Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23](I)[S:24][C:17]=12)[NH2:11].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[F:7][C:8]1[CH:9]=[C:10]([NH2:11])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:24][C:17]=12
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)sc23)c(F)c1
Temperature: 80 °C

Procedure:
A vigorously stirred mixture of cesium carbonate (190 mg, 0.583 mmol), 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 150 mg, 0.388 mmol), phenylboronic acid (59.2 mg, 0.486 mmol), toluene (4 mL) and EtOH (1 mL) was degassed under nitrogen for 10 minutes, and then Pd(PPh3)4 (22.4 mg, 0.0194 mmol) was added. The reaction mixture was heated at 80° C. for 18 hours, then cooled to room temperature and diluted with water (20 mL). The reaction mixture was extracted with EtOAc, and the organic layer was dried organic over sodium sulfate, filtered and concentrated. The residue was purified on a Biotage 40S (2:1 EtOAc/Hexane). The product was a light orange solid (75 mg, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J=5.5 Hz, 1H), 7.75 (m, 3H), 7.46 (t, J=7.2 Hz, 2H), 7.40 (m, 1H), 7.06 (t, J=8.8 Hz, 1H), 6.54 (m, 1H), 6.50 (m, 2H), 3.84 (br s, 2H). LRMS (ESI pos) m/e 337 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[NH4+:32]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:32][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]2)cc1
Yield: 46.4 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 5.5 g (0.1 mole) of ammonium chloride in 150 ml of dry dimethylformamide were heated for 6 hours at 150° C. After cooling, the mixture was poured onto water and the precipitated crystals were filtered off under suction, washed several times with water and dried in a stream of nitrogen. Purification by column chromatography (silica gel; n-heptane plus increasing amounts of ethyl acetate) and recrystallization from ethanol gave 3.6 g of the title compound of melting point 176°-179° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][N:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>CO.[C].[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:32]=[CH:33][CH:34]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[C:18]([F:19])([F:20])[F:21])=[N:24][CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(Oc3ccc(N)cn3)c2)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.5 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(5-nitropyridin-2-yl)oxy]-4-(trifluoromethyl)phenyl}benzamide (1.78 g, 3.78 mmol) in methanol (50 mL) was added 10% palladium-carbon powder (350 mg), and the mixture was stirred at room temperature for 11 hr under a hydrogen atmosphere of 2.4 atm. 10% Palladium-carbon powder was filtered off by celite filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.44 g, 87%) as a brown amorphous substance.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
To a 25-mL RB flask, equipped with a condenser, was added tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid (0.71 g), sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g) tetrakis(triphenylphosphine)-palladium (0) (0.173 g) and ethylene glycol dimethyl ether (10 mL). The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100° C. for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×20 mL) and the combined organic extracts were washed with sat NH4Cl (20 mL) and brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (6:1=hexane:ethyl acetate with 1% NH3) to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as promptly as practical: 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and methanamine hydrochloride (8.45 mg, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid. 1H NMR(CHLOROFORM-d) δ: 8.37 (br. s., 1H), 7.58-7.89 (m, 3H), 7.15 (br. s., 1H), 6.87 (d, J=8.8 Hz, 2H), 6.07 (d, J=4.5 Hz, 1H), 5.06 (dt, J=13.6, 2.5 Hz, 1H), 4.42 (dd, J=10.1, 3.8 Hz, 1H), 3.55 (br. s., 2H), 3.36 (br. s., 4H), 3.08-3.24 (m, 1H), 2.56-3.08 (m, 8H), 2.40 (dd, J=13.5, 1.1 Hz, 1H), 1.74 (br. s., 2H). [M+H] calc'd for C23H28N6O2S, 453; found, 453.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Cl:35])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
184 mg (0.5 mmol) {4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol are suspended in 15 ml toluene. Pyridine (44 μl, 0.55 mmol) and thionyl chloride (40 μl, 0.55 mmol) are added and the mixture is stirred at RT for 16 h. A second portion of the same amounts of pyridine and thionyl chloride are then added and the mixture stirred for 1 additional hour. The solvent is evaporated and the residue suspended in water containing a small amount of sodium bicarbonate (pH ˜8). After filtration, the product was thoroughly washed with water and ether and dried to give crude title compound; m.p.>300° C.; Rf(dichloromethane/ethanol 95:5 plus 1% conc. ammonia)=0.42; HPLC tR=11.33 min.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.Br[CH2:27][CH2:28][CH2:29][C:30]#[N:31]>C(N(CC)CC)C>[C:30]([CH2:29][CH2:28][CH2:27][NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)#[N:31]
Reactant: N#CCCCBr
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Yield: 40 %

Procedure:
To 50 ml of toluene were added 2.02 g of triethylamine and 5.04 g of 2-(trans-3-aminostyryl)benzothiazole at room temperature, and then 2.96 g of 4-bromobutyronitrile was added to carry out the reaction at 110° C. for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent under reduced pressure, the residue was purified through silica gel column chromatography by use of ethyl acetate-ethyl ether-n-hexane (2:5:5) to give 2.55 g (yield 40%) of the title compound as colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[C:19](/[CH2:20][OH:21])=[CH:18]\[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: COC(=O)c1cccc(Br)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(/C(=C\C2CCCCC2)CO)c1
Yield: 74.7 %

Procedure:
Following the method of example 46a, Suzuki coupling of 3-bromo-benzoic acid methyl ester (1.05 g, 4.88 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.48 g, 5.56 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.32 g, 0.28 mmol) and cesium fluoride (2.2 g, 14 mmol) in dioxane (15 mL) gives the title compound (1.0 g). MS (m/e): 257 (M+H−H2O).
Reaction SMILES: C([O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1)=[O:6])CC.[OH-].[Na+].Cl>C(O)C>[C:19]([N:9]1[C:10]2=[N:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[C:15]2[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCCOC(=O)c1cn(C(C)(C)C)c2ncc([N+](=O)[O-])cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1cc(C(=O)O)c2cc([N+](=O)[O-])cnc21
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a suspension of 5.00 g (16.38 mmol) of 1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid propyl ester in 50 mL of 95° ethanol, it was added 2M NaOH (50 mL; 100 mmol) under stirring. The mixture was heated to reflux for 1 hour obtaining the complete consumption of the substrate. The resulting solution was cooled to room temperature and concentrated under reduced pressure to a slurry that was diluted with 250 mL of water and washed with 100 mL of a 1:1 mixture of diethyl ether and ethyl acetate. The aqueous layer was treated with 5M HCl (37 mL; 185 mmol) under efficient stirring at room temperature. The precipitate was filtered off, washed twice with 10 mL of water and dried so as to afford 3.84 g of the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([OH:18])=O)(=[O:10])[CH3:9].CCN=C=NCCCN(C)C.Cl.Cl.[NH2:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1>C(Cl)Cl>[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([NH:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:18])(=[O:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
Triethylamine (4.8 mL), 2-acetoxycinnamic acid (7.1 g) and WSC.HCl (6.6 g) were added to a methylene chloride (180 mL) suspension of methyl L-tryptophanate hydrochloride (7.3 g) at 0° C. The mixture was stirred for 20 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residual oily product obtained by distilling off the solvent under a reduced pressure was purified by silica gel column chromatography (BW-127ZH, chloroform:methanol=100:1), to give the captioned compound (8.9 g, 76%) as crystals.
Reaction SMILES: II.[CH:3]1([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][S:13]C2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>CO>[CH:3]1([CH2:9][CH2:10][NH:11][CH2:15][CH2:14][S:13][S:13][CH2:14][CH2:15][NH:11][CH2:10][CH2:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C1CCC(CCN2CCSC2)CC1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C1CCC(CCNCCSSCCNCCC2CCCCC2)CC1
Yield: 102.8 %

Procedure:
A solution of iodine (378 mg) in methanol (5 ml) is added dropwise to a solution of N-(2-cyclohexylethyl)thiazolidine (594 mg) in methanol (10 ml) at room temperature with stirring. After the dropping, the mixture is stirred at room temperature for 30 minutes. A 4 N aqueous sodium hydroxide solution (10 ml) is added to the reaction mixture, and the mixture is concentrated under reduced pressure. Chloroform is added to the concentrate, and the whole is extracted. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 571 mg (51%) of the titled compound (Reference compound No. 19-1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][F:22])=[C:15]([C:23]([OH:25])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH:30]1([NH:32][C:23]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][F:22])=[O:25])[CH2:31][CH2:29]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCF)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCF)cc1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 212.1 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(5-fluoropentyl)-1H-1,2,3-triazole-4-carboxylic acid (353 mg, 1.01 mmol) obtained in Example 111b), HOBt (55.3 mg, 0.405 mmol, 0.4 eq.) and cyclopropylamine (0.094 ml, 1.32 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 4.5 ml), WSC (218 mg, 1.11 mmol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 12.5 hr. The reaction mixture was diluted with 2% aqueous sodium carbonate solution (20 ml), and the mixture was stirred at room temperature. The precipitate was collected by filtration, washed with water and dried to give a white powder. This was crystallized from ethyl acetate-diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (333 mg, 0.859 mmol, 85.1%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(=S)=S>[C:5]([C:17]1[CH:16]=[CH:15][C:14]2[O:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][O:12][C:13]=2[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=COc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
12.5 g of aluminum trichloride are added to a mixture of 4.27 g of acetyl chloride and 7.5 g of ethyl 1,4-benzodioxin-2-carboxylate in 150 ml of carbon disulfide at 0° C. The reaction mixture is stirred at room temperature for 14 hours. After acid hydrolysis with 50 ml of hydrochloric acid (2N) and extraction of the aqueous phase with dichloromethane, the organic phase is washed with saturated sodium hydrogen carbonate solution and then dried over magnesium sulfate. The acylated product is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 7:3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]([CH3:36])[C@@H:7]1[CH2:14][N:13]2[C:15]3[CH:16]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=[CH:19][C:20]=3[C:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:12]2[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=2[O:9][CH2:8]1)=O>C1COCC1>[NH2:1][CH2:2][CH2:3][CH2:4][N:6]([CH3:36])[C@@H:7]1[CH2:14][N:13]2[C:15]3[CH:16]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=[CH:19][C:20]=3[C:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:12]2[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCN)COc1ccccc1-3
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCCN)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl(7R)-7-[β-alanyl(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.2 M) in THF was treated with BH3-DMS complex (2 M in THF; 10 eq.) and the resulting mixture was stirred for 3 h at RT. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 476 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].C([O-])(O)=O.[Na+].CCOC(C)=O>CC#N>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf20 (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:3]=1.[Br-].[CH:28]1([Zn+])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O1CCCC1.[Cl-].[NH4+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]1([CH:9]([C:4]2[CH:3]=[C:2]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[S:6][C:5]=2[CH2:7][CH3:8])[O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCc1sc(Br)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Reactant: [Zn+]C1CCCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-ethylthiophen-3-yl)(cyclohexyl)methoxy]benzoate (1.20 g) synthesized above in N-methylpyrrolidone (30 mL) were added 0.5M cyclohexylzinc bromide-tetrahydrofuran solution (8.22 mL) and bis(tri-tert-butylphosphine)palladium (70.0 mg) at 0° C., and the mixture was stirred for 1 hr under an argon atmosphere while heating to 80° C. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title compound (0.56 g, 46%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:20]([C:19]3[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][OH:12])=[CH:17][CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(Cl)cnc(N)c1N
Reactant: O=Cc1ccc(OCCO)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCO)cc3)nc12
Temperature: 110 °C

Procedure:
5-Chloro-4-methoxypyridin-2,3-diamine (0.498 g, 2.9 mmol) was dissolved in DMF (7 ml). Iron(III)chloride hexahydrate (0.06 g, 0.2 mmol) was added and the mixture heated to is 80° C. 4-(2-Hydroxyethoxy)benzaldehyde (0.48 g, 2.9 mmol) dissolved in DMF (4 ml) was added dropwise, and the reaction mixture was heated at 110° C. for 11 h with air bubbling through the solution. The solvent was removed by evaporation, the solid residue was dissolved in warm methanol and filtered through a short plug of silica gel. Following evaporation and recrystallization (methanol), the title compound was isolated (0.26 g, 28%).