Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>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.COCCOC>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:33]=[C:34]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
Phenylboronic acid (1.2 g), Pd(PPh3)4 (364 mg) and potassium phosphate (4 g) were added in that order to a DME (60 mL) solution of methyl 3-benzyloxy-5-{[(trifluoromethyl)sulfonyl]-oxy}benzoate (2.5 g), and stirred at 85° C. for 7 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and the residue was diluted with ethyl acetate, water was added to it, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[O:4]1)[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[F:25])[O:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH3:14])[C:5](=[O:15])[O:4][C:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[C:8]=2[CH:9]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)OC(=O)N(C)c2ccc(Oc3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 8.6 %

Procedure:
To a stirred solution of 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.30 g, 1.28 mmol) and 3-chloro-4-fluorophenylboronic acid (0.67 g, 3.83 mmol) in methylene chloride (15 mL) was added triethylamine (0.6 mL, 4.3 mmol) and copper (II) acetate (0.46 g, 2.56 mmol). The reaction mixture was stirred at room temperature for 6 days and partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated to give 6-(3-chloro-4-fluorophenoxy)-4,4-diethyl-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a yellow oil (0.04 g, 9%). 1H NMR (DMSO-d6): δ 7.45 (t, J=9.1 Hz, 1H), 7.21 (dd, J=6.2, 3.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.08 (m, 2H), 6.99 (m, 1H), 3.29 (s, 3H), 2.01 (m, 2H), 1.88 (m, 2H), 0.79 (t, J=7.3 Hz, 6H). MS (ESI) m/z 364/366 ([M+H]+); HRMS: calcd for C19H19ClFNO3, 363.1037. found (ESI+), 364.1106.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]2.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH:21]([N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]3)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Yield: 61.3 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)quinolin-3-yl)ethanone (19 mg, 0.0448 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35 mg, 0.12 mmol) to afford the desired product (13.9 mg, 61%) as an orange solid. 1H NMR (500 MHz, DMSO) δ 11.27 (s, 1H), 9.07 (s, 1H), 8.03 (dd, J=8.7, 2.1 Hz, 1H), 7.96-7.87 (m, 2H), 7.35-7.27 (m, 3H), 7.16 (d, J=2.1 Hz, 1H), 7.03-6.97 (m, 1H), 4.45 (br s, 1H), 2.95-2.84 (m, 1H), 2.84-2.73 (m, 1H), 2.65 (s, 3H), 2.21 (s, 6H), 2.14-2.06 (m, 2H). ESI MS m/z 505 [C28H25Cl2N3O2+H]+; HPLC 98.5% (AUC), tR=11.22 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][OH:13])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:14](N(CC)CC)C>C(O)=O.CO>[OH:13][CH2:12][CH2:11][N:10]1[C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[CH:9][C:2]=2[N:1]=[CH:14]1
Reactant: N#Cc1cccc(N)c1NCCO
Reactant: CCN(CC)CC
Solvent: CO
Solvent: O=CO
Product: N#Cc1cccc2ncn(CCO)c12
Yield: 70 %

Procedure:
3-amino-2-[(2-hydroxyethyl)amino]benzonitrile (38 g, crude), is dissolved in formic acid (150 ml) and stirred under reflux for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to give a dark solid. This solid is dissolved in 200 ml of methanol with heating and while still hot, 60 ml of triethylamine is added and reflux for 1 hour. The mixture is concentrated under vacuum and the precipitate is filtered and washed with water then dried to give the desired compound (27 g, 70% from intermediate 11).
Reaction SMILES: [CH3:1][CH:2]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2=[N:6][NH:7][CH:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH:4]2[CH2:3]1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[CH3:1][CH:2]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2=[N:6][NH:7][C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:4]2[CH2:3]1
Reactant: CC1CC2C(=NNC2c2ccncc2)c2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC1Cc2c(n[nH]c2-c2ccncc2)-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a flask equiped with a magnetic stirring bar is charged 5.0 grams of the 5-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c]pyrazole prepared as in example 3, 25 grams of activiated manganese dioxide and 150 ml of dry benzene. The mixture is stirred for about 12 hours at room temperature, after which the manganese salts are filtered off and the solvent removed in vacuo. The solid is crystallized from ethanol to yield 4,5-dihydro-2-methyl-3-(4-pyridyl)-2H-naphtho.[1,2-c]pyrazole.
Reaction SMILES: [ClH:1].[C@@H:2]1([NH:13]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>C(OCC)(=O)C>[ClH:1].[NH2:13][C@@H:2]1[CH2:4][C@H:3]1[NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
37% hydrochloric acid (40.0 mL) in ethyl acetate (300 mL) was added dropwise to a solution of di-tert-butyl rel-(1R,2R)-cyclopropane-1,2-diylbiscarbamate (80.0 g) in ethyl acetate (500 mL) at 0° C. The reaction mixture was warmed to ambient temperature. After 16 hours, the reaction mixture was filtered. The collected solids were washed with diethyl ether and then dried under reduced pressure to afford tert-butyl rel-[(1R,2R)-2-aminocyclopropyl]carbamate HCl salt. MS ESI calc'd. for C8H17N2O2 [M+H]+ 173. found 173. 1H NMR (300 MHz, DMSO-d6) δ: 8.36 (bs, 3H), 7.14 (s, 1H), 2.87-2.86 (m, 1H), 2.50-2.49 (m, 1H), 1.39 (s, 9), 1.09-1.02 (m, 1H), 0.92-0.86 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[N+:4]([C:7]1[CH:48]=[CH:47][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH2:45])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].CCN(CC)CC.[C:56](Cl)(=[O:58])[CH3:57]>C(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH:45][C:56](=[O:58])[CH3:57])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:47][CH:48]=1)([O-:6])=[O:5]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a stirred solution of (5R,7R)-4-(4-(aminomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate trihydrochloride (30 mg, 0.042 mmol) and Et3N (0.034 mL, 0.19 mmol) in DCM (1 mL) was added acetyl chloride (0.0033 mL, 0.046 mmol) at about 0° C. under N2. The reaction was stirred at about 0° C. for about 30 minutes and diluted with DCM. The reaction mixture was washed with saturate aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH/DCM) to give (5R,7R)-4-(4-(acetamidomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (28 mg, 68%) as an oil. LCMS (APCI+) m/z 647 [M+H]+; Rt=3.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.C([Li])CCC.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([I:17])=[CH:5]2
Reactant: Cn1ccc2cc(Cl)ccc21
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: Cn1c(I)cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 5-chloro-1-methylindole (10.0 g, 60.4 mmole) and n-butyl lithium (29 mL of 2.5 M sol'n in hexanes, 72.5 mmole) in diethyl ether is heated at reflux temperature for 3 hours, cooled to 0° C., treated with iodine (18.4 g, 72.5 mmole), stirred at 0° C. for 1 hour, warmed to room temperature, stirred for 1 hour, and treated with aqueous sodium sulfite. After phase separation, the organic phase is dried over MgSO4 and concentrated in vacuo to give the title product as a brown oil which solidified on standing, 16.5 g (93.7% yield). The title product is used as in Example 4.
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[CH:17][C:10]=1[O:11][CH2:12][C:13]([O:15]C)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:1]([C:9]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[CH:17][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(C(=O)c3ccccc3)c(OCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetate (0.55 g), tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added a 1N aqueous sodium hydroxide solution (1.5 mL) and the mixture was stirred at room temperature for 3 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[2-benzoyl-5-[4[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetic acid as a colorless amorphous compound (0.41 g, 76%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16].[C:30]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16]
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2(O)CCCCC2)cc1NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 84253.7 %

Procedure:
Diisopropylamine (140 g, 1.39 mol) and 800 mL dry THF were added to a dry 12 L 4 neck flask with a mechanical stirrer under nitrogen. The solution was cooled to −40° C. and n-BuLi (1.29 mol) was added slowly while keeping the inside temperature around −40° C. The mixture was stirred for 45 min at −40° C. and then cooled to −78° C. To this solution, a solution of 3-tert-butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (99 g, 0.384 mmol) in 3.2 L THF was added drop wise. The mixture was stirred for 60 min at −78° C. and then cyclohexanone (118 g, 1.19 mmol) was added in 30 seconds. The mixture was stirred for 30 min at −78° C. The reaction mixture was quenched with 0.75 L of NH4Cl (sat). The aqueous phase was extract with 0.75 L of EtOAc. Combined the organic phase and washed them with 5 L of brine, Dried over Na2SO4, filtered and evaporated to a residue to afford 115 g (84%) of 3-tert-Butoxycarbonylamino-5-(1-hydroxy-cyclohexyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:28]1([N:27]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)cc1
Yield: 75.7 %

Procedure:
Adding 0.66% by weight toluene solution in an amount of 100 microliter prepared by dissolving tri-t-butylphosphine into a mixed solution prepared by dissolving 4.50 g of 4-bromo-4′-(N-1-naphthyl-N-phenylamino)biphenyl, 1.11 g of aniline, 183 milligram of tris(dibenzylideneacetone)dipalladium(O) and 1.35 g of t-butoxysodium into toluene in an amount of 100 milliliter, the resultant solution was stirred at a room temperature for 5 hours. After the completion of the reaction, the solution was filtered with a use of celite and the filtrate was extracted with toluene. Concentrating the filtrate under a reduced pressure, the resultant crude product was refined by means of a column and as a result, 3.50 g of pale yellow powder was obtained
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH:24]=[O:25])=O)(C)C>ClCCl>[NH:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH:24]=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cc2cnccc2[nH]1
Yield: 75.5 %

Procedure:
Add to a solution of 2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (8b-1, 9.8 g, 30.6 mmol) in 100 ml THF, 6 ml of concentrated HCl. Stir the reaction mixture at room temperature for 20 h, basify with saturated sodium bicarbonate solution, pour into EtOAc, wash with saturated sodium bicarbonate and brine, dry the organic phase over MgSO4, filter, and concentrate to give a mixture of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester and 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 as a solid. Separate the mixture by flash chromatography (silica, 1-3% MeOH/CH2Cl2) to give 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (5.0 g ) as an oil and 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 (1.0 g) as a tan solid. Add TFA (5.0 mL) dropwise to a solution of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (5.0 g, 20.3 mmol) in 250 ml dichloromethane. Heat the reaction mixture at reflux for 3 hours, concentrate, dilute the residue with 300 ml EtOAc, wash with saturated sodium bicarbonate solution (3×) and brine, dry the organic phase (MgSO4), filter and concentrate to yield 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 (2.24 g) as a pure solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[CH:13]=[C:14]([Cl:16])[N:15]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([O:27]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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.C1(C)C=CC=CC=1>[C:25]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[CH:13]=[C:14]([Cl:16])[N:15]=2)=[C:4]([CH3:24])[CH:3]=1)(=[O:27])[CH3:26]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCC(COC)n1cc(Cl)nc(Nc2c(C)cc(Br)cc2C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC(COC)n1cc(Cl)nc(Nc2c(C)cc(C(C)=O)cc2C)c1=O
Yield: 39.5 %

Procedure:
To the product of Example 15 (250 mg), bis(triphenylphosphine)palladium(II) chloride (11 mg), and tetrakis(triphenylphosphine)palladium(0) (17 mg) in a dry flask under nitrogen was added toluene (1.5 mL) and 1-ethoxyvinyl tributyl tin (260 mg). The reaction was heated at reflux 18 hours, and then concentrated in vacuo. The residue was taken up in ether (15 mL) and saturated aqueous potassium fluoride (15 mL), and filtered. The layers were separated, and the ether layer was stirred with 1N HCl (aq., 15 mL). The layers were separated and the ether layer was dried over MgSO4 and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (3:7) as eluent to afford the title compound (90 mg). Elemental analysis calcd. for C19H24N3O3Cl: C, 60.39; H, 6.40; N, 11.12. Found: C, 60.51; H, 6.31; N, 11.00.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[N:14][CH:13]([N:29]3C(=O)C4=CC=CC=C4C3=O)[C:12]2=[O:40])=[CH:2]1.O.NN>O1CCCC1>[NH2:29][CH:13]1[N:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH:2]=2)[C:12]1=[O:40]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1csc2ccccc12
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2csc3ccccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of (3RS)-1-(benzothiophen-3-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phtalimido-1H-1,4-benzodiazepin-2-one (0.980 g) in tetrahydrofuran (10 ml) was added dropwise hydrazine monohydrate (0.109 g) under stirring at ambient temperature. The mixture was stirred for 1 hour at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was allowed to stand to ambient temperature. The resultant precipitates were filtered off and washed with tetrahydrofuran. The filtrate and washing were combined and concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel with an eluent of chloroform and methanol to afford (3RS)-3-amino-1-(benzothiophen-3-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl 4-methyl-2-[(2S)-4-(4-oxo-piperidine-1-yl)-benzoylamino]-pentanoic acid ethyl ester(which was obtained in Example 165) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp >85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.18 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.45-1.95 (m, 5H), 2.55-2.92 (m, 5H), 2.92 (s, 3H), 3.70-3.85 (m, 2H), 4.10 (q, J=7.1 Hz, 2H), 4.40-4.55 (m, 2H), 6.82 (d, J=8.3 Hz, 1H), 6.94 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 2H), 8.33 (d, J=7.7 Hz, 1H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 591.2847. Found: 591.2840.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:7])[CH:6]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>>[C:17]([O:7][C:5]1[N:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(=O)n(CCOc2ccccc2)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Oc1cc(C)nn1CCOc1ccccc1

Procedure:
0.1 mol (21.8 g) of 3-methyl-1-(β-phenoxyethyl)-5-pyrazolone was heated with 0.2 mol (20.4 g) of acetic anhydride in the presence of 0.11 mol (8.2 g) of sodium acetate for 2 hours.