43 mmol) was dissolved in dioxane along with carbonyldiimidazole (0.2 g, 1.23 mmol), methanesulfonamide (0.14 g, 1.47 mmol) and Hünig's base. The reaction was heated to reflux overnight then cooled and submitted to standard aqueous workup. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@@H:9]([CH2:28][C:29](=[O:42])[N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:22])[C@@:13]1([CH:25]=[C:26]=[O:27])OC)=[O:11].C(=O)([O-])O.[Na+].[F:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1.Cl>O1CCOCC1.O>[F:48][C:49]1[CH:57]=[CH:56][C:52]([C:53]([NH:8][C@@H:9]([CH2:28][C:29](=[O:42])[N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:22])[C@H:13]2[CH2:25][C:26]([O:4][CH3:3])=[O:27])=[O:11])=[O:54])=[CH:51][CH:50]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CO[C@]1(C=C=O)C(=O)N(CC(=O)O)CCN1C(=O)[C@@H](N)CC(=O)N1CCN(c2ccncc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C[C@@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](CC(=O)N1CCN(c2ccncc2)CC1)NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R,S)-[4-[2-amino-4-oxo-4-[4-(pyridin-4-yl)piperazin-1-yl]butyryl]-3-methoxy-carbonylmethyl-2-oxopiperazin-1-yl]acetic acid trifluoroacetic acid salt (0.25 g) produced in Working Example 21, an aqueous solution of sodium hydrogen carbonate (0.15 g), water (2.5 ml) and 1,4-dioxane (2.5 ml) was added 4-fluorobenzoyl chloride (0.051 ml) and the solution was stirred for 1 hour at room temperature. The pH of the reaction solution was adjusted to 3 with 1N hydrochloric acid and the solution was concentrated under reduced pressure. The concentrate was purified by means of CHP-20 column chromatography (eluent:H2O→15% acetonitrile aqueous solution→20% acetonitrile aqueous solution→25% acetonitrile aqueous solution→30% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.10 g) as a white amorphous powdery product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:74]([NH:81][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(NCc3ccccc3)cccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D, 0.100 g, 0.192 mmol), Pd2(dba)3 (0.018 g, 0.019 mmol), Xantphos (0.022 g, 0.038 mmol), and toluene (1.922 ml). Benzylamine (0.042 ml, 0.384 mmol) was added and the reaction was stirred for one hour at 100° C. The reaction was filtered through a plug of diatomaceous earth, which was then washed with ethyl acetate. The filtrate was concentrated, dissolved in 1 mL of DCM, and TFA (0.1 ml, 1.298 mmol) was added. The reaction was concentrated and purified via HPLC (50-95% MeCN:H2O with 0.1% TFA modifier) to afford 5-(benzylamino)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.48 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0, 9.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 2H), 7.34-7.27 (m, 4H), 7.24-7.17 (m, 1H), 6.51 (dd, J=2.2, 6.6 Hz, 1H), 4.50 (s, 2H). m/z (ESI) 397.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.ClC(Cl)(O[C:9](=[O:15])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH:24]([C:26]1[C:31]([I:32])=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>ClCCl>[CH:1]1([NH:4][C:9]([NH:25][NH:24][C:26]2[C:31]([I:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: NNc1ncccc1I
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNc1ncccc1I)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 237.9 %

Procedure:
Cyclopropylamine (0.12 g, 2.2 mmol) in dichloromethane (3 mL) was added to a solution of triphosgene (0.22 g, 0.74 mmol) in dichloromethane (5 mL) at 0° C. under argon. Triethylamine (0.59 mL, 4.2 mmol) in dichloromethane (3 mL) was then added and the resulting mixture was stirred at room temperature for 2 hours and then cooled to 0° C. 2-Hydrazino-3-iodopyridine (preparation 26b, 0.50 g, 2.1 mmol) in dichloromethane (5 mL) was added and the resulting mixture was stirred at room temperature overnight. The solution was cooled to 0° C. and a solid precipitated. The solid was filtered, washed with diethyl ether and dried to yield the title compound (0.56 g, 83%) as a white solid.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12](O)=O)[NH:3]1.[C:15]1(=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[CH:17]=[CH:16]1.[C:27](OC(=O)C)(=O)C>>[CH3:27][C:16]1[N:3]2[CH2:2][C:11]3[C:6]([CH2:5][C:4]2=[C:12]2[C:17]=1[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[C:15]2=[O:26])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Product: Cc1c2c(c3n1Cc1ccccc1C3)C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
A mixture of 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid hydrochloride (4.0 g) and 1,4-naphthoquinone (5.5 g) in acetic anhydride (115 ml) was heated at 100° C. with stirring for 5.5 hours. The reaction mixture was cooled and the green crystalline solid was collected by filtration, washed with acetic anhydride and ether and dried. Recrystallisation from acetic anhydride afforded the title compound (3.5 g), decomposes 240°-245° C. (cap.) without loss of crystalline form λmax (in ethanol) 245 (ε60,470), 265.5 (ε15,270) and 386 nm (ε7706).
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([N:27]=[C:28]=[S:29])=[O:26]>C1COCC1>[C:16]([O:15][C:13]([C:3]1[C:4]2[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C:5]=2[S:12][C:2]=1[NH:1][C:28]([NH:27][C:25](=[O:26])[C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([O:21][CH3:20])[CH:23]=1)=[S:29])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cccc(C(=O)N=C=S)c1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 3-methoxybenzoyl isothiocyanate (0.20 g, 1.01 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl-2-(3-(3-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.32 g, 0.68 mmol, 68% yield) was isolated as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.71 (s, 1H), 9.06 (s, 1H), 7.51-7.49 (m, 1H), 7.44-7.40 (m, 2H), 7.19-7.13 (m, 1H), 4.74 (apparent t, J=1.5 Hz, 2H), 3.89 (s, 3H), 2.77 (apparent t, J=1.5 Hz, 2H), 1.64 (s, 9H), 1.31 (s, 6H).