Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([CH:12]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O>[CH2:7]([O:9][C:10]([C:12]1([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
6.7 g potassium carbonate was added to 7 g 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 50 mL DMF and stirred at RT. After 30 min 6.1 g ethyl bromoacetate was added and the reaction was stirred at RT over night. The reaction was diluted with water and extracted with ethyl acetate/hexane (1/1). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to give 5.6 g of the desired product.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[CH3:11][C:10]1[C:9]2[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:15]([Cl:16])[C:8]=2[O:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCCc1cc(Cl)c2oc(C(=O)OCC)c(C)c2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cl)c2oc(C(=O)O)c(C)c2c1O
Yield: 85.5 %

Procedure:
To a solution of 2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (22 gm, 0.074 mole) in methanol (1.2 liter) was added 2N sodium hydroxide (120 mL) and the resulting solution was refluxed for a period of 6 hours. The reaction mixture was concentrated in vacuo. The residue was acidified with 3N hydrochloric acid and then extracted with ethylacetate. The organic phase was dried (Na2SO4), concentrated in vacuo, and 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofurancarboxylic acid (17 gm; 88%) was isolated by filtering the solid after suspending in hexane; m.p.: 200°-203° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN2C(=O)CC2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC1CN2C(=O)CC2O1

Procedure:
(3RS, 5SR)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (150 mg, 0.89 mmol) was hydrogenated with 100 mg of 10% palladium on activated carbon in 25 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 1 hr. After removal of catalyst by filtration, (3RS, 5SR)-3-aminomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one in ethyl acetate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Yield: 92.1 %

Procedure:
A solution of the 22-4 (0.141 g, 0.268 mmol) in 25 mL absolute EtOH was treated with 10% Pd—C (0.015 g, 10% by wt) at room temperature under an argon atmosphere. Then ammonium formate (0.101 g, 1.61 mmol) was added and the heterogeneous mixture was refluxed for 30 minutes. The reaction was >50% complete (by ms). At this point, more Pd—C (0.008 g, 5% by wt) and NH4CO2 (0.050 g, 0.80 mmol) were added and the mixture refluxed for an additional 30. minutes (reaction complete by ms). The solution was then filtered through a Celite plug, washed with EtOH (75 mL), and concentrated in vacuo to afford 0.130 g 22-5.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH:23]=C)[CH:18]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH:23]=[O:29])[CH:18]=4)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c(-c3ccc(CCC)cc3)noc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(-c2noc3c2CCc2cc(C=O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 85 h
Yield: 92.2 %

Procedure:
To 3-(4-propylphenyl)-7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole (Preparation 20D, 0.205 g, 0.650 mmol) in THF (2 mL) were added sequentially N-methylmorpholine-N-oxide (0.3 mL, 0.650 mmol) and osmium tetroxide (0.102 mL, 0.013 mmol) at room temperature. The contents were stirred at room temperature for 85 h. Next, sodium periodate (0.209 g, 0.975 mmol) dissolved in 1.5 mL of water was added at room temperature and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (20 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazole-7-carbaldehyde (0.19 g, 0.599 mmol, 92% yield) as a tan solid. LCMS M+1=318.2.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][C:26](=[O:27])[CH:25]=[CH2:24])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)Oc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
5 g (22 mmol) 2-hydroxy-9H-thioxanthen-9-one was dissolved in 100 acetone. 50 mg BHT, 10.6 g 77 (mmol) K2CO3 and 5.6 g (44 mmol) 3-chloropropionyl chloride were added. The mixture was refluxed for 3 hours. The salts were removed by filtration after cooling down to room temperature and the solvent was removed under reduced pressure. The residue was treated with 100 ml water and the crude 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester was isolated by filtration. 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester was further purified using preparative column chromatography on a Prochrom LC80 column, using Kromasil Si 60A 10μ as silica and methylene chloride as eluent at a flow rate of 150 ml/min. 1.16 g of 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester (19%) was isolated. The isolated compound had a purity of 99%. This analysis was confirmed by 1H-NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 303 (M+, 52), 302 ([M—H]+, 74), 286 (30), 108 (100), 92 (63), 65 (52).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:12][C:13]([NH2:15])=[S:14])[CH3:11].[O-]CC.[Na+].[C:20]([CH2:22][C:23](OCC)=[O:24])#[N:21].S(=O)(=O)(O)O>CCO.O>[NH2:21][C:20]1[N:12]([CH:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:11])[C:13](=[S:14])[NH:15][C:23](=[O:24])[CH:22]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(NC(N)=S)c1nc2ccccc2[nH]1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(c1nc2ccccc2[nH]1)n1c(N)cc(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.7 %

Procedure:
To a suspension of N-[1-(1H-benzimidazol-2-yl)ethyl]thiourea (0.33 g, 1.5 mmol, obtained from Example 9(a)) in EtOH (2 mL) was added, dropwise, sodium ethoxide (21% w/w, 1.67 mL, 4.5 mmol) and a solution of ethyl cyanoacetate (0.48 mL, 4.47 mmol) in EtOH (1 mL), while heating the reaction to 80° C. during 1 h 20 minutes. The reaction was kept at 80° C. for an additional 2 h 40 minutes. After cooling to r.t., water (50 mL) and 2M sulphuric acid was added. The formed solid was collected by filtration, washed with H2O and dried to give the title compound (0.21 g, 50%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([CH2:19][CH2:20][C:21](O)=O)[CH2:18]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH:18]2[CH2:13][CH2:19][CH2:20][CH2:21]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: O=C(O)CCC1CCCCC1
Product: O=C(CCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanebutyric acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[OH-].[Li+].[H][H]>O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (20 g) in water (100 ml) was adjusted to a pH of 8 by the addition of 1N lithium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmosphere hydrogen pressure, using a palladium-on-carbon catalyst (0.6 g catalyst containing 10% pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino- 4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the filtrate by the addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol and drying, the melting point was 255°-256°C.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.CCCC[N+](CCCC)(CCCC)CCCC.[OH-].O.CC1C=CC2C(=C([OH:63])C=CC=2)N=1>CS(C)=O.[Cu]I>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:17]1[C:2]([OH:63])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: Cc1ccc2cccc(O)c2n1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@H](N)COc1cc2c(cc1O)c1ccncc1c(=O)n2C
Temperature: 120 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.099 mmol) (as prepared in Ex. 3, Part A), tetra-N-butylammonium hydroxide. 30H2O (0.463 g, 1.784 mmol) and water (1.5 mL) was added over 0.1 h to a stirred solution of copper(I) iodide (1.89 mg, 9.91 μmol) and 2-methyl 8-quinolinol (3.16 mg, 0.020 mmol) in DMSO (1 mL). The reaction mixture was heated to 120° C. and stirred for 14 h. The resulting mixture was cooled to room temperature. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate) to afford a (S)-8-((2-amino-4-methylpentyl)oxy)-9-hydroxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.004 g, 0.011 mmol, 12% yield) as a brown solid. LC/MS (ESI) m/e 342.2 [(M+H)+, calcd for C19H24N3O3, 342.2]; HPLC retention time (method F): tR=1.62 min. HPLC retention time (method B): tR=5.88 min. 1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 8.62 (d, J=6.00 Hz, 1H), 7.96 (d, J=5.60 Hz, 1H), 7.56 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.67-3.70 (m, 1H), 3.49-3.59 (m, 2H), 1.81-1.85 (m, 1H), 1.56-1.63 (m, 2H), 1.05 (d, J=6.80 Hz, 3H), 0.98 (d, J=6.80 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:29][CH:30]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:13][C:14]1[CH:18]=[C:17]([NH:19][S:20]([C:23]2[S:24][C:25](Br)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[O:16][N:15]=1>>[CH3:13][C:14]1[CH:18]=[C:17]([NH:19][S:20]([C:23]2[S:24][C:25]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[O:16][N:15]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)on1
Yield: 20.9 %

Procedure:
N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 3-nitrobenzene boronic acid (362 mg, 2.17 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (700 mg, 2.17 mmol). Purification by column chromatography using 10% MeOH/CHCl3 gave 166 mg of the pure sulfonamide (21% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([O:13][C@@H:14]([C@H:16]2[CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[C:18](=[O:29])[CH2:17]2)[CH3:15])[C:5]2[N:6]([CH3:10])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:12]=[C:11]([O:13][C@@H:14]([C@H:16]2[CH2:20][NH:19][C:18](=[O:29])[CH2:17]2)[CH3:15])[C:5]2[N:6]([CH3:10])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2cc(Br)cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccccc4)C3)c2n1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(Br)cc(O[C@H](C)[C@H]3CNC(=O)C3)c2n1C

Procedure:
(R)-4-((R)-1-(5-bromo-1,2-dimethyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one in TFA (3 mL) was heated in a microwave reactor for 3 h at 140° C. The reaction mixture was then concentrated to give (R)-4-((R)-1-(5-bromo-1,2-dimethyl-1H-benzo[d]imidazol-7-yloxy)ethyl)pyrrolidin-2-one which was used for next step without further purification. LC/MS found for C15H18BrN3O2 as (M+H)+ 353.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]#[N:24]>>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1/[C:22](=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)/[C:23]#[N:24]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: N#CCc1nc2ccccc2s1
Product: Cn1cc(/C=C(\C#N)c2nc3ccccc3s2)c2ccccc21
Yield: 100.3 %

Procedure:
1-Methylindole-3-carboxaldehyde (79 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 157 mg, 99%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])=[O:25])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
To a solution of 26.9 g of 1,3-benzodioxole-5-sulfonamide in 100 ml of acetone was added 150 ml of a 1N sodium hydroxide solution. A solution of 26.4 g of 4-chlorophenylisocyanate in 85 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for 18 hours, the reaction mixture was filtered and 150 ml of 1N hydrochloric acid were added to the filtrate, thereby providing a precipitate. One liter of water was added, and the solid was recovered by filtration to provide the desired title product in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:17])[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2

Procedure:
103 G. of 8-fluoro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one are suspended in 550 ml. of ethanol and treated with 24.3 g. of sodium borohydride. The mixture is heated under reflux for about 10 minutes. After the addition of water, the mixture is extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate, evaporated, and there is obtained 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol as an oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:31][CH3:32])[CH2:25][C@@H:26]([CH:28]2[CH2:30][CH2:29]2)[OH:27])[C:5]1=[O:33])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH2:25][C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C[C@H](O)C2CC2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-one prepared above in Step A (175 mg, 0.350 mmol) and water (9.5 μL, 0.52 mmol) in DCM (3.9 mL) was added Dess-Martin periodinane (222 mg, 0.524 mmol) at rt. After being stirred at rt for 40 min, the reaction was quenched (1 M aq. Na2S2O3), extracted (2×DCM), and washed (2×sat. NaHCO3 and 1×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 15% and 25% EtOAc/Hex) provided the title compound as a colorless film.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cccc([C@H]2C[C@H]2C(=O)O)c1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Cis-2-(3-nitrophenyl)cyclopropanecarboxylic acid (355 mg, 1.7 mmole), described in Example 21, was dissolved in 50 ml ethanol and 20 mg of PtO2 was added. Hydrogenation at atmospheric pressure for 1 hr. followed by filtration and evaporation of the solvent afforded 288 mg of cis-2-(3-aminophenyl)cyclopropanecarboxylic acid. 177 mg (1 mmole) of cis-2-(3-aminophenyl)cyclo-propanecarboxylic acid was dissolved in water (1 mL), t-BuOH (1 mL) and 2M NaOH (0.5 mL, 1 mmole). 250 μL (1.1 mmole) of di-tert-butyl dicarbonate was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and water and acidified with dilute H2SO4 and extracted with dichloromethane affording 264 mg of pure BOC protected cis-2-(3-aminophenyl)-cyclopropanecarboxylic acid. This acid was transformed to BOC protected title compound according to the Procedure in Example 7. Finally, deprotection with THF 1 and 6M HCl 1 gave the title product. Analysis: Calculated: C 59.5, H. 5.0, N 18.5.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:1]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC
Reaction time: 2 h
Yield: 38 %

Procedure:
A magnetically stirred mixture of veratraldehyde (9.00 g., 93% pure), hydantoin (5.00 g.), fused, anhydrous sodium acetate (10 g.) and glacial acetic acid (20 ml) was refluxed (bath temperature 160°-165°) for 1.5 hours (solution within 5 minutes, crystallization during heating period). On cooling, water was added. The mixture was stirred for 1 hour, refrigerated 2 hours, filtered, washed with water and dried overnight at 55°/10 mm. The title compound was obtained as a yellow solid: 4.72 g. (38% yield) m.p. 280°-282°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)OCc1ccccc1

Procedure:
In one example, 4-chloro-3-nitroaniline reacted with CbzCl in dichloromethane in the presence of diisopropylethylamine. The product benzyl 4-chloro-3-nitrophenylcarbamate was isolated following flash chromatography. Following procedures in Examples 12, 13, and 15, final product benzyl 1-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxalin-6-ylcarbamate was isolated following reverse-phase HPLC with C(18) column eluting with water and acetonitrile. The product of the reaction, benzyl 1-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxalin-6-ylcarbamate, is a compound of formula I in which R1 is —CH2CH2NHAc, R2 is benzyloxycarbonyl, R3 is 4-methoxyphenyl.