Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCN(c2cc(Cc3ccccc3)c(Br)cn2)CC1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(c2cc(Cc3ccccc3)c(C#CC3(O)CN4CCC3CC4)cn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 270 mg of 4-benzyl-5-bromo-2-(4-hydroxypiperidino)pyridine, 130 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis(triphenylphosphine)palladium(0), 2 mg of cuprous iodide, 0.35 ml of triethylamine and 2 ml of N,N-dimethylformamide was stirred at 100° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the reaction solution was extracted with ethyl acetate-aqueous dilute ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 120 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:15]1[C:16]2[N:17]([N:21]=[C:22]([Cl:24])[N:23]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:24][C:22]1[N:23]=[C:16]2[C:15]([NH:1][C:2]3[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:19]=[CH:18][N:17]2[N:21]=1
Reactant: CN(c1ncccc1N)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[N:1]1[O:11][C:9]([O-:10])=[C:4]2[N+:3]=1[CH2:8][CH2:7][O:6][CH2:5]2
Reactant: O=NN1CCOCC1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: [O-]c1on[n+]2c1COCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The crude 4-nitrosomorpholine-3-carboxylic acid (11.0 g) from step 1 was dissolved in THF (250 ml) and cooled to 0° C. A solution of trifluoroacetic anhydride (7.4 ml, 52 mmol) in THF (20 ml) was added with stirring over 10 min. The resulting mixture was stirred at 0° C. for 5 hr, and warmed to room temperature for 16 hr. The solvent was evaporated and the residue was diluted with 250 ml of ethyl acetate and stirred with 30 g of anhydrous potassium carbonate. The mixture was filtered through a pad of silica gel and the filtrate evaporated. The residue was washed with a mixture of ethyl acetate-ether to give 3.80 g of a white solid; mp 132-133° C.; MS (ESI) m/z 143.1 (M+H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].[CH2:31]([N:33](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][CH3:31])=[O:23])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C(C)C)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.014 g (0.21 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.082 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-295) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH3:41])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.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.[Cu]I>[CH3:41][N:13]([CH3:12])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.1 %

Procedure:
A mixture of 3-ethynylimidazo[1,2-b]pyridazine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)—N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.016 g (0.014 mmol) of Pd(PPh3)4, 0.004 g (0.021 mmol) of CuI, and 0.09 mL (0.51 mmol) of N,N-diisopropylethylamine in 3.5 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 3 days (reaction pushed to completion with additional equivalents of reagents and heating to 80° C.). The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM; MeOH was pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:4])=[O:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:2]([C:5]2[CH:6]=[C:7]([C:14]3[NH:15][C:16](=[O:27])[C:17]4[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=4[N:19]=3)[C:8]3[O:12][CH2:11][CH2:10][C:9]=3[CH:13]=2)(=[O:4])=[O:3])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)cc4c3OCC4)nc12
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)cc4c3OCC4)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 6a (1.25 g, 0.003 mole) was dissolved in THF (10 ml) and added to a solution of 1-methylpiperazine (1 ml) in THF (10 ml). The resulting mixture was stirred at room temperature for 1 h. The THF was then removed in vacuo, and the residue was treated with cold water (50 ml). The resulting white precipitate was filtered under suction, washed with water (2×10 ml), drained and recrystallized from 90% ethanol, thereby yielding 7a.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:34]=[C:35]([CH:39]([CH3:43])[CH2:40][CH:41]=O)[CH:36]=[CH:37][CH:38]=1)([CH3:32])[CH3:31].CC(O)=O>C1COCC1>[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH2:40][CH:41]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[CH3:43])[CH:34]=1)([CH3:32])[CH3:31]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C=CCC(C)c2cccc(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Potassium t-butylat (17.1 mL, 17.1 mmol, 1.0 equiv., 1M in THF) was added to a solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (7.90 g, 17.1 mmol, 1.0 equiv.) in THF (17 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(3-isopropylphenyl)butanal (3.24 g, 17.1 mmol, 1.0 equiv.) in THF (8.5 mL) was added, and the mixture was stirred at 25° C. 12 h. After addition of 20% aq. AcOH-solution at 25° C., the aqueous layer was extracted with hexane. The combined organic phases were washed with MeOH/H2O (4:1; 2-3x), dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 4.03 g (80%) of the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[F:39]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[C:34]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[N:8]=1)=[O:5]
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (4.59 g, 20.6 mmol) in THF (45 ml) was cooled to 5° C. under nitrogen. A solution of 1.0 M lithium bis(trimethylsilyl)amide in THF (20.6 ml, 20.6 mmol) was added dropwise maintaining the temperature below 10° C. After 10 minutes a solution of 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (5.29 g, 20.6 mmol, JRD fluorochemicals Ltd) in THF (9 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched using 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried with magnesium sulphate, filtered and solvent removed in vacuo. The crude material was dissolved in DCM and applied to a 330 g silica cartridge. The cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min. The required fractions were combined and evaporated in vacuo, to give the title compound as a white solid (6.75 g). The white solid (6.75 g) was dissolved in ethyl acetate (70 ml) and heated to 50° C. Cyclohexane (280 ml) was then added dropwise over 20 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A36) the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[N:23]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:23]=[CH:24][CH:25]=[CH:26]4)[C:16]2=[CH:15][N:14]=1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5ncccc5c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and quinolin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-5182). LCMS (M+H)+=420.1.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:2]2[CH2:7][CH2:6][N:5]([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[C:24]([O:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][C:21]=3[N+:31]([O-:33])=[O:32])[CH2:4][CH2:3]2)=[N:9]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)N2CCN(c3nsc4ccccc34)CC2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-piperazin-1-yl-benzoisothiazole hydrochloride (5.29 g, 20.7 mmol) and 4,5-dimethoxy-2-nitrophenylacetic acid (5 g, 20.7 mmol) were combined in 200 mL methylene chloride with triethylamine (5.77 mL, 41.4 mmol). This solution stirred for 15 min before bis-(2-oxo-3-oxazolidinyl) phosphinic chloride (5.26 g, 20.7 mmol) was added. After stirring overnight at rt, the reaction was quenched with water and extracted into methylene chloride. The organic layer was washed with 0.5 N HCl, water, sodium bicarbonate then water before it was dried over Na2SO4 and concentrated. The residue was taken up in methylene chloride and washed with water. The organic layer was dried over sodium sulfate, and concentrated then purified by MPLC using a Biotage prepacked silica gel cartridge eluting with 3% methanol in methylene chloride to afford 6.5 g of a tan solid. Yield 71%; 100% purity at 214 nm; LCMS (APCI): 443 [M+H]+; mp 170° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[O:12][C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:19][C:15]1[CH:14]=[C:13]2[C:18]([CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)[CH2:10][C:11]([CH3:21])([CH3:20])[O:12]2)=[CH:17][CH:16]=1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC3CO3)cc2O1

Procedure:
Reaction of 4-(3-Trifluoromethylphenyl)-2,2-dimethyl-7-chromanol with epichlorohydrin, by an analogous method to that described in Example 1, gave 7-(2,3-epoxypropoxy)-4-(3-trifluoromethylphenyl)-2,2-dimethylchroman. Reaction of this epoxide with methylamine, by an analogous method to that described in Example 2 gave 4-(3-trifluoromethyl-phenyl-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethylchroman, (benzoate salt, m.p. 145°-157°).
Reaction SMILES: [NH2:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:23][CH2:24][CH2:25][O:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:36]>[Cu](Cl)Cl.C(O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:20]([O:21][CH3:22])[CH:19]=[CH:18][CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:33]=[C:34]([CH3:35])[C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2cccc(OC)c2N)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3c(OC)cccc3c2=O)cc1
Temperature: 100 °C

Procedure:
To a 100-mL round bottom flask were added 2-amino-N-(4-sec-butyl-phenyl)-3-methoxy-benzamide (0.533 g, 1.79 mmol), 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.382 g, 1.96 mmol), anhydrous copper (II) chloride (0.722 g, 5.37 mmol), and anhydrous ethanol (40 mL). The mixture was refluxed at 100° C. under N2 for 5 hours. The mixture was concentrated to dryness. Water (approximately 20 mL) was added and extracted with EtOAc (3×50 mL). The EtOAc solutions were combined and dried over Na2SO4. The crude product was purified by column chromatography on silica gel using hexane/EtOAc (1:1 to 1:2) as eluent. The product fractions were concentrated to dryness then re-crystallized in ether to afford the title compound as white solid. Yield: 0.460 g (54%). MP 158-159° C. 1H-NMR (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.46 (t, 1H), 7.24 (d, 1H), 7.12 (d, 2H), 7.05 (d, 2H), 7.00 (s, 2H), 4.03 (s, 3H), 3.89 (m, 2H), 3.75 (m, 2H), 2.56 (m, 1H), 2.11 (s, 6H), 1.52 (m, 2H), 1.19 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.27 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:13]=[CH:12][C:11]=2[N:26]2[CH2:31][CH2:30][CH:29]([C:32](OC)=[O:33])[CH2:28][CH2:27]2)=[O:8])[CH:3]=1.[NH3:36]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:13]=[CH:12][C:11]=2[N:26]2[CH2:31][CH2:30][CH:29]([C:32]([NH2:36])=[O:33])[CH2:28][CH2:27]2)=[O:8])[CH:3]=1
Reactant: N
Reactant: COC(=O)C1CCN(c2ccc(CN[C@H](C)c3ccccc3)cc2NC(=O)c2cc(C)on2)CC1
Product: Cc1cc(C(=O)Nc2cc(CN[C@H](C)c3ccccc3)ccc2N2CCC(C(N)=O)CC2)no1
Temperature: 75 °C
Yield: 23 %

Procedure:
To (R)-methyl 1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxylate 61 (0.220 g, 0.46 mmol) was added ammonia (2 M in MeOH, 50 mL). The reaction mixture was heated to 75° C. in a sealed tube for 7 d, and concentrated in vacuo. Purification by flash column chromatography on silica gel (1% to 10% MeOH (2 M NH3) in DCM) gave (R)-1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxamide 62 (0.048 g, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=6.7 Hz, 3H), 1.76-1.84 (m, 4H), 2.24 (m, 1H), 2.52 (s, 3H), 2.67 (t, J=8.8 Hz, 2H), 2.95 (d, J=11.5 Hz, 2H), 3.43 (d, J=13.3 Hz, 1H), 3.48 (d, J=13.7 Hz, 1H), 3.71 (q, J=6.5 Hz, 1H), 6.71 (s, 1H), 7.19 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.22 (d, J=3.9 Hz, 1H), 7.31-7.38 (m, 6H), 8.22 (s, 1H), 9.73 (s, 1H). Mass spectrum: calculated for C26H31N5O3 461.2. found 462.3 (M++1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 150 °C
Yield: 44.3 %

Procedure:
To a solution of 6-(trifluoromethyl)pyridin-2-ol (1.205 g, 7.39 mmol) in DMF (7 mL), was added 3,4-difluorobenzaldehyde (0.776 mL, 7.04 mmol) and K2CO3 (1.167 g, 8.44 mmol). The mixture was heated with a microwave condition at 150° C. for 1 h. After cooling, the mixture was diluted with EA, washed with water, brine, and concentrated. The residue was purified via flash chromatography to afford the title compound (890 mg, 44.3% yield) as a white solid. LCMS: rt=2.62 min, [M+H+]=286
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11]=[N:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:14][C:15]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[I:31]N1C(=O)CCC1=O>CC(C)=O>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[I:31][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:15]1[CH:14]=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=[N:11][C:10]=1[O:9][CH3:8]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2 g 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole trifluoroacetate and 1.3 g N-Iodosuccinimide (NIS) in acetone is stirred for 4 h at ambient temperature. The product is isolated by filtration, washed with acetone and used without further purification