Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](O)=[O:4].[CH3:7][S:8]([CH3:11])(=[NH:10])=[O:9].[Cl:12][C:13]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22].C[O-].[Na+]>COCCOC>[Cl:12][C:13]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21]([O:23][CH:2]([CH3:6])[C:3]([N:10]=[S:8]([CH3:11])([CH3:7])=[O:9])=[O:4])=[O:22]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(Br)C(=O)O
Reactant: CS(C)(=N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(OC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)N=S(C)(C)=O

Procedure:
from 2-bromopropionic acid, dimethyl sulphoximine and 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoic acid using sodium methylate as the base and 1,2-dimethoxyethane as the solvent there is obtained N-{2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyloxy]-propionyl}-S,S-dimethyl-sulphoximine as a yellow resin; 1H-NMR (CDCl3): 8.20-6.90 (m,6H), 5.28 (q,1H), 3.37 (s,6H), 1.62 (d,3H);
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)[C:12](=[O:28])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[N:29]1[CH:34]=[CH:33]C=C[CH:30]=1.[CH2:35]([NH:37][CH3:38])[CH3:36]>C1COCC1>[CH2:34]([N:29]([CH3:30])[CH:24]([CH3:25])[C:23]([NH:22][C:17]1[C:18]2[C:19](=[O:21])[C:20]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4](=[O:5])[CH:3]([N:37]([CH3:38])[CH2:35][CH3:36])[CH3:2])[C:12](=[O:28])[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:27])[CH3:33]
Reactant: c1ccncc1
Reactant: O=C(CCCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCCl)cccc1C2=O
Reactant: CCNC
Solvent: C1CCOC1
Product: CCN(C)C(C)C(=O)Nc1cccc2c1C(=O)c1c(NC(=O)C(C)N(C)CC)cccc1C2=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
Add 1,8-Bis(3-chloropropionamido)anthraquinone (compound 4, 0.42 g, 1.0 mmol) with pyridine (0.5 ml) and N-ethylmethylamine (0.6 ml, 6 mmole), dissolved in 20 ml dehydrated THF. The mixture is reacted in a mini-reactor. The reaction temperature is 70-80° C. in an oil bath and the reaction time is 6 hours. The reacted mixture is poured into 50 ml ice water, extracted with ethyl acetate and recrystallized from ethanol to get compound 4k.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([I:19])C(=O)C1>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (500 mg, 2.90 mmol) in acetic acid (20 ml) was added NIS (650 mg, 2.89 mmol). The resulting solution was stirred overnight at room temperature and then diluted with water (40 ml). The solids were collected by filtration to afford 5-chloro-4-iodo-2-nitroaniline as a brown solid (800 mg, crude). To a solution of 5-chloro-4-iodo-2-nitroaniline (800 mg, crude) in water (4 ml) and ethanol (20 ml) was added Fe powder (600 mg, 10.74 mmol) and ammonium chloride (430 mg, 8.04 mmol). The resulting solution was stirred overnight at reflux and then cooled to room temperature. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (200 ml) and washed with brine (100 ml), dried over Na2SO4 and concentrated under vacuum to afford 4-chloro-5-iodobenzene-1,2-diamine as a brown solid (600 mg, crude).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[N+:21]([O-])=O)=[O:4].[H][H]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[CH:7][C:6]=1[NH2:21])=[O:4]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Reaction time: 18 h

Procedure:
In a Parr apparatus, hydrogenate an ethanolic solution of 3-nitro-2′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (5.54 g, 0.0169 mol) under 55 psi of hydrogen using tetrakis(triphenylphosphine)palladium (0) (300 mg). After 18 hours, filter the mixture through celite and concentrate under reduced pressure to give 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>[Pd].CO>[CH2:32]([C:13]1[CH:14]=[C:15]([C:16]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=1)[CH3:33]
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (62.0 mg, 0.140 mmol) and palladium on activated carbon (Aldrich, St. Louis, Mo. 10% Pd, 19.1 mg) were added to MeOH (2.0 mL) and TFA (0.30 mL). The reaction flask was evacuated and back-filled with hydrogen, and the reaction was stirred at room temperature for one hour. Then, the hydrogen balloon was removed, and stirring was continued at room temperature, without the balloon of hydrogen, for 90 minutes. Then, the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (45° C.-50° C.), and stirring was continued under nitrogen overnight. The reaction was cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH and a couple of drops of TFA. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (50° C.). Then, the material was washed with Et2O, MeOH, and Et2O, collected, and dried under high vacuum overnight to give 5-ethyl-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (17.8 mg, 35% yield). MS (ESI pos. ion) m/z 362 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.53 (s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=2.54 Hz, 1H), 8.22-8.13 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 2.85 (s, 3H), 2.65 (q, J=7.37 Hz, 2H), 1.26 (t, J=7.53 Hz, 3H).
Reaction SMILES: I[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[C:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24](=[O:32])(=[O:31])[NH:23][N:22]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CC#N.O.C(Cl)Cl>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:16]1[C:17]2[C:13](=[CH:12][C:11]([F:10])=[CH:19][CH:18]=2)[C:14]([C:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24](=[O:31])(=[O:32])[N:23]([CH2:2][CH3:3])[N:22]=2)=[C:15]1[CH3:20])([CH3:41])([CH3:40])[CH3:39]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Iodoethane (5 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 173A (0.4 g), dihydro-2H-pyran-4(3H)-one (0.179 g), sodium cyanoborohydride (0.112 g), and acetic acid (0.5 mL) in tetrahydrofuran (3 mL) was stirred overnight. The solvents were removed under reduced pressure. The residue was purified with flash column chromatography on silica gel eluting with 100:5:0.5 ethyl acetate/methanol/NH4OH to give the desired product.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
8.85 grams of 5-tert.-butyl-2,3,-dimethyl-4-hydroxyphenylacetic acid, 9.45 grams of n-octadecanol and 0.665 grams of p-toluenesulfonic acid monohydrate were dispersed in 500 ml of toluene and heated at reflux for 7 hours. A little ether was added to the cooled reaction mixture to prevent precipitation. The reaction solution was then successively washed with water, saturated sodium bicarbonate solution and water once again until neutral. After drying over anyhyrous sodium sulfate and filtering, the clear filtrate was concentrated at reduced pressures. After washing with cold acetonitrile, the dried ground residue was crystallized from n-heptane yielding white cyrstals melting at 79° to 81° (Compound 15).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[O:35][CH3:36]>ClCCl.CO>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:30][C:29]=1[O:35][CH3:36]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1C(C)CCCC1C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.663 mmol) of 4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]-3-methoxyphenylamine. Yield: 150 mg (49% of theory); melting point: 225° C.-227° C.; C26H28ClF3N2O3 (M=508.96); calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:20]=[C:21]([CH3:24])[S:22][CH:23]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cs1
Temperature: 85 °C

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.060 g, 0.19 mmol), EtOH (3.3 mL) and DMF (0.44 mL), 4-(1H-pyrazol-1-ylmethyl)-benzaldehyde (0.039 g, 0.21 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a off-white solid (0.036 g, 37%); 1H-NMR (500 Mz, DMSO-d6): δ 2.62-2.69 (m, 7H), 3.63 (s, 2H, NCH2), 3.66-3.74 (m, 4H), 5.42 (s, 2H, NCH2), 6.30 (t, J=2.0 Hz, 1H), 7.31 (s, 1H, thiazole 5-H), 7.34 (d, J=8.0 Hz, 2H, ArH), 7.48-7.51 (m, 1H), 7.86 (m, 1H), 8.08-8.15 (m, 3H, 2ArH and imidazo[4,5-b]pyridine 5-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.16 min—505/507 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 505.1687, calculated for C25H26N8SCl (M+H)+: 505.1690.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([NH:15]C(=O)C)[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[C:24]([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:24])=[O:9])=[O:5]
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)c(F)c1
Reactant: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(N)cc1F
Temperature: 35 °C

Procedure:
A mixture of 35 g. of 3-(2-fluoro-4-acetamidobenzoyl)propionic acid, 700 ml. of methanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76 hours. The solution is cooled to 35° C. and poured onto 7 g. of anhydrous sodium acetate while stirring. The reaction mixture is stirred in an ice-bath. The solid is collected and washed with cold methanol to yield methyl 3-(2-fluoro-4-aminobenzoyl)propionate as a white solid. A mixture of this solid, 9.2 g. of hexadecyl bromide and 4.2 g. of potassium carbonate is stirred for 20 hours at 125° C. under nitrogen. The mixture is then cooled to 25° C. and 30 ml. of water is added. After stirring, the product is filtered and washed with water. Recrystallization from methanol affords methyl 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:66]=[CH:65][C:44]([CH2:45][N:46]2[C:50]3=[N:51][CH:52]=[CH:53][C:54]([O:55][C:56]4[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][C:57]=4[F:63])=[C:49]3[C:48]([CH3:64])=[N:47]2)=[CH:43][CH:42]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:63][C:57]1[CH:58]=[C:59]([NH:62][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:60]=[CH:61][C:56]=1[O:55][C:54]1[CH:53]=[CH:52][N:51]=[C:50]2[N:46]([CH2:45][C:44]3[CH:65]=[CH:66][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[N:47]=[C:48]([CH3:64])[C:49]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (37 mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol), and HOBt (64 mg, 0.48 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. 3-Fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (30 mg, 0.079 mmol; prepared as in Example 5, Step D) was added, followed by Et3N (0.066 mL, 0.48 mmol). After stirring for 15 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 45 mg (96%) of the desired product. LRMS (ESI pos) m/e 594.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.72 (dd, 1H), 8.28 (d, 1H), 7.99 (dd, 1H), 7.92 (dd, 1H), 7.51 (m, 2H), 7.41 (m, 1H), 7.32 (m, 3H), 7.24 (d, 2H), 6.84 (d, 2H), 6.75 (t, 1H), 6.28 (d, 1H), 5.54 (s, 2H), 3.76 (s, 3H), 2.71 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −113.2, −128.7.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:9][CH3:10])=[C:14]([CH3:21])[CH:13]=1
Reactant: COc1cc(N)ccc1Br
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1cc(N)ccc1-c1ccc(Cl)cc1C

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromo-3-methoxyaniline and (4-chloro-2-methylphenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:19]2([CH3:23])[CH2:22][O:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(C)COC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (3.0 g) and K2CO3 (5.5 g) in N,N-dimethylformamide (10 mL) is added 3-(bromomethyl)-3-methyloxetane (2.95 g). The mixture is stirred for 12 hours at room temperature and then partitioned between saturated aqueous NaHCO3 solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→70:30) to give the title compound. Yield: 3.5 g; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.C(Cl)Cl.[C:33](=[O:37])([O:35][CH3:36])N>O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([CH3:13])([CH3:12])[CH2:10][NH:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:33](=[O:37])[O:35][CH3:36])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COC(N)=O
Reactant: CC(C)(CNc1ccc(CN)cn1)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)NCc1ccc(NCC(C)(C)c2ccc(F)cc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a 20 dram vial was added 5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine (100 mg, 0.37 mmol, 1.0 equiv), DIPEA (57 mg, 0.44 mmol, 1.2 equiv) and CH2Cl2 (1.2 mL). The mixture was cooled to 0° C., and methyl carbamate (35 mg, 0.4 mmol, 1.0 equiv) was then added. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was then diluted with water (2 mL) and extracted with ethyl acetate (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography, affording 20 mg of methyl (6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate (m/z [M+H]=332).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.O1CCCC1.[F:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[C:21]([NH:29][CH3:30])[CH:20]=1>CCCCCC.O>[F:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](=[O:24])[CH2:12][C:11]2[N:7]([CH3:6])[N:8]=[N:9][N:10]=2)=[C:21]([NH:29][CH3:30])[CH:20]=1
Reactant: CNc1cc(F)ccc1C(=O)OC
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNc1cc(F)ccc1C(=O)Cc1nnnn1C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (50 ml of 1.6M solution) was added slowly to a stirred mixture of 1,5-dimethyltetrazole (7.84 g) and dry tetrahydrofuran (170 ml) at 0°-5° under nitrogen. The mixture was stirred at 0°-5° for 0.5 hour and then methyl 4-fluoro-2-methylaminobenzoate (4.84 g) was added in portions at 0°-5°. The mixture was stirred at room temperature for 3 hours and then poured into water (500 ml). The resulting mixture was extracted with dichloromethane (5×60 ml). The extract was dried and evaporated to give an oil which partially solidified overnight. The solid was collected by filtration, washed with toluene and dried in vacuo to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 132°-134°.
Reaction SMILES: [I:1]I.N[C:4]1[C:8]([CH:9]2[CH2:11][C:10]2([Br:13])[Br:12])=[CH:7][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:5]=1.N(OC(C)(C)C)=O>ClCCl>[Br:12][C:10]1([Br:13])[CH2:11][CH:9]1[C:8]1[C:4]([I:1])=[N:5][N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[CH:7]=1
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(I)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (0.55 g) was added to a stirred solution of the title compound of Example 8 (0.40 g) in dichloromethane (10 ml), followed by the dropwise addition of t-butyl nitrite (0.21 g). The reaction mixture was stirred at room temperature for 2 hours, then partitioned between dichloromethane and aqueous sodium thiosulphate solution and the organic phase separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using hexane and then dichloromethane as eluants, followed by reverse phase HPLC on C18 silica, using a mixture of acetonitrile:water:methanol (30:60:10) as eluant, to produce the title compound as an off-white foam. δ (CDCl3): 1.84 (t,1H), 2.26 (dd,1H), 2.67 (dd,1H), 7.20 (s,1H), 7.72 (s,2H). MS (thermospray): M/Z [M+H] 602.4; C13H6Br2Cl2F3IN2 +H requires 602.74.