Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2N)[CH2:11][CH2:10]1.[I:19]CI>C1COCC1.[Cu](I)I>[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[I:19])[CH2:11][CH2:10]1
Reactant: Nc1cnccc1C1CC1
Reactant: ICI
Agent: I[Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Ic1cnccc1C1CC1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Isoamyl nitrite (2.62 gm, 22.38 mmol) was added to the stirred solution of 4-cyclopropylpyridin-3-amine (1.0 g, 7.46 mmol) in dry THF (15 mL) under argon atmosphere. This was followed by the addition of diiodomethane (3.0 mL, 22.38 mmol) and copper iodide (1.42 g, 7.46 mmol). The resulting mixture was refluxed at 80° C. for 1 hour. The reaction mixture was cooled, filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 600 mg of the product (34% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1

Procedure:
Prepared by a method analogous to that described in example 1 from (R)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-formylphenyl boronic acid, tetrakis(triphenylphosphine)palladium (0), sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions. The aqueous layer was extracted by chloroform and evaporated to gave the title compound; MS (ES+) 341 (MH+)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(O)C>C(Cl)(Cl)Cl.CO>[CH3:24][S:25]([O:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)(=[O:27])=[O:26]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(COS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
2-Hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.2 g) was added to anhydrous pyridine (24 ml). The mixture was stirred on ice, during which methanesulfonylchloride (625 mg) was added thereto, followed by stirring at room temperature for 100 minutes. Methanesulfonylchloride (283 mg) was added again and stirred at the same temperature for 50 minutes. After completion of the reaction, a small amount of ethanol was added, and the mixture was brought to dryness under reduced pressure. The residue was dissolved in a solvent mixture of chloroform and methanol (10:1), washed with diluted HCl, sodium bicarbonate water, and aqueous NaCl solution in this order, and dried. When the solvent was evaporated, 1.6 g (quantitative assay) of the title compound was obtained. This substance was recrystallized from a solvent mixture of chloroform-n-hexane, obtaining colorless powdery crystals having a melting point of 200°-203° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][NH:44][CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]([CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCN(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 24.6 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (10 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (0.057 mL, 0.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provided the title compound (13 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.O=S(Cl)[Cl:20].CCOC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([Cl:20])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccc(Cl)cc2CCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Yield: 71.6 %

Procedure:
To a mixture of 13.3 g (54 mmol) of 8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 290 mL of toluene at −15° C. and under an atmosphere of nitrogen was added via syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) of SOCl2. The extent of reaction was monitored by TLC (50% EtOAc in hexanes). When completed the mixture was poured into 300 mL of 1.0 N aqueous NaOH and extracted with EtOAc (5×). The combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in EtOAc, quickly filtered through basic alumina, and concentrated again to yield a product which was triturated with pentane to yield 10.22 g of the title compound as a tan solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:3].[S:17]1[CH:21]=[C:20]([C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[N:19]=[CH:18]1>N1C=CC=CC=1>[CH:6]1([CH2:5][O:4][C:2]([N:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=[C:22]2[C:20]2[N:19]=[CH:18][S:17][CH:21]=2)=[O:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)OCC1CCCCCCCCCC1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: O=C(OCC1CCCCCCCCCC1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.3 G. (0.082 moles) of cycloundecylmethyl chloroformate is added dropwise at room temperature to 16.4 g. (0.082 moles) of 2-(4-thiazolyl)-benzimidazole suspended in 200 ml. of pyridine. The temperature rises spontaneously to 35° C and the reaction mixture is then stirred overnight at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue is treated with methylene chloride and washed 3 times with 2.5N hydrochloric acid and twice with water. The methylene chloride is treated with charcoal, filtered and evaporated to dryness in vacuo affording 25 g. of an oil which solidifies on standing and is recrystallized from hexane affording 20 g. of 1-cycloundecylmethoxycarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 86° to 87° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])(=[O:7])=[O:6]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)CCCCl
Product: CCN(CC)S(=O)(=O)CCCCl

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and diethylamine. High vacuum drying gave the title compound (570 mg, 95%) which was used without characterization in the next step.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH3:4].F[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[CH2:3]([C:5]1[N:6]=[CH:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)[CH3:4]
Reactant: CCc1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cn(-c2ccc(C(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
NaH (0.068 g in 60% oil dispersion, 1.7 mmol) was added to a solution of compound 16 (0.180 g, 1.8 mmol) in DMF (6 mL) with stirring at room temperature. The mixture was stirred for 15 min and a solution of 4′-fluoroacetophenone (0.215 g, 1.56 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 80° C. for 1 h, and then cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated to a yellow solid. Compound 17 crystallized to form white color needles upon standing at room temperature. The yield was 0.270 g, 67%. The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=215. Purity was >98%.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[N:16]2[C:17](=[O:31])[C@@H:18]([NH:23][C:24](=[O:30])[C@@H:25]([N:27](C)[CH3:28])[CH3:26])[CH2:19][CH:20]=[CH:21][CH2:22][C@H:15]2[CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:9][C:10]([C@H:12]1[N:16]2[C:17](=[O:31])[C@@H:18]([NH:23][C:24](=[O:30])[C@@H:25]([NH:27][CH3:28])[CH3:26])[CH2:19][CH:20]=[CH:21][CH2:22][C@H:15]2[CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](C(=O)N[C@H]1CC=CC[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O)N(C)C
Agent: CN[C@@H](C)C(=O)N[C@H]1C/C=C\C[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O
Agent: C[C@@H](C(=O)N[C@H]1C/C=C\C[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O)N(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN[C@@H](C)C(=O)N[C@H]1CC=CC[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O

Procedure:
Product 11I is reconstituted in 20% trifluoroacetatic acid in dichloromethane (50 mL). Stirring until reaction complete by HPLC. Toluene is added and concentrated to an amber oil. The product is dissolved in dichloromethane and washed with saturated bicarb followed by drying over anhydrous magnesium sulfate, filtering and concentrating. HPLC purification to yield 12. LCMS characterization ES+413.1 (m+1).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:66])=[CH:63][CH:62]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCCC1
Yield: 74 %

Procedure:
The compound of example 532 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-chloro benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:33])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:33])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][C:24]([CH:27]5[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]5)=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(C3CCNCC3)s2)c1
Agent: C=O
Agent: [Na+]
Product: CN1CCC(c2cnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)s2)CC1

Procedure:
Analogously to Example 28.5, 6-(3,5-difluorophenyl)-2-[3-(5-piperidin-4-ylthiazol-2-yl)benzyl]-2H-pyridazin-3-one is reacted with formaldehyde and sodium triacetoxyborohydride to give 6-(3,5-difluorophenyl)-2-{3-[5-(1-methylpiperidin-4-yl)thiazol-2-yl]benzyl}-2H-pyridazin-3-one (“A92”), ESI 479.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2cccc(F)c2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.2 %

Procedure:
A mixture of (S)-1-(7-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 7 (367 mg, 1.44 mmol), 6-chloro-9H-purine (222 mg, 1.44 mmol) and DIPEA (0.74 mL, 4.31 mmol) in n-butanol (3.5 mL) was stirred in a sealed tube for 48 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The product thus obtained was further purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in EtOAc) followed by (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in MeOH. The suspension was then diluted with diethyl ether and the solid collected by filtration affording 124 as a white solid (103 mg, 19%). LCMS: RT 3.40 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 8.17-8.04 (2H, m), 7.98-7.86 (1H, br), 7.75-7.35 (6H, m), 7.19 (1H, td, J=8.09, 4.87 Hz), 7.02 (1H, dd, J=11.60, 8.02 Hz), 5.37 (1H, bs), 1.56 (3H, d, J=6.86 Hz)
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:38][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccn2)c1
Yield: 38 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.155 g, 0.289 mmol) and 2-tributylstannyl pyridine (0.210 g, 0.571 mmol) in dry toluene (8 mL) is purged with N2 and then tetrakis(triphenylphospine)pallium (0) (0.033 g, 0.029 mmol) is added. The reaction is heated to 100° C. and stirred for 20 hours under N2. The reaction is cooled, and the solvent is removed in vacuo to give crude 3-{2-methyl-4-[3-methyl-5-(2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester. This ester is dissolved in ethanol (8 mL), treated with 5 N NaOH (2 mL) and heated to reflux until saponification is complete. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to give crude product that is purified by preparative HPLC to afford 0.056 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[CH3:14].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:15]1([CH:2]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1sc(-c2ccccc2)cc1C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-2-methyl-5-phenylthiophene (1.08 g) synthesized above, methyl 4-aminobenzoate (1.07 g), sodium iodide (1.06 g) and N,N-dimethylacetamide (20 mL) was added sodium carbonate (668 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (10 mL) and ethanol (10 mL) 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred heated under reflux for 2.5 hr. 1N Aqueous sodium hydroxide solution (5 mL) was added again, and the mixture was further stirred with heated under reflux for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained white solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.21 g, 84%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].Cl.[O:9]([CH2:16][CH2:17][CH2:18][NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.O>C(Cl)Cl>[O:7]=[C:2]([NH:19][CH2:18][CH2:17][CH2:16][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: NCCCOc1ccccc1
Reactant: COC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(=O)NCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloro(oxo)acetate (1.77 mL) was added to a stirred solution of (3-phenoxypropyl)amine hydrochloride (3000 mg) and pyridine (2.98 mL) in DCM (100 mL) at 0° C. After the addition was complete the solution was allowed to warm to ambient temperature and stirred for 16 hours. Water (50 mL) was added and the mixture was extracted with DCM (2×75 mL). The organic extracts were combined, washed with brine (50 mL), dried and concentrated in vacuo to give an oil. This was purified by flash chromatography on a 90 g Biotage™ silica column using a gradient of 10-60% EtOAc in hexane as the eluent to give methyl oxo[(3-phenoxypropyl)amino]acetate (3212 mg) as a solid; 1H NMR δ (CDCl3) 7.60 (1H, bs), 7.28 (2H+CHCl3, m), 6.94 (3H, m), 4.07 (2H, t), 3.90 (3H, s), 3.58 (2H, quartet), 2.08 (2H, m), +0.1 mole of EtOAc; MS m/e MH+ 238.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH:29]([B-](F)(F)F)=[CH2:30].[K+].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)CC>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH:29]=[CH2:30])=[N:9]2)=[CH:5][CH:4]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1nn(Cc2ccc(OC)cc2)c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A stirred mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (2.45 g, 5.00 mmol; prepared as in Example 7, Step B), potassium vinyltrifluoroborate (0.804 g, 6.00 mmol), triethylamine (0.693 mL, 5.00 mmol), and n-propanol (20 mL) was sparged with N2 for 5 minutes, and then Pd(dppf)Cl2 (82 mg, 0.10 mmol) was added. The sealed reaction was heated at 10° C. for 2 hours. The product and residual starting material were separated from catalyst and other by-products and re-subjected to the reaction conditions as follows. The reaction was concentrated in vacuo. The residue was partitioned between DCM (30 mL) and water (30 mL). The phases were separated, and the aqueous phase was re-extracted with DCM (2×10 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was separated from catalyst and other by-products by Biotage Flash 40, eluting with 20% EtOAc/hexanes then 1:1 EtOAc/hexanes. The product and starting material (1:1 ratio by 1H NMR) was resubjected to the same reaction conditions as above. After 2 hours at 100° C., all starting material had been consumed. After workup and Biotage Flash 40 purification as before, the product was obtained as an off-white solid (1.29 g, 66%). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=6 Hz, 1H), 7.33 (d, J=9 Hz, 2H), 7.18 (m, 1H), 7.01 (t, J=9 Hz, 1H), 6.82 (d, J=9 Hz, 2H), 6.52 (m, 2H), 6.34 (m, 1H), 6.23 (m 1H), 5.62 (s, 2H), 5.45 (m, 1H), 3.81 (br s, 2H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29]3)[C:23]=2[CH3:39])=[C:8]2[C:12]=1[NH:11][C:10]1[CH:13]=[N:14][C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][C:9]2=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29]3)[C:23]=2[CH3:39])=[C:8]2[C:12]=1[NH:11][C:10]1[CH:13]=[N:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1c(C(N)=O)ccc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cnc(C(=O)O)cc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
A solution of ethyl 8-carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (0.26 g, 0.502 mmol) and lithium hydroxide monohydrate (0.070 g, 1.757 mmol) in THF-ethanol-water (3:1:1, 20.10 mL) was stirred at room temperature overnight. After 18 h, residual starting material was observed by LCMS. The mixture was heated at 50° C. for 2 h, then cooled to room temperature and concentrated. The residue was suspended in water and treated with 1 M aqueous HCl (to pH 1-2). The precipitate was collected by filtration, washed with water and dried to provide the desired product as a pale yellow solid (0.205 g, 76%). LCMS (M+H)+ m/z 490.1.