Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1.[CH3:32]N(C=O)C.[H-].[Na+].IC>O>[NH2:1][C:2]1[C:7]([N:8]([CH3:32])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
54 mg (0.13 mmol) of ethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 2 are added to 5 ml of DMF, the mixture is cooled to 0° C., and 7.67 mg (0.19 mmol) of sodium hydride are added. Then 18.14 mg (0.13 mmol) of iodomethane are added dropwise, and the mixture is stirred for one hour. The mixture is mixed with water and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is purified first by column chromatography (mobile phase: dichloromethane/methanol=10:1) and then by preparative RP-HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2[nH]c(C)nc2s1
Yield: 80.4 %

Procedure:
Ethyl 2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-thieno[2,3-d]imidazol-5-carboxlate (745 mg) was dissolved in ethanol (10 ml) and 6N hydrochloric acid (10 ml) was added, which was followed by reflux under heating for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the solution became weak alkaline, and the mixture was stirred with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the objective compound (370 mg) as white crystals.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:34][O:33][C@H:32]5[C@@H:27]([O:28]C(C6C=CC=CC=6)[O:30][CH2:31]5)[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:34][O:33][C@H:32]([CH2:31][OH:30])[C@@H:27]([OH:28])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@H](CO)[C@@H](O)C2)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (476 mg, 0.710 mmol) under nitrogen in anhydrous DCM (6.0 mL) was added 4A molecular sieves (1.6 g). The mixture was cooled to 0° C., then triethylsilane (0.85 mL, 619 mg, 5.33 mmol) and TFA (0.41 mL, 607 mg, 5.33 mmol) were added. The mixture was stirred at 0° C. for 1.5 hours, and then allowed to stir 1 hour at room temperature. The mixture was then cooled to 0° C. and a saturated aqueous solution of potassium carbonate (30 mL) was added dropwise over 3 minutes. After stirring at room temperature for an additional 5 minutes, the mixture was filtered, diluted with saturated aqueous sodium bicarbonate (30 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 25 g silica gel cartridge eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 25 column volumes with a 15 column volume hold at 100% EtOAc. The product fractions were combined and concentrated under reduced pressure to give the desired product as a white solid. LC-MS: calculated for C30H36ClN3O5Si 581.21, observed m/e: 582.31 (M+H)+ (Rt 2.66/4 min).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[OH:13].Br[CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:8](=[O:16])[N:9]([CH2:14][CH3:15])[N:10]=[CH:11][C:12]=1[O:13][CH2:18][C:19]1[S:20][C:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: CCn1ncc(O)c(Cl)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(OCc2ccc(C(=O)c3ccc(Cl)cc3)s2)c(Cl)c1=O
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To 20 ml of N,N-dimethylformamide were added 1.9 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone, 3.2 g of 2-bromomethyl-5-(4-chlorobenzoyl)-thiophene and 1.5 g of potassium carbonate, and the mixture was stirred at 50° to 60° C. for 2 hours. After cooling, the reaction mixture was poured into 50 ml of water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 4.0 g of a crude product. The crude product was recrystallized from 2-propanol to obtain 3.1 g of 4-chloro-5-[{5-(4-chlorobenzoyl)-2-thienyl}-methyloxy]-2-ethyl-3(2H)-pyridazinone, m.p. 168.0°~168.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[H][H]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCO
Product: COc1cc(F)ccc1N
Yield: 99.6 %

Procedure:
Paladium/carbon(Pd/C, 5%, 0.5 g) was added to a solution of 4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which was then stirred for 1 hour under 30 psi of hydrogen pressure. The reaction mixture was filtered to remove paladium/carbon, and concentrated to give 1.35 g of the titled compound. (Yield 100%)
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 18: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodomethane (0.01 g). MS m/z (rel. intensity, 70 eV) 325 (M+, 63), 324 (bp), 305 (13), 191 (32), 133 (24).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:8]([CH:12]=O)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:24])[C:19]([NH2:23])=[CH:20][C:21]=1[CH3:22]>ClCCl.CO>[CH:1]([NH:4][C:5]([C:7]1[C:8]([C:12]2[NH:23][C:19]3[CH:20]=[C:21]([CH3:22])[C:16]([O:15][CH3:14])=[CH:17][C:18]=3[N:24]=2)=[N:9][NH:10][CH:11]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: COc1cc(N)c(N)cc1C
Reactant: CC(C)NC(=O)c1c[nH]nc1C=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2nc(-c3n[nH]cc3C(=O)NC(C)C)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 235(a) above but using 3-formyl-pyrazole-4-carboxylic acid-isopropylamide [198 mg, Reference Example 60)] and 4-methoxy-5-methyl-benzene-1,2-diamine [166 mg, Reference Example 29(b)] and subjecting the reaction product to flash chromatography on silica eluting with dichloromethane/methanol (95:5) followed by recrystallisation from a mixture of ethyl acetate and n-pentane there was prepared 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide (145 mg) as a white solid. LC-MS (Method H): RT=2.09 minutes, 314.27 (M+H)+, 312.29 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=O)[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.P(Cl)(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(Br)c12
Temperature: 105 °C
Yield: 98.1 %

Procedure:
Step 1 A suspension of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 2.2 g, 6.09 mmol) in phosphorus oxychloride (45.4 mL, 487 mmol) was heated at 105° C. for 1 h. The suspension was cooled to rt and concentrated to give a brown solid, which was suspended in water. The precipitate was collected by filtration, washed with water and dried to provide ethyl 5-bromo-8-cyano-9H-carbazole-2-carboxylate (2.05 g, 98%) as light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H) 8.71 (d, J=8.57 Hz, 1H) 8.24 (s, 1H) 7.95 (d, J=8.57 Hz, 1H) 7.89 (d, J=8.13 Hz, 1H) 7.61 (d, J=8.13 Hz, 1H) 4.39 (q, J=7.10 Hz, 2H) 1.37 (t, 2H). Mass spectrum m/z 360, 362 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 106 was prepared from 1-(4-chlorophenyl) cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.32–7.23 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.4 Hz), 2.93 (d, 2H, J=10.8 Hz), 2.86–2.79 (m, 2H), 2.48–2.41 (m, 3H), 2.37–2.30 (m, 4H), 2.07 (m, 1H), 1.98–1.61 (m, 11H), 1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:20](=[O:21])[CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CNC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the ethyl 1-(3-benzylazetidin-1-yl)-3-phenylpropan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=O)[NH:7][CH:8]=1>P(Cl)(Cl)(Cl)=O>[ClH:2].[Cl:1][C:4]1[C:3]([Cl:2])=[CH:8][N:7]=[CH:6][N:5]=1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cncnc1Cl
Temperature: 90 °C
Yield: 49.1 %

Procedure:
A suspension of 5-chloropyrimidone hydrochloride (1.0 g, 6.0 mmol) in phosphorous oxychloride (4 mL) was heated at 90° C. for 90 min then cooled to room temperature and filtered. The crude product was purified by sublimation under reduced pressure to furnish the title compound 20 as a crystalline white solid (273 mg). This compound was unstable to air and was used immediately in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32].CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 μL, 0.10 mmol). The mixture was stirred at room temperature for 1 h before being filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to yield N-(1-(2-acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.15 (t, J=5.9 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m, 2H), 1.41 (s, 9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99% CH3CN, 3 min run; ESI-MS 516.4 m/z (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:4]=1)#[N:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1)[CH:4]=[C:3]2[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc([N+](=O)[O-])ccc32)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc(N)ccc32)CC1
Temperature: 85 °C
Yield: 21.4 %

Procedure:
1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.59-8.43 (m, 1H), 8.31-8.18 (m, 1H), 8.13-8.04 (m, 1H), 4.93-4.80 (m, 1H), 4.23-4.03 (m, 2H), 3.06-2.85 (m, 2H), 2.09-1.96 (m, 2H), 1.94-1.80 (m, 2H), 1.45-1.36 (m, 9H) tert-butyl 4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.02 g, 2.75 mmol), Iron (0.923 g, 16.52 mmol), and ammonium chloride (1.031 g, 19.28 mmol) were suspended in a mixture of Ethanol (10 mL)/Water (10 mL). The reaction mixture was heated in oil bath at 85° C. for 20 min. The reaction mixture was filtered through Celite, then washed with water, MeOH and EtOAc. The combined filtrates were concentrated to almost dryness, then mixed with aq. NaHCO3 and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to give tert-butyl 4-(5-amino-3-cyano-1H-indol-1-yl)piperidine-1-carboxylate (200 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13][N:12]=2)[CH:6]=1.[Li+].[OH-]>COCCOC.O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][NH:17][C:16]([C:15]1[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:6]=2)=[N:12][O:13][C:14]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: COC(=O)Cc1cccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)Cc1cccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 51 is dissolved in DME (2 mL). A solution of 1 M LiOH in H2O (0.2 mL) and is added and the mixture is stirred overnight at room temperature. The mixture is concentrated, then acidified with 1 M HCl, extracted with EtOAc (10 mL), dried over MgSO4, filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound I1 as an off-white solid: 1H-NMR (400 MHz, CD3CN) δ=7.61 (s, 1H), 7.57 (m, 1H), 7.38 (m, 5H), 7.33 (d, J=2.4 Hz, 1H), 7.28 (m, 2H), 7.20 (dd, J=9.2, 2.8 Hz, 1H), 7.16 (t, J=5.2 Hz, NH), 6.90 (d, J=8.8 Hz, 1H), 4.04 (t, J=5.2 Hz, 2H), 3.63 (q, J=5.2 Hz, 2H), 3.59 (s, 2H). MS calculated for C26H21Cl2N2O5 (M+H+) 511.0, found 511.0.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33]Cl)[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:29][N:31]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:15][CH:14]=2)=[CH:25][CH:26]=1
Reactant: CCN(CC)CCCl
Reactant: O=C(c1ccc(O)cc1)c1c(Cc2ccc(Cl)cc2)oc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
A solution of 2-(4-chlorobenzyl)-3-(4-hydroxybenzoyl)benzofuran (2.0 g., 5.5 mmol.) of 50 ml. of toluene is added to a slurry of 0.5 g. of a 57% sodium hydride dispersion (0.01 mol.) in 5 ml. of toluene. The reaction mixture is refluxed for 10 minutes, then 0.82 g. (5.5 mmol.) of 2-diethylaminoethyl chloride is added and the mixture is heated at 90° for four hours. The mixture is filtered and the filtrate concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1cc(F)cc(Sc2ccc(Br)cc2)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(F)cc(F)c3)cc2)c1C
Yield: 56.3 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.176 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3,5-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.14 g, 53%) as a solid. MS calcd. for C26H18ClF2O2S [(M−H)−] 467, obsd. 467.2.
Reaction SMILES: C([O:5][C:6](=[O:14])[C@H:7]([CH3:13])[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])(C)(C)C>Cl.O1CCOCC1>[CH3:13][C@H:7]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([OH:14])=[O:5]
Reactant: C[C@H](CS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](CS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.9 %

Procedure:
Part D: To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)-propionic acid t-butyl ester was added 20 mL of 4N hydrochloric acid/dioxane and the mixture stirred at room temperature for 19 hours. The solvent was removed under reduced pressure to afford 2.18 g of crude product, which was recrystallized from ethyl acetate/hexane to yield 1.44 g of 2(S)-methyl-3-(methylsulfonyl)propionic acid as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[OH:1][C:2]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cc(C)cc(-c2ccccc2)c1O
Temperature: 75 °C
Yield: 71.8 %

Procedure:
2′-Hydroxy-3′-bromo-5′methylacetophenone 233 (0.46 g, 2 mmol) and phenylboronic acid (0.24 g, 1 eq.) are dissolved in DME (10 ml) and placed under a nitrogen atmosphere. Na2CO3 (0.50 g, 3 eq.) in water (10 ml) is added, followed by Pd(Ph3)4 (0.12 g, 0.05 eq.) and the reaction mixture heated to 75° C. for 12-18 h. Most of the DME is removed in vacuo and the reaction mixture is diluted with ether, washed with water, brine, and dried (MgSO4), and concentrated in vacuo to give an oil. Purification by flash chromatography (5/95 EtOAc/hexanes) afforded 2′-Hydroxy-3′-phenyl-5′methylacetophenone 234 as a yellow solid (0.32 g, 71% yield) (Example 519, Table IIIa).