Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]=O.[H][H]>[C].[Pd].CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: C=O
Reactant: [H][H]
Reactant: OCCN1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(CCO)CC1
Yield: 84 %

Procedure:
A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g, 76.8 mmol), 37% aqueous formaldehyde solution (11.5 ml, 154 mmol), 10% palladium carbon catalyst (1.0 g) and methanol (100 ml) was stirred for 13 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. To the obtained residue was added 2N hydrochloric acid, and the mixture was washed with diethyl ether (200 ml). Sodium hydroxide (16 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (4×200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (9.3 g, 84%) as a pale-yellow liquid.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:21]4)[N:14]=2)=[CH:9][C:8]=1[C:34]([F:37])([F:36])[F:35])[CH3:5].Cl>C1COCC1.C(O)(C)C.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:21]4)[N:14]=2)=[CH:9][C:8]=1[C:34]([F:36])([F:37])[F:35])[CH3:3]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Sodium hydroxide (36 mg) was added to a solution of ethyl 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoate (D117) (89 mg) in THF (1 mL), isopropanol (1 mL) and water (0.5 mL). The mixture was stirred at room temperature until LCMS showed no starting material. The mixture was neutralized with 2 M HCl till pH ˜6.0. The crude product was purified by Mass Directed Auto Prep to afford of 3-(5-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-2-yl)propanoic acid (E92) (40 mg). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.70 (2H, t), 2.99 (2H, t), 5.55 (1H, m), 6.35 (1H, s), 7.46 (1H, d), 7.77 (1H, dd), 8.23 (1H, s), 8.64 (1H, d), 9.22 (1H, d), 11.36 (1H, s), 12.25 (1H, s); MS (ES): C22H19F3N4O4 requires 460; found 461.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:25][C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CC(C)(N)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 230.2 %

Procedure:
Following General Procedure F, tert-butyl 2-[4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]propan-2-ylcarbamate (10 mg, 0.020 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) to afford the desired product (9.7 mg, 97%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.71 (d, J=8.4 Hz, 2H), 7.60 (d, J=5.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 6.06 (d, J=5.4 Hz, 1H), 1.86 (s, 6H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=10.89 min
Reaction SMILES: OCCN(CC)CC.[NH2:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[S:17]([OH:20])(=[O:19])=[O:18].[F:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([F:30])[C:25]([F:31])=[C:24]([C:32]#[N:33])[C:23]=1F>CS(C)=O>[NH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:23]2[C:24]([C:32]#[N:33])=[C:25]([F:31])[C:26]([F:30])=[C:27]([C:28]#[N:29])[C:22]=2[F:21])[CH:13]=[CH:12][C:11]=1[S:17]([OH:20])(=[O:18])=[O:19]
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Agent: CCN(CC)CCO
Solvent: CS(C)=O
Product: N#Cc1c(F)c(F)c(C#N)c(Nc2ccc(S(=O)(=O)O)c(N)c2)c1F
Temperature: 75 °C

Procedure:
To a mixture of N-(β-hydroxyethyl)diethylamine (5.86 g) and 2,4-diaminobenzene sulphonic acid (7.52 g) in dimethylsulphoxide (45 cm3) was added 1,2,4,5-tetrafluoro-3,6-dicyanobenzene (8.25 g) portionwise with stirring. The mixture was heated at 75° C. for 4 hours then poured into ice/water (140 cm3) to give a solution of 2-amino-4-(2,4,5-trifluoro-3,6-dicyanophenylamino)benzene sulphonic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ncc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@@H](CC(=O)c1cnc(=O)[nH]c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
To a solution of (S)-3-(4-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-3-o-tolylpropan-1-one (700 mg, 1.53 mmol, Eq: 1.00) in dioxane (18 mL) was added 37% aq. hydrochloric acid solution (2.56 mL, 30.6 mmol) and the resulting solution was first stirred at ambient temperature for 45 min and then 2½ h at 60° C., then poured onto sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (592 mg, 97%). White solid, MS (ESI+): m/z=: 397.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[S:25])[S-:24])[CH:19]=[CH:20][CH:21]=1.C([NH+](CC)CC)C.O>C(#N)C.CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)([OH:4])[CH2:2][S:25][C:23]2=[S:24])[CH:19]=[CH:20][CH:21]=1
Reactant: S=C([S-])Nc1cccc(Cl)c1
Reactant: NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: CC[NH+](CC)CC
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(C2(O)CSC(=S)N2c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 g of the product of Example 5 and 5.5 g of the product of Example 6 are dissolved in 60 ml of acetonitrile, and the mixture is stirred for 5 h at ambient temperature. It is then poured into 500 ml of water, extracted with dichloromethane, the dichloromethane phase is then washed with water, then dried over magnesium sulphate and evaporated off. The solid obtained is taken up in ether and filtered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[C:23]([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:10]=1)[C:5]([O:7][CH3:23])=[O:6])([O-:13])=[O:12]
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a suspension of 3-bromo-5-nitrobenzoic acid 45.1.A (10.0 g, 40.7 mmol, available from Apollo) and pyridin-4-ylboronic acid (7.40 g, 60.9 mmol) in toluene (100 mL) was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.3 g, 4.07 mmol), and 2M Na2CO3 aqueous (100 mL). The mixture was stirred for 3 hours at 90° C. at which time the mixture was condensed. The residue was dissolved in water (200 mL) and washed with EtOAc (50 mL). The water layer was then condensed, the residue was triturated with methanol (200 mL), and then filtered. Sulfuric acid (5 mL) was then added to the mother liquor and stirred at reflux overnight. The mixture was then concentrated, neutralized with saturated aqueous NaHCO3 (100 mL), and extracted with DCM (2×100 mL). The combined organic layers were then concentrated to afford methyl 3-nitro-5-(pyridin-4-yl)benzoate 45.1.B (5.60 g, 53% yield) which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[OH2:8].[Cl:1][C:2]1[C:15]([S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[Cl:1][C:2]1[C:15]([S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O
Product: O=C(O)C1Cc2cc(S(=O)(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 80 °C

Procedure:
To a well stirred mixture of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (5.2 g) and 2-thienylsulfonyl chloride (3.6 g) protected from the atmosphere with a calcium chloride tube is added the anhydrous aluminum chloride (2.6 g) over a five minute period. The reaction mixture is stirred at 25° C. for 18 hours and at 90° C. for one hour, then poured into ice water (150 ml) and hydrochloric acid (15 ml). The esterified product is extracted into ether, washed with brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The residue is warmed (80° C.) in 10% NaOH (100 ml) for one hour to obtain a solution which is acidified with hydrochloric acid (25 ml) to obtain the product as a viscous oil. The product is extracted into ether, washed with brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydro-5-(2-thienylsulfonylbenzofuran-2-carboxylic acid hemihydrate melts at 189°-193° C. after purification by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1c(Cl)cccc1N1CCNCC1
Yield: 78.5 %

Procedure:
To a stirred solution of 3-chloro-2-methylaniline (compound 26, 21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (compound 27, 30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].C(O[C:24](=[O:40])[CH:25]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C.[C:41]12([NH:51][C:52](=[O:55])[CH2:53]Br)[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>C1COCC1>[C:41]12([N:51]3[C:52](=[O:55])[CH2:53][C:25]([CH2:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)([CH2:33][C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)[C:24]3=[O:40])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2
Reactant: CCOC(=O)C(Cc1ccncc1)Cc1ccncc1
Reactant: O=C(CBr)NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CC(Cc2ccncc2)(Cc2ccncc2)C(=O)N1C12CC3CC(CC(C3)C1)C2
Temperature: -25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a distilled THF solution (30 ml) at -78° C. under a nitrogen atmosphere containing diisopropylamine (1.13 ml, 8.032 mmol distilled from sodium metal) was added butyllithium (BuLi) (8.032 mmol). The solution was allowed to warm to approximately -25° C., recooled to -78° C. and stirred for 1 hour. The lithium diisopropylamide (LDA) solution was added (via cannula) to a separate flask containing 3-pyridin4-yl-2-pyridin-4-ylmethyl-propionic acid ethyl ester (2.056 g, 8.032 mmol) in THF (30 ml) at -78° C. The red mixture was allowed to warm to approx. -25° C., recooled to -78° C., and stirred for 1 hour. To this lithium enolate solution was added (via cannula) a solution of N-adamantan-1-yl-2-bromo-acetamide (2.186 g, 8.032 mmol) in THF (10 ml) at -78° C. The mixture was kept at -78° C. for 16 hours, warmed to ambient temperature and stirred for two additional hours. The mixture was quenched with EtOAc, washed with an equal volume of H2O and brine, dried (Na2SO4) and concentrated in vacuo to a brown oil. The crude mixture was chromatographed on silica gel (1:1 acetone:hexane) to afford 475 mg (14%) of the title compound as a white solid, which was recrystallized from isopropyl ether, mp 137°-138.5° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH:10]1[NH:19][C:20](=[O:29])[CH2:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:16]2>O1CCOCC1>[CH:9]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH:10]1[NH:19][C:20](=[O:29])/[C:21](/[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[CH:3]\[N:4]([CH3:5])[CH3:6])[CH2:18]2
Reactant: O=C(CC(=O)C1CCCC1)NC1C2CC3CC(C2)CC1C3
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=C(\C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.587 mL, 4.42 mmol) was added to N-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide (Intermediate#72), (1.023 g, 3.53 mmol) in 1,4-dioxane (25 mL). The resulting solution was stirred at 100° C. for 2 hours. The resulting mixture was evaporated to dryness to afford (Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide (1.210 g, 99%).
Reaction SMILES: C(O)(=O)[CH2:2][C:3]([CH2:8]C(O)=O)([C:5](O)=O)[OH:4].[C:14]([O:18][C:19]([NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[CH:51]=[CH:50][C:30]([C:31]([NH:33][C:34]3[CH:49]=[CH:48][CH:47]=[CH:46][C:35]=3[C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)=[O:37])=[O:32])=[C:29]([O:52][CH:53]3[CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55][CH2:54]3)[CH:28]=2)[CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].FC1C=CC([C:71](NC2C=CC=CC=2C(NC2C=CC(Cl)=CN=2)=O)=[O:72])=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=1.C(OC(NC1CCNC1)=O)(C)(C)C>>[C:14]([O:18][C:19]([NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[CH:51]=[CH:50][C:30]([C:31]([NH:33][C:34]3[CH:49]=[CH:48][CH:47]=[CH:46][C:35]=3[C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)=[O:37])=[O:32])=[C:29]([O:52][CH:53]3[CH2:54][CH2:55][N:56]([O:4][C:3]([CH3:8])([CH3:5])[CH3:2])[C:57](=[C:71]=[O:72])[CH2:58]3)[CH:28]=2)[CH2:23]1)=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)Nc3ccccc3C(=O)Nc3ccc(Cl)cn3)c(OC3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)Nc3ccccc3C(=O)Nc3ccc(Cl)cn3)c(OC3CCN(OC(C)(C)C)C(=C=O)C3)c2)C1

Procedure:
Using methods substantially equivalent to those described in Example 4-F except that saturated aqueous citric acid was used instead of water in the workup, 2-[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (234 mg, 0.32 mmol, 44%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and 3-tert-butoxycarbonylaminopyrrolidine.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([S:55][CH3:56])=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[C:39]([S:55][CH3:56])[N:37]5[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(SC)n2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and 6-fluoro-3-methylsulfanyl-1-tributylstannanyl-imidazo[1,5-a]pyridine (crude from Step 4) were dissolved in DMF (2 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 109 mg (82%) of 2-(6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(O)C.O.Cl.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([CH:11]2[C:20]([CH3:21])([CH3:22])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[NH:12]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N)cc(Cl)c1)N2
Yield: 83.5 %

Procedure:
To a solution of methyl 2-(3-chloro-5-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (124 mg, 0.33 mmol) in ethanol/water (2 mL/0.5 mL) was added 2 drops of conc. hydrochloric acid and iron (370 mg, 6.62 mmol). The mixture was stirred and heated to reflux for 4 h. LC-MS showed most of SM was consumed. The mixture was dried over silica gel and washed through a short column with petroleum ether:ethyl acetate=3:1 to afford 95 mg of methyl 2-(3-amino-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a brown solid. (Yield=83%). MS (ESI+APCI) M+1=345.
Reaction SMILES: B.C1COCC1.C1COCC1.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[CH:21]([CH2:37][CH3:38])[C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:26]=2)[CH:21]([CH2:37][CH3:38])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC1C(=O)N(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 47.3 %

Procedure:
At 0° C., 5 ml of 1 M borane-THF solution was added dropwise to 30 ml of anhydrous THF solution containing 1.47 g of 4-(4-benzyl-2-ethyl-3-oxopiperazin-1-yl)-2-trifluoromethylbenzonitrile synthesized in Reference Example 5-1, and the mixture was stirred for 4 hours. After addition of 10 ml of methanol and 38 ml of 1 N hydrochloric acid to the mixture with stirring, the reaction solution was evaporated under reduced pressure, the resulting residue was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 0.67 g of the title compound was obtained from hexane-ethyl acetate (5:1, v/v) eluate as yellow oily substance.
Reaction SMILES: [O:1]=[C:2]([N:7]1[CH2:10][CH2:9][C@H:8]1[C:11]1[N:15]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:14]=[N:13][N:12]=1)[C:3](=[O:6])OC.[CH3:25][C:26]([Mg]Cl)([CH3:29])[CH2:27][CH3:28].[Cl-].[NH4+].CO>O1CCCC1.ClCCl>[O:1]=[C:2]([N:7]1[CH2:10][CH2:9][C@H:8]1[C:11]1[N:15]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:14]=[N:13][N:12]=1)[C:3](=[O:6])[C:26]([CH3:29])([CH3:25])[CH2:27][CH3:28]
Reactant: COC(=O)C(=O)N1CC[C@H]1c1nnnn1CCCc1cccnc1
Reactant: CCC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1c1nnnn1CCCc1cccnc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
(2S)-1-(1,2-Dioxo-2-methoxyethyl)-2-(1-[3-(3-pyridyl)-1-propyl]-1H-tetrazol-5-yl)azetidine from Reference Example 19 (95.8 mg, 0.290 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (THF) (1.0 mL) and cooled to about −78° C. under an argon atmosphere. To this solution, 1,1-dimethylpropylmagnesium chloride in THF (380 μL of 1M, 0.380 mmol, 1.3 eq) was introduced via syringe. After stirring the resulting homogeneous mixture at about −78° C. for about 3 hours, the mixture was poured into saturated ammonium chloride and extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated. Flash chromatography of the residue (0-10% methanol in dichloromethane) afforded 8.7 mg (8% yield) of the product as a colorless semisolid along with 30.3 mg recovered starting material (32% yield). 1H NMR (CDCl3) δ 0.78 (t, 3H, J=6.9); 0.97-1.18 (series of s, 6H); 1.54 and 3.17 (series of m, 8H); 3.82-4.66 (series of m, 4H); 5.33-5.90 (series of dd, 1H); 7.21-7.31 (m, 1H); 7.57 (d, 1H, J=7.7); 8.49 (s, 2H).