Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(=O)C)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2cc(C(C)=O)oc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])c2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-acetyl-7-methoxybenzofuran (4.0 g) in acetic anhydride (50 mL) at 0° C. was added 70% nitric acid (1.5 mL) drop-wise. The mixture was warmed to room temperature and stirred for 3 h then poured into ice-cold saturated sodium carbonate (200 mL). Solid sodium carbonate was added carefully with stirring until basic (pH=8). The mixture was filtered and the solid collected by vacuum filtration. The solid was boiled in 100 mL (methanol) for 1 h, then cooled to 0° C. and filtered to give 2-acetyl-7-methoxy-4-nitrobenzpfuran (2.1 g). 1H NMR (300 MHz) δ 8.29 (d,J=8.9 Hz, 1H), 8.14 (s,1H), 7.00 (d,J=8.9 Hz, 1H), 4.14 (s,3H), 2.68 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=[C:11]2[N:10]=[CH:9]1)=O)(C)(C)C.C[O:31][C:32](=O)[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([Br:39])[CH:34]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:13]=[C:12]3[NH:8][C:9]([C:32]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([Br:39])[CH:34]=4)=[O:31])=[N:10][C:11]3=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
The mixture of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester (600 mg, 1.49 mmole), methyl-2-bromo-isonicotinate (321 mg, 1.49 mmole), and tetrahydrofuran (5 ml) was cooled to −78° C. Lithium diisopropylamide (2N, 2.23 ml, 4.46 mmole) was added slowly. Reaction mixture was stirred at −78° C. for 2 hours. Reaction was quenched with water and extracted with EtOAc. EtOAc layer was concentrated and crude product was purified by using silica gel chromatography, eluting with 0% to 40% of EtOAc in CH2Cl2 to afford 4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 16.6%). 1H NMR (400 MHz, CD2Cl2) δ 1.58 (s, 9H), 3.59 (m, 4H), 3.74 (m, 4H), 6.89 (d, J=9.03 Hz, 1H), 8.03 (d, J=9.03 Hz, 1H), 8.39 (d, J=5.03 Hz, 1H), 8.61 (d, J=5.02 Hz, 1H), 8.67 (s, 1H). MS(ESI) m/z 488 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([O:20]C)=O)[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN=C=NCCCN(C)C>CO.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][S:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CSc1ccccc1)C(=O)N1CCOCC1
Reaction time: 16 h

Procedure:
A solution of Example 175A (600 mg, 1.92 mmol) and 2M aqueous lithium hydroxide (4 mL) in methanol (10 mL) at room temperature was stirred for 5 hours and concentrated. The concentrate was treated with morpholine (263 mg, 3 mmol), EDCI (555 mg, 2.88 mmol), DMAP (20 mg) and DMF (20 mL), stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with water (50 mL), and brine (20 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 367 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17](Cl)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.CCOC(C)=O>C1(C)C=CC=CC=1.CCO.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.O>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17]([C:33]3[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Temperature: 100 °C
Yield: 95.7 %

Procedure:
To a solution of 1D (20 mg, 0.066 mmol) in toluene (0.5 mL) and EtOH (0.3 mL) was added a 2M aqueous solution of Na2CO3 (0.3 mL, 0.6 mmol). The resulting solution was purged with argon for 30 minutes and 2A (23.3 mg, 0.099 mmol) was added, followed by a catalytic amount of Pd(PPh3)4. The reaction was heated to 100° C. for 15 minutes, then cooled to ambient temperature. EtOAc and H2O were added, the layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 100% CH2Cl2 then 100% EtOAc) to afford 2B (23.7 mg, 96%). HPLC Rt=3.182 min; LCMS Found: (M+H)+=376.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([OH:36])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](O)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (96 mg, 1.1 mmol) and triethyloxonium tetrafluoroborate (0.20 g, 1.1 mmol) in tetrahydrofuran (2 mL) became a solution after stirred for 15 min. After another 45 min, this solution was added to a mixture of trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (95 mg, 0.36 mmol) in ethanol (2.9 mL) and heated at reflux for 2 h. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 0.8%). LCMS calculated for C16H20N3O2S (M+H)+: m/z=318.1. Found: 318.0.
Reaction SMILES: [CH3:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[O:7])=[O:6])=[O:3]>[Pd].O.C(O)C>[CH3:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)(=[O:7])=[O:6])=[O:3]
Reactant: CC(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)NS(=O)(=O)c1cccc(N)c1
Yield: 70 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(methylcarbonylaminosulphonyl)-3-nitrobenzene (2.9 g, 12 mmol), 10% palladium on carbon (0.4 g, 14% (w/w)) in water (3 ml) and ethanol (150 ml), the title compound (1.8 g, 70%) was afforded as a colourless soiid. mp 148°-150° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.92 (3H, s), 5.64 (2H, brs), 6.80 (1H, dd, J=8.0 and 1.7 Hz), 6.98 (1H, d, J=7.6 Hz), 7.10 (1H, dd, J=2.0 and 2.0 Hz), 7.21 (1H, dd, J=7.9 and 7.9 Hz), 11.87 (1H, brs).
Reaction SMILES: [C:1]1([O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)=[CH:21][CH:20]=3)=[CH:16][C:15]=2[CH:36]=1>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:34])[CH:28]=4)=[CH:23][CH:24]=3)=[CH:16][C:15]=2[CH:36]=1
Reactant: [O-]c1ccccc1
Reactant: COc1ccc2oc(-c3ccc(C=Cc4cccc(C(=O)O)c4)cc3)cc2c1
Agent: [Na+]
Product: COc1ccc2oc(-c3ccc(C=Cc4cccc(C(=O)Oc5ccccc5)c4)cc3)cc2c1

Procedure:
Following the procedure described in Example 6 above but using sodium phenolate in place of methyl alcohol and 5-methoxy-2[4-(3-carboxystyryl) phenyl]benzofuran instead of 5-chloro-2-[4-(4-carboxystyryl)phenyl]benzofuran, there is obtained as the product 5-methoxy-2-[4-(3-carbophenoxystyryl)phenyl]benzofuran.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]#N)=[CH:2]1.[PH2]([O-])=[O:15].[Na+].O.N1C=CC=CC=1>C(O)(=O)C.[Ni]>[CH:12]([C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH:2]=1)=[O:15]
Reactant: O=[PH2][O-]
Reactant: N#Cc1c[nH]c2ccccc2c1=O
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=Cc1c[nH]c2ccccc2c1=O
Temperature: 60 °C

Procedure:
The 4-(1H)-quinolone-3-nitrile (12 g) and sodium hypophosphite (16.12 g) were dissolved in a mixture of acetic acid:water:pyridine=125 ml: 125 ml:250 ml and 4 g of Raney Nickel (W2 grade) added (Backeberg and Staskim, J.C.S. 1962, 3691). The reaction mixture was heated at 60° C. for four hours, then the hot suspension was filtered and the catalyst cake washed with warm ethanol into the filtrates. The combined filtrates and washings were evaporated to one-third of the original volume and on equal volume of water added. The precipitated solid was filtered off, washed with water and dried to give the required 3-formyl compound as a light-brown solid, m.p. 268°-270° C. (3-formyl-4(1H)-quinolone).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:13][C:12]2=[O:22])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:41]([CH:50]=O)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:41]([CH2:50][N:19]2[CH2:18][CH2:17][C:14]3([NH:13][C:12](=[O:22])[N:11]([CH2:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[C:15]3=[O:16])[CH2:21][CH2:20]2)[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CS(=O)(=O)c1ccc(CN2C(=O)NC3(CCNCC3)C2=O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC3(CC2)NC(=O)N(Cc2ccc(S(C)(=O)=O)cc2)C3=O)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To 187 mg (0.50 mmol) of 3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride was added 5 mL of DCM followed by 0.066 mL of triethylamine (0.50 mmol) and a solution of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.93 mL of a 148 mg/mL solution, 0.50 mmol). The solution was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride was added (159 mg, 0.75 mmol). The solution was stirred overnight. The resulting mixture was evaporated to dryness and purified by chromatography on Bond Elute™ (10 g) using 1:1 EtOAc:Hexane followed by 1% methanol in DCM. After evaporation of the desired fractions, 93 mg (31%) of (3S,4S)-3-[3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:42](O)=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[OH:15][C@@H:7]([CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])[C@@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:42]([C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:43])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:4])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Yield: 26.8 %

Procedure:
A mixture of 880 mg (2.5 mmol) of (S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 1.99 g (7.5 mmol) of t-butoxycarbonyl-L-phenylalanine. 1.05 ml (7.5 mmol) of triethylamine and 3.32 g (7.5 mmol) of BOP in 100 ml of acetonitrile was stirred at room temperature for 6 days. Thereafter, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. The organic solution was dried over sodium sulfate and evaporated and the residue was triturated twice with hexane. The residue was chromatographed on 100 g of silica gel with a 98:2 mixture of chloroform and methanol. Recrystallization of the thus-obtained crude product from methylene chloride and hexane yielded 400 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4 -isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a white powder, melting point 82°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 66.7 %

Procedure:
To a solution of 6-[2-(2-chloro-5-methoxy-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (1.57 g) in tetrahydrofuran (50 ml) was added sodium hydride (55% dispersion in mineral oil, 208 mg). The mixture was stirred at room temperature for 3.5 h and then placed in an ice bath. A solution of methyl iodide (0.677 g) in tetrahydrofuran (1 ml) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 1.5 h. The solvent was evaporated and the residue was dissolved in EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give the title compound (1.09 g) as a colorless gum. MS (m/e)=360.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:13][NH:14][C@H:15]([C:17]([C:19]1([NH2:38])[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH3:36])[C:20]1=[O:37])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]([C:17]([C:19]2([NH2:38])[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH3:36])[C:20]2=[O:37])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN[C@@H](C)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@@H](C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O)N(C)C(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(N′-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-E), the title compound was prepared as a white solid.
Reaction SMILES: CC([CH:5]1[CH2:10][CH:9]([C:11]2[C:19]3[C:14](=[C:15]([C:21]([NH2:23])=[O:22])[CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:27].C(OCC)C>CO.O1CCOCC1>[ClH:27].[Br:20][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([C:21]([NH2:23])=[O:22])[CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCN1C(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl-4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-1-piperidinecarboxylate (which may be prepared according to WO2005067923A1, 74 g) was dissolved/suspended in methanol (300 mL) and to this was added 4N HCl in dioxane (200 mL). The reaction mixture was stirred for 2 hours. Diethyl ether (400 mL) was added and the solid was collected by filtration. This was washed with diethyl ether (300 mL) and dried in vacuo to give the title compound (66.53 g) as pale yellow solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.C[O-:17].[K+]>CN1CCCC1=O>[CH3:15][C:7]1[C:5]2[NH:6][C:2](=[O:17])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc2sc(Cl)nc2c1C
Reactant: C[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2sc(=O)[nH]c2c1C
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A solution of 22.5 g (93 mmol) of methyl 2-chloro-4-methyl-benzothiazole-5-carboxylate in 360 ml of N-methylpyrrolidone was admixed with 13.6 g (186 mmol) of potassium methoxide and heated at 100° C. for 5 hours. After cooling, the resulting precipitate was filtered off with suction and the filtrate was admixed with water. The pH of the reaction solution was then adjusted to pH 1, the aqueous solution was extracted three times with ethyl acetate and the combined organic phases were washed and dried. The solvent was removed under reduced pressure and the residue was purified by trituration with methylene chloride/n-hexane. This gave, in a yield of 55%, 11.38 g (51 mmol) of methyl 4-methylbenzothiazol-2-one-5-carboxylate of m.p. 262° C.-266° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][CH:16]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCCC2)cc1
Reaction time: 3 h
Yield: 198.2 %

Procedure:
Two identical reactions were set up side-by-side as follows. To a mixture of 1-[2-(4-nitro-phenoxy)-ethyl]-pyrrolidine (17.61 g, 74.5 mmol) and 5% palladium on carbon (2.0 g) was added 125 mL of ethyl acetate. The reaction mixture was hydrogenated at 45 psi at room temperature for 3 hr. The mixture was filtered through diatomaceous earth under nitrogen, and the filter cake was washed with ethyl acetate and methanol. The combined filtrates from both reactions were concentrated to yield 30.46 g (99%) of the title compound. MS 207.2 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH2:28][CH3:29])=[O:17])=[CH:4][C:3]=1[O:30]C.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH2:28][CH3:29])=[O:17])=[CH:4][C:3]=1[OH:30]
Reactant: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)c(OC)c3)cc12
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)c(O)c3)cc12
Temperature: 30 °C
Reaction time: 72 h
Yield: 2.1 %

Procedure:
The product from Example 96 (0.050 g, 0.11 mmol, 1.0 equiv) was cooled to −78° C. in 1.5 mL CH2Cl2 and BCl3 (1.0 M in CH2C2, 1.70 mL, 1.71 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 30° C. and stirred for 72 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl and the product was extracted into EtOAc. The organic layer was washed with sat'd NaCl and concentrated en vacuo. The residue purified by reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA over 6 minutes, retention time 3.48 min) to provide 1 mg (0.7%) of the title compound as a white solid. MS (ES+) m/e 425 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23C[CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.N12CC([CH2:29][OH:30])(CC1)CC2>>[CH3:29][O:30][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[C:10]([O:12][CH2:13][C:14]12[CH2:20][N:17]([CH2:16][CH2:15]1)[CH2:18][CH2:19]2)=[O:11]
Reactant: OCC12CCN(CC1)C2
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: COc1ccc2[nH]cc(C(=O)OCC34CCN(CC3)C4)c2c1

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethyl 5-methoxy-1H-indole-3-carboxylate was synthesized using the procedure described for (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate using 1-Azabicyclo[2.2.1]heptan-4-ylmethanol. MS: (m/e) 300.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:5][CH:4]1[C:6](O)=[O:7].[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:6]([CH:4]4[CH2:5][CH:3]4[C:2]([F:10])([F:9])[F:1])=[O:7])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C1CC1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CC3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylcyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (30.9% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.98, 7.00, 3.97-3.57, 2.20, 1.65, 1.50, 1.26, 0.75, 0.46, 0.09. MS (ES+) m/z 412 (M+1).