Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[CH3:38][N:39]([CH3:49])[C:40]1[N:45]=CC(B(O)O)=C[N:41]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:41][C:40]([N:39]([CH3:49])[CH3:38])=[N:45][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CN(C)c1ncc(B(O)O)cn1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: CN(C)c1ncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cn1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-(dimethylamino)pyrimidin-5-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=542, obsd.=542).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([C:31]([F:37])([F:36])[F:30])(=[O:34])=[O:33])[N:13]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine, 0.128 ml of trifluoromethanesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating and drying. In this way 315 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1>>[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:30])=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCn2ccnc2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCn2ccnc2)cc1

Procedure:
4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with imidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.1 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]1[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3][C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:6][C:5]=2[CH:15]=1)[CH3:19]
Reactant: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1N
Reactant: O=C(Cl)c1ccccc1
Product: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1NC(=O)c1ccccc1
Yield: 69.1 %

Procedure:
5-Amino-6-diethylamino-2-(cyclohexyl)-1H-benzo[d]-imidazole (27 mg, 0.1 mmol) was reacted with benzoyl chloride (11 mg, 0.1 mmol) in the same manner as that described above to give the desired product (27 mg, 74% yield) as white powder: 1H-NMR (300 MHz, CDCl3) δ 0.98 (t, 6H, J=7.2 Hz), 1.16 (m, 3H), 1.57-1.70 (m, 5H), 1.98 (m, 2H), 2.87 (m, 1H), 3.03 (q, 4H, J=7.2 Hz), 7.57 (m, 3H), 7.57 (s, 1H), 8.00 (dd, 2H, J=1.8, 8.4 Hz), 8.96 (s, 1H); ESI MS m/z 391.0 [M+H]+.
Reaction SMILES: C1COCC1.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[C:15]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)=[O:27])[C:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22])=[O:17].[Cl-].[NH4+].[CH3:37][C:38]([CH3:40])=[O:39]>>[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[C:15]([C:16]([C:18]1[CH:25]=[CH:24][CH:23]=[C:20]([CH:21]([OH:22])[CH2:37][C:38](=[O:39])[CH3:40])[CH:19]=1)=[O:17])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)=[O:27]
Reactant: O=Cc1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CC(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
At −78° C., 1.0 M sodium hexamethylenedisilazane-THF solution was added dropwise to 10 ml of THF solution containing 300 mg of 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzaldehyde and 69 μl of acetone and stirred for 15 minutes. This was mixed with appropriate amounts of saturated ammonium chloride aqueous solution and purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 184 mg (53%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(1-hydroxy-3-oxobutyl)phenyl]propane-1,3-dione (Reference Example 7-1) from a hexane-ethyl acetate (2:1-1:2) eluate. ES+: 445
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:20]([N:17]3[CH2:16][CH2:15][CH:14]([C:13]([F:23])([F:12])[F:24])[CH2:19][CH2:18]3)=[O:21])[N:7]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Product: O=C(Oc1nn(C(=O)N2CCC(C(F)(F)F)CC2)c2cc(F)ccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 340 mg (1.578 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 255-257° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=2[C@H:6]1[CH2:21][N+:22]([O-])=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[NH2:22][CH2:21][C@H:6]1[C@H:5]([CH2:3][OH:2])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]1=2
Reactant: COC(=O)[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1CO

Procedure:
A solution of trans-2-Chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester (4) (4.6 g, 13.23 mmol) in dry THF (23 ml) is added at—15° C. to a mixture of THF (23 ml) and 3.5 M Lithium aluminum hydride (LAH) suspension in THF/Toluene (15.1 ml, 52.9 mmol).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:13][O:12][C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[NH:6]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CCO.O>[CH:7]1([NH:6][C:5]2([CH2:13][OH:12])[CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCC2(C1)COC1(CCCC1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC1(NC2CCCC2)CCCC1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 6-aza-12-oxadispiro[4.1.4.2]tridecane (124 g, 0.69 mol) dissolved in EtOH (600 mL) held at −13° C. with an ice/MeOH bath was added NaBH4 (38 g, 1.0 mol, 1.45 equiv.) in portions at a rate that the temp. did not exceed 10° C. (approximately 30 min.). The reaction mixture was allowed to warm to room temp. and stirred overnight. The reaction mixture was diluted with water (500 mL) and concentrated under reduced pressure. The residual paste was separated between EtOAc (1 L) and water (600 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane as a white powder (107 g, 85%): 1H NMR (CDCl3) δ1.23-1.28 (m, 2H), 1.46-1.57 (m, 8H), 1.58-1.69 (m, 4H), 1.82-1.86 (m, 2H), 2.94-3.06 (m, 1H,), 3.30 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[C:10]2[C:13]2([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH2:15][CH2:14]2)=[CH:5][C:4]=1[CH3:21].C(OC(N1CCC[C@H]1C(O[BH-](OC(=O)[C@@H]1CCCN1C(OC(C)(C)C)=O)OC(=O)[C@@H]1CCCN1C(OC(C)(C)C)=O)=O)=O)(C)(C)C.[Na+].[C:69]([OH:74])(=[O:73])[C:70]([OH:72])=[O:71].N>ClCCl.CCOCC>[C:69]([OH:74])(=[O:73])[C:70]([OH:72])=[O:71].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH:10]2[C:13]2([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH2:15][CH2:14]2)=[CH:5][C:4]=1[CH3:21]
Reactant: COc1cc2c(cc1C)CCN=C2C1(c2ccsc2)CC1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O[BH-](OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: N
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(cc1C)CCNC2C1(c2ccsc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of 7-methoxy-6-methyl-1-[1-(3-thienyl)cyclopropyl]-3,4-dihydroisoquinoline (2.0 g, prepared in a similar manner to that described in Example 6) in dichloromethane (87 ml) was added slowly to an ice-cooled stirred mixture of sodium tris[(S)-N-(tert-butoxycarbonyl)prolyloxy]borohydride (11.4 g) in dichloromethane (70 ml). After standing at about 4° C. for 2 days a further portion of the reducing agent (2.0 g) was added and the mixture stirred at ambient temperature for 3 hours, then saturated aqueous oxalic acid solution (150 ml) was added. This mixture was stirred for 1 hour then basified with concentrated aqueous ammonia solution and extracted with dichloromethane (4×100 ml). The combined extracts were washed with water (100 ml) then brine (100 ml) then dried over magnesium sulphate and the solvent removed in vacuo to give a pale orange gum. The gum was dissolved in ether (150 ml) and treated with a solution of oxalic acid in ether (0.43M; 20 ml) and the resulting precipitate filtered then recrystallised from ethanol to give a single enantiomer of 7-methoxy-6-methyl-1-[1-(3-thienyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinoline oxalate (1.2 g) which was used without further characterisation.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]=[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1CCCCC1COCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCCC1COCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
An oven-dried 250 mL one-necked round bottomed flask was charged with methyltriphenylphosphonium bromide (4.3 g, 12.3 mmol) and dry THF (20 mL) and then cooled to −78° C. To this solution was added n-BuLi (2.8 M in hexane, 4.3 mL, 12.3 mmol) over 10 min by syringe. The resultant red ylide solution was then warmed to rt, stirred for 3 hours, and cooled to −78° C. To this ylide solution was added 2-((benzyloxy)methyl)cyclohexanone (1.8 g, 8.6 mmol) in dry THF (5 mL) via syringe over 10 min. After being stirred for 1 hour at −78° C., the reaction mixture was warmed to rt slowly and stirred for 10 hours. After that the reaction mixture was cooled to 0° C., quenched with aq. NaHCO3 (60 mL), and extracted with ether (3×60 mL). The organic layer was washed with brine (60 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed with hexane-Et2O isocratic 10% as eluant to give the title compound as clear oil. MS m/z 217.1 (M+1).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=O)[NH:4][C:5]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Na+]>C1COCC1>[CH:7]12[O:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[CH2:5][NH:4][CH2:3]1
Reactant: O=C1NC(=O)C2C3CCC(O3)C12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C1CC2OC1C1CNCC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.00 g (29.91 mmol) of 10-oxa-4-azatricyclo[5.2.1.02,6]decane-3,5-dione (example IV, step 1) were suspended in 150 ml of absolute THF under argon and cooled in an ice bath. 2.27 g (59.82 mmol) of lithium aluminum hydride are added in portions, and the mixture is stirred at 0° C. overnight. The reaction solution is hydrolyzed with saturated sodium chloride solution and distilled water, the resulting suspension is filtered, and the solid is washed with ethyl acetate. The organic phase of the filtrate is separated off, and the aqueous phase is extracted once more with ethyl acetate. The combined organic phases are dried and filtered, and the solvent is removed in vacuo. The residue is suspended in diethyl ether, filtered, washed with diethyl ether and dried. 730 mg (13% of theory) of the product are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:41])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]5)=[O:28])=[C:25]([F:41])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 102 mg, 0.36 mmol) and caesium carbonate (213 mg, 0.65 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. tris-dibenzylideneacetonedipalladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated at 110° C. overnight. The mixture was filtered, and the filtrate loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light orange gum (99 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[Cl-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][Zn+]>C1(P([Pd-4](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)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)=[N:9][N:8]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Reactant: Clc1cccc(C[Zn+])c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1nc(Cc2cccc(Cl)c2)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (1.46 g, 3.33 mmol), 3-chlorobenzylzinc chloride (0.5 M in tetrahydrofuran, 6.8 ml, 3.40 mmol), tetrakis(triphenylphosphino)palladium(0) (384 mg, 0.33 mmol), and tetrahydro-furan (10 ml) were combined and stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous ammonium chloride, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 10% ethyl acetate in hexanes) to give 436 mg (30%) of 2,2-dimethyl-propionic acid 5-bromo-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.88 (s, 1H), 7.24-7.18 (m, 4H), 6.41 (s, 2H), 4.25 (s, 2H), 1.18 (s, 9H); MS: m/z 436.1, 438.1 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH:30]([OH:32])[C:29]2[CH:28]=[N:27][C:26]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH:30]([OH:32])[C:29]3[CH:28]=[N:27][C:26]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)c(Cl)c1)CC2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(F)c(Cl)c1)CC2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 132 (35 mg, 0.0650 mmol) in THF (1 mL) cooled to 0° C. was added TBAF (91 μL, 0.0911 mmol) and reaction was stirred at RT for 2 h. The reaction was concentrated and the resulting residue was purified on a reverse phase column (SP4) eluting with a MeCN/H2O gradient (5 to 95% MeCN) to afford 17.2 mg (62.4%) of I-20: LCMS (ACPI-pos) m/z 424.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])(OCC)=O>O.C(#N)C>[C:26]1(=[O:35])[N:13]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:12])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: COc1ccc(C(C)N)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.3 %

Procedure:
To a stirred solution of 1-(3′,4′dimethoxyphenyl)ethylamine (1.81 grams, 10.0 mmol) and sodium carbonate (1.14 grams, 10.8 mmol) in a mixture of water (80 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (2.19 grams, 10 mmol). The resulting suspension was stirred for 3.5 hours at room temperature and then filtered to afford 1.24 grams (40%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 0.85 grams (27%) of the product as white crystals: mp 124-125° C.; 1H NMR (DMSO-d6) δ7.96-7.78 (m, 4H), 7.09-6.81 (m, 3H), 5.40 (q, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.72(s, 3H), 1.81 (d, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ167.6, 148.4, 148.0, 134.4, 132.9, 131.3, 122.9, 118.8, 111.5, 110.8, 55.4, 48.6, 17.7. Anal. Calculated for C18H17NO4. Theoretical: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.63; H, 5.45; N, 4.42. HPLC 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH3:27])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:9].[OH-].[Na+:29]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH3:27])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1)=[O:9].[Na+:29]
Reactant: CCCOc1ccc(C=CC(=O)Nc2ccc(CC(=O)O)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCOc1ccc(C=CC(=O)Nc2ccc(CC(=O)[O-])cc2)cc1OC

Procedure:
184 Milligrams of 4-(3'-methoxy-4'-propoxycinnamoylamino)phenylacetic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The solution was warmed for 30 minutes. After cooling, ether was added to the solution and the precipitated crystals were collected by filtration to obtain sodium 4-(3'-methoxy-4'-propoxycinnamoylamino)phenylacetate.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CCc1ncccc1CO
Solvent: ClCCl
Product: CCc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (2-ethylpyridin-3-yl)methanol (3.0 g, 21.9 mmol) in anhydrous dichloromethane (150 mL) was added tribromophosphane (2.3 mL, 24.2 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was dried in vacuo, affording 3-(bromomethyl)-2-ethylpyridine, which was used without further purification.