Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][C:4]1[NH:5][C:6]2[C:11]([C:3]=1[CH2:1][CH3:2])=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2
Reactant: CCc1c[nH]c2cc(C(=O)OC)ccc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCc1c(Cl)[nH]c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-ethylindole-6-carboxylate (138 mg) in dichloromethane (5 ml) was added sulfuryl chloride (0.066 ml), and the mixture was stirred at 20° C. for 1 hour. The resulting mixture was poured into ice and extracted with ethyl acetate. The combined organic phase was washed with aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to give methyl 2-chloro-3-ethylindole-6-carboxylate (58.2 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:47].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:40])[CH3:41])[O:13][N:12]=1)=[O:47]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CSc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (20 mg, 0.033 mmol) in dichloromethane (1 mL) at 0° C. was added meta-chloroperoxybenzoic acid (15 mg, 0.066 mmol). The mixture was stirred at 0° C. for approximately 30 minutes. Aqueous sodium bicarbonate was added and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution) to afford ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (12 mg, 0.019 mmol, 57%). 1H-NMR (400 MHz, CDCl3) δ 8.39 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz, 2H), 8.05-8.03 (m, 2H), 7.68 (d, J=9 Hz, 2H), 7.31 (s, 3H), 7.07 (d, J=9 Hz, 2H), 5.10-4.90 (m, 2H), 4.80-4.58 (m, 2H), 3.22 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). LRMS m/z 623 (M+H)+.
Reaction SMILES: [C:1]([S:5](/[N:7]=[CH:8]/[C:9]1[N:17]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])=[O:6])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>O>[CH3:3][C:1]([CH3:4])([S:5]([NH:7][CH2:8][C:9]1[N:17]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])=[O:6])[CH3:2]
Reactant: COC(=O)c1cc2n(c1/C=N/S(=O)C(C)(C)C)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2n(c1CNS(=O)C(C)(C)C)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 238a (4.0 g, 12.8 mmol, 1.0 eq.), NaBH4 (2.9 g, 76.9 mmol, 6.0 eq.), and methanol (100 mL). The reaction mixture was stirred at room temperature for 1 h. After this time water (50 mL) was added to the reaction and the resulting mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (3×50 mL). The combined organic layer was evaporated under reduced pressure to afford 238b (3.9 g, 96%), which was directly used in next step without further purification. MS: [M-C4H10NOS]+ 192.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:18]([OH:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.[I+].[Cu+]>[C:18](=[O:26])([S:25][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: OC(=S)c1ccccc1
Agent: [Cu+]
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [I+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C(Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-iodo-1H-indazole (103e, 0.224 g, 0.66 mmol), thiobenzoic acid (0.093 ml, 0.79 mmol), 3,4,7,8-tetramethyl-1,10-phenantroline (0.031 g, 0.13 mmol) and N,N-diisopropylamine (0.220 ml, 1.32 mmol) in toluene (2.5 ml) was added copper(I) iodine (2.245 μl, 0.07 mmol). The resulting mixture was stirred at 110 C O/N. The reaction mixture was cooled to r.t. diluted with EtOAc and washed with water. The organic phase was the dried the solvent evaporated and then purified on HPLC. The relevant fractions were collected freezdried to give 45 mg of product (20% yield) which was analysed by LC/MS.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:35])(=[O:34])[N:22]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)(=[O:35])=[O:34])=[CH:28][CH:29]=1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a solution of 4-{5-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (66 mg, 130 μmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2M NH3 in MeOH to give 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol). To a solution of 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol) in DCM (5 mL) was added DIPEA (35 μL, 202 μmol) followed by methane sulfonylchloride (1 mL of a 78 μL, 1 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 30 minutes. Water and saturated NaHCO3 were then added, extracted, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give the title compound (49 mg). 1H NMR (400 MHz, DMSO): δ 8.03 (d, J=2.52 Hz, 1H), 7.54 (d, J=7.47 Hz, 1H), 7.35 (dd, J=8.95, 2.54 Hz, 1H), 7.17 (t, J=8.01 Hz, 4H), 6.51 (d, J=8.98 Hz, 1H), 3.91 (br s, 1H), 3.51 (d, J=11.88 Hz, 2H), 3.25 (d, J=7.31 Hz, 2H), 2.86 (m, 5H), 1.97 (d, J=12.65 Hz, 2H), 1.44-1.49 (m, 2H), 0.82 (d, J=6.63 Hz, 6H). LCMS (m/z, Method B) ES+ 485.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([N:24]=[N+]=[N-])([Cl:23])[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Zn].C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([NH2:24])([Cl:23])[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=NNC(Cl)(N=[N+]=[N-])C=C1Nc1ccc(Br)cc1F
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=NNC(N)(Cl)C=C1Nc1ccc(Br)cc1F
Reaction time: 3 h

Procedure:
To the stirred solution of 6-azido-4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (122 mg, 0.30 mmol) in 5 ml of mixed solvents (3:1 v/v, dichloromethane/acetic acid) is added zinc powder (98 mg, 1.5 mmol) at room temperature. After three hours, the reaction mixture is poured into ethyl acetate (50 μl). The organic layer is washed with water, saturated NaHCO3 (30 ml×3) and saturated NaCl (30 ml×3). The organic layer is dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][C:21]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:35][C:32]2[CH:31]=[CH:30][C:29]([C:21]([CH3:22])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:20])=[CH:34][CH:33]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-(1-methyl-1-phenyl-ethyl)-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].C(Br)C>>[CH2:18]([O:20][P:21]([CH2:15][C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:17])(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19]
Reactant: O=C(CBr)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOP(=O)(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCC

Procedure:
A solution of 168.0 g (0.56 mol) (R)-4-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one and 188.6 mL (1.1 mol) of triethylphosphite was stirred for 1.5 h at 60° C., while the ethylbromide formed was distilled off. The reaction mixture was concentrated by evaporation i. vac. and the residue remaining was purified by chromatography on silica gel. The desired product was obtained in the form of a yellowish-brown oil.
Reaction SMILES: [Na+].[Br-:2].N[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([OH:8])=[O:7].N([O-])=O.[Na+].[OH-].[Na+].C>Br.O.CCOCC>[Br:2][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [Br-]
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Cuprous bromide was prepared by heating a deep purple solution of CuSO4.5H2O (33 mmol, 8.25 g) and NaBr (66 mmol, 6.75 g) in HBr (33 mL, 48%) and adding Cu powder (66 mmol, 4.2 g) in portions until the purple solution became a colorless solution. This solution was then added in portions to a hot solution (ca.90° C.) of 2-amino-6-methylbenzoic acid (33 mmol, 5 g) in H2O (80 mL) and HBr (11.5 mL). This was followed by the dropwise addition of a solution of NaNO2 (99 mmol, 6.85 g) in H2O (20 mL) to this stirred heated solution over a period of 25 min. The dark-brownish mixture was heated at ca.90° C. for 1 hr and then was heated at reflux for another 30 min before it was cooled to room temperature and stirred for 2 hr. Then, the mixture was poured into ice (˜500 g), 5% NaOH solution was added until pH 14 was reached and the resulting dark suspension was filtered through celite. The yellow filtrate was acidified with conc. HCl to pH 1. Extractive work-up (Et2O, 3×150 mL) gave a dark residue which was dissolved in Et2O (100 mL), charcoal was added and the resulting solution was heated to reflux. Filtration and concentration gave a material which was recrystalized from Et2O/petrolium ether in hexane (100 mL) to afford the 2-bromo-6-methylbenzoic acid (3.5 g, 49%, HR MS: Obs. mass. 213.9633. Calcd. mass. 213.9629, M+) as a crystalline light pink solid; mp 104-106° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C@@H:48](O)[CH3:49])=[CH:44][CH:43]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C@H:48]([N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[C:3]([C:18]([O:20][CH3:21])=[O:19])[C:4]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)=[C:5]3[CH:10]=[CH:9]2)[CH3:49])=[CH:44][CH:43]=1
Reactant: C[C@H](O)c1ccc(F)cc1
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc2c(ccn2[C@H](C)c2ccc(F)cc2)c1-c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
A suspension of methyl 6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (117 mg, 0.417 mmol) (Example 1, Step F) and triphenylphosphine (175 mg, 0.668 mmol) in tetrahydrofuran (THF) (3960 μl) under N2 was treated with (S)-1-(4-fluorophenyl)ethanol (84 μl, 0.668 mmol), heated to 65° C., and treated with DIAD (130 μl, 0.668 mmol). After stirring for 30 min, the reaction was cooled to rt, then concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) afforded (R)-methyl 1-(1-(4-fluorophenyl)ethyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (18.6 mg, 0.046 mmol, 11.07% yield) as pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.37 (d, J=8.1 Hz, 2 H), 7.32-7.18 (m, 4 H), 7.14 (d, J=3.7 Hz, 1 H), 7.03-6.94 (m, 2 H), 6.40-6.28 (m, 2 H), 3.62 (s, 3 H), 2.68 (s, 3 H), 2.41 (s, 3 H), 1.88 (d, J=7.2 Hz, 3 H); LCMS (m/z) ES+=403 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19].Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>ClCCl>[CH2:24]([N:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:31])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](CC(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 255B (31.28 g, 126.6 mmol) in dichloromethane (500 mL) was added N-benzylglycine ethyl ester (24.46 g, 126.6 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (24.3 g, 126.6 mmol), and pyridine (70 mL). After addition of the reagents, the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The solution was concentrated and then partitioned between ethyl acetate and HCl (1 M, aqueous). The organic solvent was collected, and the aqueous again washed with ethyl acetate. The organic solvent was combined, washed with K2CO3 (2 M aqueous), washed with brine, and dried with MgSO4. Concentration of the dried solution afforded the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10]3=[C:11]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.[CH:27](=O)C1C=CC=CC=1>>[CH2:19]([C:17]1[C:16](=[O:26])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]([CH:18]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:2]3[CH3:1])[C:20]1[CH:21]=[CH:27][CH:23]=[CH:24][CH:25]=1
Reactant: CN1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Reactant: O=Cc1ccccc1
Product: CN1c2ccccc2-n2cc(Cc3ccccc3)c(=O)c3cccc1c32
Yield: 30 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 15<step 3> was reacted with benzaldehyde (0.13 mL) to obtain the title compound (102 mg; 30%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.N([O-])=O.[Na+].N(O)=O.[BrH:19]>O>[Br:19][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: Br
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=NO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2cc(Br)ccc21
Reaction time: 0.5 h

Procedure:
A mixture of 16.8 gm 5-aminophthalide in 34 ml 48% aqueous hydrobromic acid was cooled to 0° in an ice bath and a solution of 7.8 gm sodium nitrite in 15 ml water was added at less than 5°, using internal ice cooling as necessary. The nitrosation mixture was stirred for an additional 30 minutes at about 0° with an excess of nitrous acid (positive to starch-iodide test paper). After 30 minutes, the diazonium salt was added portion wise over about 35 minutes to a mixture of 28.2 gm freshly prepared cuprous bromide and 18 ml 48% aqueous hydrobromic acid at room temperature (the bulk of the diazonium salt was maintained at about 0°). The temperature of the reaction mixture rose to about 38° and considerable frothing occurred. The mixture was stirred for an hour, then the product was filtered off and washed neutral with water. After recrystallization from 100 ml isopropanol the product weighed 15.7 gm and melted at 153°-157°.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:5]1=[O:24])=[N+]=[N-].N1C2C=CC=CC=2NCCC1>>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]([CH2:20][CH:21]2[CH2:22][CH2:23]2)[C:5]1=[O:24]
Reactant: [N-]=[N+]=NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: c1ccc2c(c1)NCCCN2
Product: NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Temperature: -23 °C

Procedure:
Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-1,5-bis-cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared as a white solid. Purification was by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in the MeOH) followed by recrystallization from warm CH2Cl2/hexanes (1:1) to −23° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)[C:12](Cl)=O>C1C=CC=CC=1>[C:8]([C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1)(=[O:10])[C:12]1[CH:11]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)n1
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
To 15 g of 6-methyl-2-pyridylcarboxylic acid (122 mmol) in 200 ml benzene is added dropwise 19.1 g (150 mmol) oxalyl chloride (dissolved in 30 ml benzene) with ice bath cooling. The solution is allowed to come to RT and is stirred 1 hour, after which it is stripped, 100 ml of benzene is added, and it is stripped again. The residue is taken up in 200 ml benzene and 41 g of aluminumtrichloride (310 mmol) is added in portions over a 3 hour period with ice bath cooling. The solution is heated to 25° for 1 hour, then heated to reflux for 2 hours, and finally cooled and stirred overnight. The mixture is poured onto ice/conc. HCl, then washed with ether. Fifty Percent (50%) sodium hydroxide is added until the precipitate is dissolved. The solution is extracted with CHCl3, washed with water, dried and stripped, leaving 6-benzoyl-2-methylpyridine.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([CH3:22])[C:16]1=[NH2+:23].[OH-].[Na+].[Cl:26][CH2:27][C:28](OC)=O>C(O)C>[Cl:26][CH2:27][C:28]1[N:23]=[C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C)n2nc(CCl)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A mixture of 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (2.0 g, 5.9 mmol) and sodium hydroxide (480 mg, 12 mmol) in ethanol (20 mL) was stirred at 60° C. for 1 h; methyl 2-chloroacetate (1.34 g, 12.4 mmol) was then added slowly. The reaction mixture heated at reflux for 4 h, then the solvent was removed. The product was purified by column chromatography to give 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine as a yellow solid (420 mg). MS (ESI): m/z 197 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCC2Cc3ccc(CC(=O)O)cc3C2)cc1
Yield: 79.4 %

Procedure:
1.95 g of [2-[(4-nitrophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid obtained in Example 22 was dissolved in 50 ml of methanol and added with 200 mg of 10% palladium on carbon, followed by stirring for 2 hours in the stream of hydrogen gas. The catalyst was removed by filtration, the filtrate was condensed and the residue was recrystallized from ethanol to obtain 1.43 g of crystals. Yield: 79%
Reaction SMILES: [C:1]([C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:18]([OH:20])=[O:19])([O:3][CH3:4])=[O:2].C(OC(=O)C)(=O)C>>[C:1]([C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:7]2[C:8]([O:20][C:18](=[O:19])[C:6]=12)=[O:10])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)O)c(C(=O)O)c1C(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(c1C(=O)OC)C(=O)OC2=O
Yield: 75.7 %

Procedure:
In a 100 mL round bottomed flask fitted with a condenser closed with a calcium chloride tube, 156.3 mg (0.55 mmol) of 7 and 0.5 ml of acetic anhydride were placed. The contents of the flask were refluxed gently for 15 min. On cooling white crystals appeared. The crystals were collected on a filter, washed with ether and purified by sublimation under high vacuum (0.05 torr) at an oil bath temperature of 130° C. to yield 110 mg (75%) of the anhydride 8. White solid; mp: 178.5°-179.5° C.; IR: 3110, 3040, 2980, 1860, 1790, 1740, 1720, 1440, 1300, 1250, 1100, 910, 900 cm-1 ; 1H NMR: δ 8.38 (s, 2H, Aryl H), 3.95 (s, 6H, CH3).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccccc2F)C1
Solvent: C1CCOC1
Product: Fc1ccccc1[C@H]1CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 235.6 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(2-fluorophenyl)piperidin-1-yl]methanone (10 mg, 0.0035 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 2.7 mg of the title compound.