Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([O:25][C:26]4[CH:34]=[C:33]5[C:29]([CH:30]=[C:31]([CH3:35])[NH:32]5)=[CH:28][CH:27]=4)=[N:20][CH:21]=[N:22]3)=[CH:17][C:16]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][O:36][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:22]=[CH:21][N:20]=[C:19]2[O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[C:31]([CH3:35])[NH:32]2)=[CH:28][CH:27]=1
Reactant: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OC1CCNCC1
Reaction time: 0.58 h
Yield: 95.4 %

Procedure:
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]quinazoline (1 g) was dissolved in dichloromethane (5 ml) and cooled in an ice bath. TFA (2.5 ml) was added and the reaction mixture stirred at this temperature for 35 minutes. The volatiles were removed by filtration and the residue taken up into ice cold water. The pH was adjusted to 12 with sodium hydroxide 2N and extracted twice with dichloromethane. The combined extracts were washed in turn with water and brine and dried over magnesium sulphate and the solvent evaporated under vacuum to give 6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)oxy]quinazoline (0.765 g) as a solid foam.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][N:20]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[Cl:18][C:4]1[CH:3]=[C:2]([C:19]#[N:20])[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[CH:5]=1
Reactant: Cc1nc2c(Br)cc(Cl)cc2n1C1CCCCO1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc2c(C#N)cc(Cl)cc2n1C1CCCCO1
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (3.2 g, 9.70 mmol), Zn(CN)2 (2.3 g, 19.40 mmol), and Pd(PPh3)4 (1.1 g, 0.97 mmol) in NMP (20 mL) was stirred at 90° C. for 3 h. The reaction mixture was filtered and the filtrate diluted with EtOAc (50 mL). The organic layer was washed with water (50 mL×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM:MeOH gradient (0 to 6% MeOH) to afford 6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-4-carbonitrile as a white solid (1.0 g, 37.2%). MS (ESI): m/z=276.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([O:26]CC)=[O:25])[N:15]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[N:15]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Yield: 74.8 %

Procedure:
Ethyl 2-[3-[4-(4-chlorobenzamido)benzyl]-1H-indazol-1-yl]acetate (100 mg, 0.223 mmol) was dissolved in 3 mL tetrahydrofuran, and 1 mL methanol, 3 mL water were added. In an ice bath was, 47 mg (1.12 mmol) lithium hydroxide monohydrate was added. I was moved to be at room temperature and reacted for 10 minutes. The reaction was monitored to be complete by TLC. Diluted hydrochloric acid was added to adjust pH to be acidic. Water was added, pumping filtered, dried to obtain a white solid 70 mg, at a yield of 74.9%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N)=C(C(C[C@H](N)C(O)=O)=O)C=1.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:10]1=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)c2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione (12.5 g) prepared from L-kynurenine as described in Australian J. Chemistry Vol. 33, 633-40 (1980), and t-butyl bromoacetate (10.1 g) in acetone (700 ml) was stirred at room temperature under a dry nitrogen atmosphere. Potassium carbonate (12.5 g) was added in one portion and the resulting suspension was stirred at room temperature for 16 hours. The potassium salts were filtered off and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate (250 ml) and H2O (250 ml). The layers were separated and the organic phase dried (sodium sulfate). The residue was triturated wth petroleum ether (350 ml; bp 30°-60°) to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione, m.p. 75°-77° C., [alpha]D =-172° (c=0.96 in DMF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.[CH3:16][O:17]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)C(C)(C)C(=O)N2C
Reaction time: 1.5 h

Procedure:
Under nitrogen, combined 282 mg of 6-Methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (1.37 mmol) with 10 ml of CH2Cl2 and chilled in ice-H2O bath. Added 4.1 ml of 1.0 M titanium tetrachloride in CH2Cl2 (4.1 mmol) dropwise. Stirred in cold for 1.5 hours. Added 186 μl of α,α-dichloromethyl methyl ether (2.06 mmol and stirred in cold for 15 minutes, then at room temperature overnight. Poured over ice-H2O, extracted three times with CH2Cl2. The combined organics were extracted with brine, sat. NaHCO3, brine, dried (MgSO4) and the solvent evaporated in vacuo to 289 mg of green solid (91%). 1H NMR (400 MHz, CDCl3) δ 1.35 (6H, s), 3.25 (3H, s), 3.98 (3H, s), 6.42 (1H, s), 7.68 (1H, s), 10.35 (1H, s), M/z (APCI+) 234.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:41])=[C:5]([C:32]([O:39]C)=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:11]([CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:36][O:35][C:34]1[C:3](=[O:2])[C:4]([CH3:41])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[C:11]([CH:25]=2)[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[O:13])[C:32](=[O:39])[C:33]=1[O:37][CH3:38]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]-4-trifluoromethylaniline (140 mg, 0.2473 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (399 mg, 0.7416 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (60 mg, 0.1119 mmol, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:28]5[S:29][C:25]([CH3:24])=[CH:26][CH:27]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(C)s4)nc3cc21

Procedure:
5-Methyl-thiophene-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 5-methylthiophen-2-carboxylic acid (125 mg, 0.89 mmol). The title compound was obtained as yellow powder (166 mg, 47%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(P(C#N)(CC)=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]/[C:14]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[CH:17][CH:18]=1
Reactant: NCc1cccnc1
Reactant: COCCOCOc1ccc(C=CC(=O)O)cc1
Agent: CCP(=O)(C#N)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
3.74 g of 4-[(2-methoxyethoxy)methoxy]cinnamic acid and 1.68 g of 3-(aminomethyl)pyridine were dissolved in 30 ml dimethylformamide, and stirred with 2.7 ml diethylphosphoryl cyanide and subsequently with 2.5 ml triethylamine on ice, followed by further stirring at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide (E)-3-[4-[(2-methoxyethoxy)methoxy]phenyl]-N-(3-pyridylmethyl)-2-propenoic acid amide as a pale yellow oil (4.54 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:19])[CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[N:25][CH:26]=1.C1(C)C=CC=CC=1>[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:15]([N:14]([CH2:17][CH3:18])[CH2:13][CH:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[OH:19])[CH3:16]
Reactant: CCN(CC)CC(O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CC(O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-bromo-5-(2-(diethylamino)-1-hydroxyethyl)benzoate (80 mg, 0.24 mmol), 5-methyl-2-(tributylstannyl)pyridine (100 μL, 0.30 mmol), tetrakis(triphenylphosphine)-palladium(0) (14 mg, 0.012 mmol) and toluene (2.6 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature, poured into brine (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (0-100% EtOAc/hexane) to yield the title compound as a yellow oil. LC-MS: 343.7 [M+1]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N(C)CCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 92 mg, 0.189 mmol), (6-methylpyridin-3-yl)boronic acid (25.9 mg, 0.189 mmol) and Na2CO3 (60 mg, 0.566 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.6 mg, 0.0094 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge. Additional purification (Isolute Flash Silica gel cartridge, 5 g, elution of impurities with EtOAc, subsequent elution of product with MeOH) afforded the title compound. LC-MS (Condition 5) tR=1.65 min, m/z=461.2 [M+H]+, m/z=459.2 [M−H]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[CH:22]=[C:23](O)[CH3:24])=O)C1C=CC=CC=1.S([O-])([O-])(=O)=[O:27].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1.O>[OH:27][CH2:24][CH:23]=[CH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH3:15]
Reactant: CC(O)=C[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@@H]1C=CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of lithium aluminum hydride (0.73 g, 19.24 mmol, 2.2 equivalents) in anhydrous tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-2--hydroxypropene (2.30 g, 8.80 mmol) in anhydrous tetrahydrofuran (20 mL). The resulting reaction mixture was heated at reflux under nitrogen for 3.5 hours. The resulting mixture was then cooled, and sodium sulfate dicahydrate (10 g) was added slowly with caution. This mixture was stirred at room temperature under nitrogen for 1 hour, and then ethyl acetate (100 mL) and water (1 mL) was added. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was then filtered through Celite®, and the filtrate was evaporated under reduced pressure. Column chromatography of the residual oil using silica gel (approximately 200 g) and elution with methylene chloride/methanol/ammonium hydroxide (9:1:0.1) afforded the title compound (1.13 g, 8.00 mmol, 91%) as clear, colorless liquid: 13C NMR (CDCl3) δ 132.6, 132.5, 69.0, 62.7, 56.6, 40.2, 31.8, 22.1; Anal. calcd for C8H15NO.0.175 H8NO [ammonium hydroxide]: C, 65.21; H, 10.88; N, 11.34. Found: C, 65.01; H, 10.71; N, 10.81.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27](Cl)=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:69][C:70]([CH3:74])([CH3:73])[C:71]#[CH:72]>CC#N.CC#N.Cl[Pd]Cl>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([C:72]#[C:71][C:70]([CH3:74])([CH3:73])[CH3:69])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(Cl)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cccc(C#CC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A vial was charged with methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-chlorobenzoate (841 mg, 2.114 mmol), dichlorobis(acetonitrile)palladium(II) (54.8 mg, 0.211 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (302 mg, 0.634 mmol) and cesium carbonate (1.79 g, 5.50 mmol). The vial was evacuated and backfilled with nitrogen gas 3×. ACN (9 mL) was added and the suspension was allowed to stir at RT for 20 min. 3,3-Dimethyl-1-butyne (0.521 mL, 4.23 mmol) was added and the reaction mixture was heated to 90° C. for 3.5 h. The reaction mixture was partitioned between water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduce pressure and the remaining residue was purified by column chromatography (10% MeOH in DCM). Methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)benzoate was obtained as an orange-brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH2:10][CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)Nc1ccccc1
Yield: 60.9 %

Procedure:
A solution of 1-(3-aminopropyl)-4-benzylpiperazine (3.0 g; 12.9 mmole) and phenyl isocyanate (1.54 g; 12.9 mmole) in methylene chloride (20 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from aqueous acetone to provide the title compound as colorless crystals (2.77 g; 61% yield), m.p. 45°-47° C.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.[OH-].[Na+]>>[C:33]([O:32][C:30]([NH:29][CH:5]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[C:4]([OH:37])=[O:3])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(-c3ccc(Oc4ccccc4)cc3)ccc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2cc(-c3ccc(Oc4ccccc4)cc3)ccc12)C(=O)O
Temperature: 30 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
2-tert-Butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]-propionic acid (17) was prepared as follows: A mixture of compound 16 (0.1 g in 4 mL MeOH) and NaOH (0.5N aqueous, 0.5 mL) was shaken at 30° C. for 24 hours. The solvent was removed under vacuum. The residue was suspended in CHCl3 (20 mL), neutralized with 0.5N HCl to ˜pH 2, and concentrated to get compound 17 as a white solid (50 mg, 53%): 1H-NMR (400 MHz, CD3OD/CDCl3 3/1) δ: 7.8-7.84 (m, 3H), 7.75 (s, 1H), 747-7.57 (m, 3H), 7.2-7.32 (m, 6H), 4.61-4.65 (m, 1H), 3.51-3.55 (m, 1H), 3.31-3.37 (m, 1H), 1.43-1.6 (m, 9H); LC/MS: m/z=495.6 [M+Na+]+ (Calc: 472.5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I.[Cl-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccccn1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccccn1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 2-[2-(N-t-butoxycarbonylamino)ethyl]-pyridine (1.8 g) in N,N-dimethylformamide (7 ml) was added dropwise to a suspension of sodium hydride (0.39 g) in N,N-dimethylformamide (7 ml) which was cooled at 0° C. The mixture was stirred at 0° C. for 1 hour. Methyl iodide (1.4 g) was added to this solution at the same temperature. After stirring at 0° C. for 1 hour and at ambient temperature for 2 hours, the mixture was poured into ice water, saturated with sodium chloride, and extracted with ethyl acetate 3 times. The combined organic layer was washed with saturated sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel chromatography (ethyl acetate:n-hexane, 3:1, V/V, as eluent) to give 2-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]-pyridine (1.47 g) as an oil.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccc3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
138.2 mg (0.65 mmol) of 4-biphenylacetic acid and 99.7 mg (0.65 mmol) of 1-hydroxy-1H-benzotriazole hydrate are initially charged at room temperature in 5 ml of dimethylformamide. 150 mg (0.72 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 138.7 mg (0.72 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 72 h. The reaction mixture is then filtered off with suction and the residue is recrystallized from 2-propanol. This gives a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20](CC2C=CC(OC)=CC=2OC)[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:17]([NH:20][C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:18])=[O:19])[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Sc3ccccc3F)c(C#N)c2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Sc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To 3-cyano-N-(2,4-dimethoxybenzyl)-4-[(2-fluorophenyl)thio]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 13, 0.320 g, 0.590 mmol) was added a 4M solution of hydrogen chloride in 1,4-dioxane (10 mL). The reaction was stirred at ambient temperature overnight before concentrating in vacuo. The residue purified by silica gel flash column chromatography (ethyl acetate:methanol elution) followed by reverse phase column chromatography to afford the title compound as a solid (0.055 g, 24%).