Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:8]=2[C:9]#[N:10])[CH2:3]1.BC1C=NC(N2CC[C@H](F)C2)=C(C=1)C#N.[Cl:39][C:40]1[N:45]=[C:44](Cl)[CH:43]=[CH:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.O.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:39][C:40]1[N:45]=[C:44]([C:12]2[CH:13]=[N:14][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]3)=[C:8]([CH:11]=2)[C:9]#[N:10])[CH:43]=[CH:42][N:41]=1
Reactant: CC1(C)OB(c2cnc(N3CC[C@H](F)C3)c(C#N)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Bc1cnc(N2CC[C@H](F)C2)c(C#N)c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccnc(Cl)n2)cnc1N1CC[C@H](F)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of 2-((S)-3-Fluoro-pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile and 5-boranyl-2-((S)-3-fluoro-pyrrolidin-1-yl)-nicotinonitrile (7) (2.64 g, ˜9.6 mmol), 2,4-dichloropyrimidine (1.2 g, 9.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol) and Na2CO3 (3.1 g, 28.8 mmol) were dissolved in 1:1 1,4-dioxane-H2O (40 mL) and the mixture was stirred at 120° C. in the microwave (250 W, stirring) for 30 minutes. The mixture was diluted with EtOAc (130 mL) and H2O (40 mL) and the layers separated. The organic phase was washed with saturated brine solution (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (40-63 mesh silica gel, 1:1 isohexane-EtOAc) to provide the title compound as a pale yellow solid (1.6 g, 55%); LCMS, Rt=2.80 min (MeOH-FA method), m/z 304 (MH+).
Reaction SMILES: Cl.Cl.C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[OH:25])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:6].O.[OH-].[Li+].Cl>CO.O>[Cl:32][C:30]1[CH:31]=[C:26]([C@@H:24]([OH:25])[CH2:23][NH:22][CH2:21][CH2:20][NH:19][C:15]2[CH:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=3)[CH:18]=[CH:17][CH:16]=2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cc(Cl)cc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cc(Cl)cc(Cl)c3)c2)c1
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A crude sample of (R)-3′-[[2-[[2-(3,5-dichlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester dihydrochloride (from Example 8, 557 mg), was treated with lithium hydroxide monohydrate (220 mg) in 3:1 methanol/water (28 mL) and stirred for 1 day. Additional lithium hydroxide monohydrate (22 mg) was added and the mixture was stirred overnight. The mixture was treated with 0.5 N aq. HCl until approximately pH6, and the resulting solid (400 mg) was collected by suction filtration. Silica gel chromatography (eluting with 6:2:0.1 chloroform/methanol/ammonium hydroxide) gave a solid that was triturated with hexanes. This material was treated with 1 N aqueous HCl, and the solid was washed by stirring with ethyl acetate. The solid was dried in vacuo to give the title compound (78.6 mg).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.Cl.[CH3:52][N:53]([CH2:55][C:56](Cl)=[O:57])[CH3:54]>ClCCl.C(N(CC)CC)C>[CH3:52][N:53]([CH3:54])[CH2:55][C:56]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)=[O:57]
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (64 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with dimethylaminoacetyl chloride hydrochloride (100 mg). The mixture was heated with a heat gun, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 573.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@@H]1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH2:28][C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.2 mg, 75%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:8][CH2:7][CH:6]2[CH2:9][CH:3]1[CH2:4][CH2:5]2.[CH2:12]([O:14]CC)[CH3:13]>C(OC(=O)C)(=O)C>[C:12]([NH:1][C:2]1([C:10]#[N:11])[CH2:8][CH2:7][CH:6]2[CH2:9][CH:3]1[CH2:4][CH2:5]2)(=[O:14])[CH3:13]
Reactant: N#CC1(N)CCC2CCC1C2
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1(C#N)CCC2CCC1C2

Procedure:
The procedure is as in Example 1, but starting from 2-amino-2-cyano-bicyclo[3.2.1]octane (8.05 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in diethyl ether (150 cc) and acetic anhydride (5.6 cc); 2-acetylamino-2-cyano-bicyclo[3.2.1]octane (10.16 g) is obtained in the form of fine white crystals which melt at 78°-80° C.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>>[CH3:11][N:9]([CH3:10])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:3]=1[OH:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1O
Yield: 0 %

Procedure:
3-(2-Methoxy-4-nitrophenoxy)-N,N-dimethylpropan-1-amine (480 mg, 1.89 mmol) was heated at 100° C. overnight in 3 ml of bromhydric acid (48% in water). Once at room temperature, 4% sodium bicarbonate solution was added and extracted with ethyl acetate. The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 0.22 mg (44% yield) of the title compound were obtained and used in the next synthetic step without further purification. Purity: 91%
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:20]=[N:21][N:22]=[CH:23]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-n1cnnc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-n1cnnc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (10 mg, 0.050 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine (15 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.091 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H19ClFN8 (M+H)+: m/z=449.1. found: 449.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.Cl.[C:24]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])([CH3:27])([CH3:26])[CH3:25]>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:32][CH2:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:33])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Product: CC(C)(C)OC(=O)CCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Yield: 28.4 %

Procedure:
Prepared according to the method of example 7 (a), using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (400 mg) and β-alanine tert-butyl ester hydrochloride (1.6 g) to afford the sub-title compound (150 mg).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].O[CH2:16][CH:17]([CH2:19]O)O>[I-].[Na+]>[F:14][C:13]1[C:7]([F:6])=[C:8]2[C:10]([CH:16]=[CH:17][CH:19]=[N:9]2)=[CH:11][CH:12]=1
Reactant: Nc1cccc(F)c1F
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Product: Fc1ccc2cccnc2c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
607.7 g (49.57 mol) of 80% sulfuric acid were placed in a 3 L eggplant flask containing a stirrer followed by cooling to 0° C. 160.0 g (1.24 mol) of 2,3-difluoroaniline were gradually added thereto. Following completion of addition, the reaction mixture was stirred for 1 hour at room temperature. 1.85 g (12.3 mmol) of sodium iodide were then added thereto followed by heating with an oil bath at 150° C. When the liquid temperature reached 150° C., 125.5 g (1.36 mol) of glycerin were dropped therein over the course of 1 hour. Following completion of dropping, the reaction mixture was stirred for 1 hour at 150° C. Next, the temperature of the oil bath was raised to 180° C. Water was distilled off over the course of 2 hours using a distillation apparatus. After confirming elimination of the raw materials, the reaction mixture was neutralized with 10 N aqueous sodium hydroxide solution while cooling in an ice water bath (internal temperature: 60° C. to 70° C.). Following neutralization, the reaction mixture was extracted with ethyl acetate before the internal temperature returned to room temperature, and then the extract was dried with magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain 185.5 g (91%) of 7,8-difluoroquinoline in the form of a light brown solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@H:5]2O.C1(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.P(C)(C)C.C1COCC1>O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@@H:5]2[NH2:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@@H]1CCOc2ccc(I)cc21
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CCOc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-6-iodochroman-4-ol (6.85 g, 24.81 mmol) and toluene (100 mL) under nitrogen at 0° C. was added diphenylphosphoryl azide (6.42 mL, 29.76 mmol). To this mixture was added a chilled solution of DBU (4.45 mL, 29.76 mmol) as a toluene solution (25 mL) via syringe. Reaction mixture was allowed to warm to ambient temperature overnight. Azide solution was filtered through silica gel using 6:1 hexanes:EtOAc as eluant. Filtrate was concentrated in vacuo, then dissolved in anh. THF (100 mL) to which was added 1.0M Me3P in THF (29.76 mL, 29.76 mmol). After 1 h, deionized H2O (5 mL) was added and reaction mixture was stirred overnight under nitrogen. Concentrated in vacuo, dissolved in EtOAc, washed with 10% NaHCO3, brine, then the organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give (4S)-6-iodochroman-4-amine as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.70 (s, 2 H), 1.86 (m, 1 H), 2.13 (m, 1 H), 4.03 (t, J=5 Hz, 1 H), 4.23 (m, 2 H), 6.60 (d, J=9 Hz, 1 H), 7.42 (d, J=9 Hz, 1 H), 7.64 (s, 1 H). MS (ESI+) for C9H10INO m/z 258.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:12]([C:3]1[C:2]([NH2:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:14]
Reactant: Nc1ccccc1Cl
Reactant: Nc1cc2ccccc2cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1cc2ccccc2cc1C(=O)Nc1ccccc1Cl
Yield: 53.9 %

Procedure:
Prepared according to Procedure A using 3-amino-2-napthoic acid (2.0 g, 10.7 mmol) and SOCl2 (1.9 mL, 26.7 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.3 mL, 21.4 mmol) and CHCl3 (50 mL). The product was recrystallized from MeOH to provide 1.71 g of a brown solid (54%). 1H NMR (CDCl3) δ: 10.88 (br s, 1H); 9.21 (s, 1H); 8.91 (s, 1H); 8.70 (dd, J=1.0, 8.3 Hz, 1H); 7.95-8.01 (m, 1H); 7.87-7.94 (m, 1H); 7.60-7.68 (m, 2H); 7.41 (dd, J=1.3, 8.0 Hz, 1H); 7.34 (dt, J=1.2, 7.8 Hz, 1H); 7.07 (dt, J=1.4, 7.7 Hz, 1H). MS (ES): m/z 297.1 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][C:9]=2[C:10]=1Br)=[O:5])[CH3:2].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][C:9]=2[C:10]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1Br
Product: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 61 %

Procedure:
According to Step 6, after reaction of 3-Bromo-5-(4-tert-butylbenzene-sulfonylamino)-1-benzothiophene-2-carboxylic acid ethyl ester (469 mg, 1.0 mmol) from Example 1c) with phenylboronic acid (176 mg, 1.44 mmol) followed by chromatographic purification (silica gel, hexane/ethyl acetate (0-100% ethyl acetate) and ethyl acetate/methanol (0-15%)), the desired compound is obtained at 61% yield (300 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:31])[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccccc4C)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 2-methylphenylboronic acid using a similar procedure to Example 4 (48%).
Reaction SMILES: Cl.[NH:2]1[C:6]2([CH2:10][CH2:9][NH:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.O>[C:12]([O:16][C:17]([N:2]1[C:6]2([CH2:10][CH2:9][NH:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1NCCC12CCCN2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC12CCNC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 1,7-diazaspiro[4,4]nonan-6-one hydrochloride (0.98 g, 5.4 mmol) in dichloromethane were added tert-butyldicarbonate (1.41 g, 6.48 mmol) and triethylamine (1.3 g, 13.5 mmol). The resulting solution was stirred overnight at room temperature. The solution was diluted with water and extracted with dichloromethane. The organic phase was separated, dried, filtered and concentrated to afford 6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl ester product as white powder (1.3 g) in 100% yield and used directly without further purification. 1H NMR (400 MHz, CD2Cl2) δ 6.13-5.74 (br, 1H), 3.59-3.20 (m, 4H), 2.75-2.49 (m, 1H), 2.16-1.76 (m, 5H), 1.43 (s, 3H), 1.42 (s, 6H). MS m/z 241.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:26][CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:9]2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2)c2ccc(F)cc2)c1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of N-(4-fluorophenyl)-N-{2-(3-methoxyphenyl)ethyl}-2-{4-(phenylmethoxy)phenyl}acetamide (6.0 g, 12.8 mmol) in phosphorous oxychloride (130 mL) under nitrogen was heated to 80° C. After 20 hours, the reaction was cooled to RT and very slowly poured over ice with vigorous stirring. Ethyl acetate (500 mL) was then added and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.61 g, 80% yield): ES-MS (m/z) 452 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[OH:31][CH2:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:36]=[CH:35][CH:34]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2cccc(CO)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 19 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (100 mg, 0.20 mmols), [3-(hydroxymethyl)phenyl]boronic acid (91 mg, 0.60 mmols), cesium carbonate (400 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (20 mg, 19%)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:22]2[CH:23]=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 90 °C
Yield: 56.7 %

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 650 mg, 2.08 mmol), 2,4-dichloropyrimidine (309.7 mg, 2.08 mmol), and Et3N (0.6 ml, 4.16 mmol) were combined in DMF (12 ml) and heated at 90° C. under nitrogen for 1.5 h. Upon cooling to room temperature, the reaction was diluted with EtOAc and water. The phases were separated, and the aqueous portion was extracted twice with EtOAc. The combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a light brown solid. The crude material was triturated with cold MeOH and filtered to give 458 mg (1.18 mmol, 57%) of the title product.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:39])([F:38])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:24])=[O:23])[CH2:18][C@H:17]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:12][CH:11]=1)([OH:9])[C:5]([F:8])([F:7])[F:6].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[ClH:1].[F:8][C:5]([F:6])([F:7])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:24])[CH2:18][C@@H:17]2[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)=[CH:12][CH:11]=1)([OH:9])[C:3]([F:39])([F:38])[F:2]
Reactant: Cc1ccc(C[C@@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: Cc1ccc(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(4-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride. 1H NMR (400 MHz, CD3OD) δ 7.86-7.83 (m, 1H), 7.61-7.56 (m, 3H), 7.24-7.20 (m, 1H), 7.13-7.07 (m, 4H), 7.05-7.00 (m, 2H), 4.15-4.08 (m, 1H), 3.86-3.81 (m, 1H), 3.66-3.55 (m, 2H), 3.41-3.33 (m, 1H), 3.10-3.03 (m, 1H), 2.61-2.53 (m, 2H), 2.51-2.46 (m, 1H), 2.29 (s, 3H). m/z (ESI, +ve ion) 578.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.50 μM; GK-GKRP EC50 (LC MS/MS)=2.62 μM.