Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CC2OCCN(Cc3ccccc3)C2=O)cc1
Temperature: -78 °C

Procedure:
A solution of the N-benzyl morpholin-3-one (4.46 g, 23.4 mmol) obtained in (i) in tetrahydrofuran (25 ml) was added dropwise over a period of 15 minutes to a solution of lithium diisopropylamide (28.0 mmol [prepared from diisopropylamine (3.93 ml, 28.0 mmol) and n-butyl lithium (2.5 M in hexanes, 11.2 ml, 28.0 mmol)]) in tetrahydrofuran (50 ml), with stirring, at -78° C. The resulting solution was stirred for 45 minutes and then 4-tert-butylbenzyl bromide (6.0 ml, 32.7 mmol) in tetrahydrofuran (25 ml) was added dropwise over a period of 10 minutes. The reaction mixture was stirred for 90 minutes and then warmed to room temperature. Addition of water (25 ml) and saturated aqueous ammonium chloride (25 ml) was followed by extraction of the aqueous phase by ethyl acetate (3×20 ml). The combined organic phases were washed with brine (20 ml), dried with sodium sulphate and evaporated in vacuo. Flash column chromatography of the resulting oil upon silica gel using hexane: ethyl acetate (1:1) as eluant afforded the desired product as a clear, faintly yellow oil, 5.29 g, M+ found: 337.
Reaction SMILES: CO[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18].[BrH:19].C(O)(=O)C>O>[Br:19][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18]
Reactant: Br
Reactant: COCCCN1C(=O)CC(=O)Nc2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(=O)N(CCCBr)c2ccccc2N1
Temperature: 60 °C
Reaction time: 4.7 h

Procedure:
To 4.9 g of the compound of Example 208, 25 ml of 30% hydrobromic acid-acetic acid solution is added and the resulting mixture is stirred at 60° C. for 4.7 hours. The resulting mixture is poured into water and the resultant is subjected to extraction with ethyl acetate. The organic layer is washed with aqueous sodium carbonate solution and brine and dried. The resultant is purified by silica gel column chromatography (ethyl acetate) to obtain 3.3 g of (209).
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[C:17]1(N)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].O>CO>[NH:5]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=[C:4]1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: Nc1ccccc1N
Agent: CO[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.32 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (3 g; 19.21 mmol) in 20 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 3.4 g of 1,2-phenylenediamine bishydrochloride, the reaction mixture was stirred further overnight and then added to 100 ml of H2O, and the resulting solid was filtered off and dried in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:34][C@:31]12[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:36])([CH3:37])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19][C@@H:18]1[C@H:17]1[C@H:48]([C:51]([CH3:53])=[CH2:52])[CH2:49][CH2:50][C@:16]1([NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:33][CH2:32]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC3CCCN(C(=O)OC(C)(C)C)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CCCNC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 80.8 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (0.019 g, 0.026 mmol) in dichloromethane (1 mL) was added TFA (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 1.75 h then was concentrated under reduced pressure. The residue was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperidin-3-ylmethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (14.2 mg, 0.021 mmol, 81% yield) as a white solid. LCMS: m/e 627.6 (M+H)+, 1.50 min (method 2).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH:16]1[CH:21]=[C:20]2[C:22]([CH:25]=O)=[CH:23][S:24][C:19]2=[CH:18][CH:17]=1>CO>[CH2:9]([N:8]1[C:3]([NH:1][N:2]=[CH:25][C:22]2[C:20]3[CH:21]=[CH:16][CH:17]=[CH:18][C:19]=3[S:24][CH:23]=2)=[CH:4][C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1csc2ccccc12
Solvent: CO
Product: CC(C)Cn1c(NN=Cc2csc3ccccc23)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Hydrazino-1-isobutyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1.2 g, 5.65 mmol) was dissolved in methanol (100 mL). To the yellow/brown solution was added thianaphthene-3-carboxaldehyde (917 mg, 5.65 mmol). A brown precipitate began to form after about 20 min. The mixture was stirred at room temperature for 3 h under nitrogen gas. HPLC showed complete formation of hydrazone (Rt=1.87 min, Kromasil, C8) The solvent was removed in vacuo and the brown slurry was pumped down to reveal a brown/yellow powder. Yield=1.85 g (92%), TLC, Rf=0.14 (CHCl3/MeOH); Rt:1.87 min. MS:357 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:11].Br[CH2:20]Cl.C([Li])CCC>CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: ClCBr
Reactant: CC(C(=O)c1ccc(F)cc1F)c1cccnn1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(c1cccnn1)C1(c2ccc(F)cc2F)CO1
Yield: 56.8 %

Procedure:
Treatment of the product of part (ii) (2.0 g) with bromochloromethane (1.15 g) and n-butyllithium (5.28 ml of a 1.6M solution in hexane) according to the method of Example 11(iii) gave the title compound as a gum (1.20 g) which was used directly in the next stage.
Reaction SMILES: [N:1]1([C:8]([N:10]([CH2:12][CH2:13][N:14]([CH3:36])[C:15]([O:17][C@@H:18]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([O:21]CC2C=CC=CC=2)=[O:20])=[O:16])[CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:8]([N:10]([CH2:12][CH2:13][N:14]([CH3:36])[C:15]([O:17][C@@H:18]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:19]([OH:21])=[O:20])=[O:16])[CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Yield: 93.2 %

Procedure:
A solution of benzyl (2S)-2-[N-[2-{N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino}ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionate (1.43 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (0.2 g) at 3 atmospheric pressure of hydrogen gas for 1 hour at ambient temperature. The solution was filtered and concentrated in vacuo to give (2S)-2-[N-[2-{N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino}ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid (1.09 g) as an oil. Rf: 0.44 (chloroform:methanol:acetic acid, 16:1:1, V/V)
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:30]=1[CH:31]=O>C(O)(=O)C>[OH:28][C:29]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:30]=1/[CH:31]=[CH:1]/[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O
Reactant: O=Cc1cc(O)ccc1O
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(/C=C/c2cc(O)ccc2O)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compounds (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 2,5-dihydroxy benzaldehyde (30c, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4c) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10](=[O:29])[O:11][C:12]2[CH:25]=[C:24]3[CH2:26][CH2:27][CH2:28][C:23]3=[CH:22][C:13]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:10](=[O:29])[O:11][C:12]2[CH:25]=[C:24]3[CH2:26][CH2:27][CH2:28][C:23]3=[CH:22][C:13]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1c(NC(=O)OC(C)(C)C)c(=O)oc2cc3c(cc12)CCC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1c(N)c(=O)oc2cc3c(cc12)CCC3
Yield: 98.3 %

Procedure:
To a solution of 3-tert-butyloxycarbonylamino-4-(2methylphenyl) -7,8-dihydro-6H-cyclopenta [g] [1 ]benzopyran-2-one (2.05 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) dropwise with ice-cooling. The mixture was stirred under ice-cooling for 1 hour, after which the solvent was distilled off. The residue was diluted with water, neutralized with saturated aqueous solution of NaHCO3 and extracted with chloroform. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 3-amino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclopenta[g] [1]-benzopyran-2-one (1.5 g, 98.4%). Recrystallization from ethanol-dichloromethane gave colorless prisms, m.p. 275°-276° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>CC(C)=O.O=[Mn]=O>[C:12]1([C:9]2[O:10][C:11]3[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccc2nc(-c3ccccc3)oc12
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=Cc1cccc2nc(-c3ccccc3)oc12

Procedure:
10 mmol of the compound from Example XVI were boiled under reflux with 50 mmol of MnO2 (active) in 50 ml of acetone for 6 h, the solid was filtered off with suction and the filtrate was concentrated. The residue was recrystallized from isopropanol. M.p.: 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 17] (0.105 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.152 g), HOBT (0.107 g) and triethylamine (0.222 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.07 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, and ethyl acetate) to give the title compound (0.1 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: Brc1cccc2c1CCN2
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCc3c(Br)cccc32)cc1
Yield: 91.5 %

Procedure:
To 4-bromoindoline (200 mg, 1.00 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.14 ml, 1.1 mmol) then add NaH (40 mg, 1.0 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 280 mg (92%) of product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:17](OCC)=[O:18]>C(OCC)(=O)C>[CH:17]([NH:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:18]
Reactant: CCOC=O
Reactant: COC(=O)C(CN)c1cccc(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(CNC=O)c1cccc(OC)c1

Procedure:
The compound obtained in Step B (20.25 g; 0.08 mol), in the form of a base, is dissolved in 130 ml of ethyl formate (1.81 mol). The reaction mixture is heated at reflux for 6 hours and then evaporated under reduced pressure. The oil obtained is taken up in ethyl acetate. The organic phase is washed with basic water (NaHCO3), dried over magnesium sulphate, filtered and evaporated to yield the title product in the form of a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1cc(C2OCCO2)co1

Procedure:
As depicted in Scheme 13 above, a mixture of furan-3-carbaldehyde (1.20 mol), ethylene glycol (1.32 mol), p-toluenesulfonic acid (4.6 grams, 0.024 mol) and benzene (100 ml) is heated to reflux for 19 hours in a 500 ml round-bottomed flask fitted with a Dean-Stark trap, while water are removed from the mixture by azeotropic distillation. Once water ceases to condense, the reaction mixture is washed with saturated sodium bicarbonate (NaHCO3, 200 ml). The combined organic phase is washed with water (100 ml) and saturated sodium chloride (NaCl, 100 ml), dried over MgSO4, and then concentrated a rotary evaporator. The residual paste is purified by distillation at 80° C. and 10 Torr (1333 pascals).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C@@H:29]5[C@@H:33]([OH:34])[CH2:32][CH2:31][NH:30]5)=O)[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.CSC.B.B.CO>C1COCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][CH:23]([NH:26][CH2:27][C@@H:29]5[C@@H:33]([OH:34])[CH2:32][CH2:31][NH:30]5)[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NC(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NC[C@H]5NCC[C@@H]5O)CC4)n3)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
184 mg (0.39 mmol) of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid [6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]amide was dissolved in 5 ml of THF, and 579 μl of 2M borane dimethyl sulfide solution in THF were added at 70° C. under nitrogen atmosphere, and the mixture was subsequently stirred at 70° C. for 2 hours. 579 μl of borane/dimethyl sulfide solution was again added, and the mixture was heated in a heating block at 70° C. for a further 4 hours. In order to decompose the excess borane, 1 ml of MeOH was added dropwise. The reaction mixture was evaporated, and 1 ml of water and 1 ml of conc HCl were added to the oily residue. The mixture was stirred at room temperature for 2 h, rendered alkaline using 2 molar NaOH and extracted with ethyl acetate. The organic phase was dried and purified by column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.N(C1C=CC=CC=1)=[C:12]=[S:13].BrC1C=CC2N(C(S)=NN=2)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([SH:13])=[N:9][N:8]=2)[C:3]=1[CH3:10]
Reactant: Cc1nc(NN)ccc1F
Reactant: S=C=Nc1ccccc1
Agent: Sc1nnc2ccc(Br)cn12
Product: Cc1c(F)ccc2nnc(S)n12

Procedure:
The title compound was prepared from 3-fluoro-6-hydrazinyl-2-methylpyridine and isothiocyanatobenzene following the procedure described for the synthesis of compound 4A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:33][C:34](=[O:36])[CH3:35])[C@H:10]([OH:32])[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26])[CH:21]=3)[O:16][C:15]3([CH2:31][CH2:30][CH2:29]3)[CH2:14]2)=[CH:4][CH:3]=1.CC(O)=O>CO.C(O)(N=NC(O)=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:33][C:34](=[O:36])[CH3:35])[C@H:10]([OH:32])[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[CH:21]=3)[O:16][C:15]3([CH2:31][CH2:30][CH2:29]3)[CH2:14]2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)Cc1cnc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccc(Cl)cc1)NC(C)=O)CC1(CCC1)O2
Agent: O=C(O)N=NC(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)(C)Cc1cnc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccc(Cl)cc1)NC(C)=O)CC1(CCC1)O2

Procedure:
The compound of Example 492 (0.100 g, 0.196 mmol) was dissolved in MeOH (2 mL) and diazenedicarboxylic acid, dipotassium salt (0.762 g, 3.92 mmol) was added. HOAc (0.673 ml, 11.8 mmol) in MeOH (2 mL) was slowly added to the heterogeneous solution and the reaction was stirred. After all the acetic acid was added and the solution went from yellow to clear and upon complete reduction, the reaction was concentrated and partitioned between 1 N NaOH and DCM. The aqueous was layer was extracted with DCM and the combined organics were washed with brine and concentrated. The crude material was dissolved in a minimal amount of MeOH and directly purified by reverse phase HPLC to afford the title compound. MS m/z: 514.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[OH:9].Br[C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17].O>CN(C)C=O>[CH3:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[O:9][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1oc2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1c(C)oc2ccccc12
Reaction time: 0.25 h

Procedure:
To a suspension of 9 g of sodium hydride (50 percent in oil) in 150 ml of anhydrous dimethylformamide were added drop-by-drop and while stirring 22.2 g (0.15 mol) of 2-methyl-3-hydroxy-benzofuran, care being taken to maintain the temperature at about 30°-35°C. The reaction medium was stirred for a further 15 minutes and then 27.2 g (0.15 mol) of methyl α-bromoisobutyrate were added, the temperature being maintained at 35°-40°C. Stirring was continued for 24 hours at room temperature, the reaction mixture was poured into water and extracted several times with ether. The ethereal extracts were collected, washed with water and dried over anhydrous sodium sulphate.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][C:10]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: CC[C@H](C)COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC[C@H](C)COc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]

Procedure:
Quantities: compound 26 (3.00 g, 0.01 mol), concentrated sulphuric acid (18 ml), concentrated nitric acid (9 ml), glacial acetic acid (40 ml).