Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:22][C:21]([CH2:23][CH3:24])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:23][CH3:24])[S:22][C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2s1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Temperature: 65 °C
Yield: 101.6 %

Procedure:
To a round bottom flask containing 7-benzyloxy-2-ethylthiazolo[4,5-c]quinolin-4-amine (11.3 g, 33.7 mmol) was added a 45 wt. % solution of hydrogen bromide in acetic acid (40 mL). The resulting solution was heated at 65° C. for 2 hours and then cooled in an ice bath. Aqueous sodium hydroxide (50% w/w solution) was added slowly until pH 7 and a pale yellow/green solid formed. The solid was isolated by filtration and air dried to provide 8.4 g of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol. MS (APCI) m/z=246.0.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:18](=O)[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:23]>P(Cl)(Cl)(Cl)=O>[Cl:23][C:18]1[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: COc1cccc2c(=O)c(C(=O)C3CCCCC3)c[nH]c12
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C(=O)C3CCCCC3)cnc12
Yield: 90 %

Procedure:
3-Cyclohexylcarbonyl-8-methoxy-4(1H)-quinolone (5.8 g, 0.02 mol) was heated under reflux in a mixture of chloroform (100 ml) and phosphorus oxychloride (15 ml) for 2.5 hours. The reaction mixture was partitioned between chloroform, ice and sodium hydrogen carbonate solution (100 g in 1.5 l) and the organic solution was washed with sodium hydrogen carbonate solution and brine. The chloroform solution was dried and evaporated to give 4-chloro-3-cyclohexylcarbonyl-8-methoxy-quinoline (5.5 g, 90%) as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)O1.Br[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[S:28][C:27]([N:29]([CH3:40])[CH:30]3[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]3)=[N:26][N:25]=2)=[C:18]([F:41])[CH:17]=1.C([O-])(O)=O.[Na+]>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>[F:41][C:18]1[CH:17]=[C:16]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[C:24]1[S:28][C:27]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:26][N:25]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Br)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cn[nH]c2)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Pd(Ph3P)4 (11 mg, 0.009 mmol) was added to a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55 mg, 0.282 mmol) and 5-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (86 mg, 0.188 mmol) in dioxane (1.5 mL), followed by a solution of NaHCO3 (60 mg, 0.564 mmol) in water (0.375 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and SiliaMetS-DMT (0.61 mmol/g, 145 mg, 0.09 mmol) was added. The resulting suspension was stirred at room temperature for ˜2 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a light brown oil. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified), collecting at 328 nm to afford the title compound as a white solid (26 mg, 32% yield). LC-MS: Rt 0.76 min; MS m/z 445.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s., 1H), 8.26 (br. s., 2H), 7.23-7.31 (m, 2H), 4.27-4.37 (m, 1H), 3.93 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:45])[NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:44])=[C:25]([CH:43]=4)[O:26][C:27](=[O:42])[CH2:28][N:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH:14]=3)[C:9]2=[O:46])[CH2:6][CH2:5][C:4](=[O:47])[NH:3]1.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[N:29]1([CH2:28][C:27]([O:26][C:25]2[CH:43]=[C:21]([NH:20][C:19]([NH:18][CH2:17][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:46])[N:8]([CH:7]3[CH2:6][CH2:5][C:4](=[O:47])[NH:3][C:2]3=[O:1])[CH2:16]4)=[O:45])[CH:22]=[CH:23][C:24]=2[CH3:44])=[O:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN1CCNCC1
Reaction time: 24 h

Procedure:
To a mixture of tert-butyl 4-(2-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate (0.65 g, 1.0 mmol) in methylene chloride (50 mL) is added 2M HCl in ether (1 mL), and the mixture will be stirred for 24 hrs. The solid precipitate is filtered, rinsed with DCM (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:20]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:22]=[C:23]([CH:32]=1)[C:24]([NH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[O:25].O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:18][C:19]2[CH:32]=[C:23]([C:24](=[O:25])[NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:22]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:20]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)nc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 123 mg (0.72 mmol) of 6-chloronicotinic acid methyl ester and 199 mg (1.44 mmol) of potassium carbonate to a solution of 100 mg (0.36 mmol) of the obtained amide compound in N,N-dimethylfommamide (10.0 ml), the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 65 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Sc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2ccc(Cl)cc2)c1
Reaction time: 8 h

Procedure:
p-Chlorothiophenol (4.52 g., 31.4 mmoles) was reacted with 5-bromo-furan-3-carboxylic acid according to the procedure of Example 15, except that the total volume of dimethylformamide was 85 ml., and the reflux period was 8 hours. The reaction mixture was cooled, filtered, the filtrate diluted with 500 ml. of water and insolubles removed by filtration. The latter filtrate was made acidic with 6 N hydrochloric acid, product was extracted into ethyl acetate and recovered by evaporation to an oil, crystallized by trituration with water (860 mg.). Two crystallizations from methanol/water gave purified 5-(4-chlorophenylthio)furan-3-carboxylic acid (150 mg., m.p. 142°-145° C., m/e 254). Analysis: Calcd. for C11H7O3SCl; C, 51.87; H, 2.77. Found: C, 51.97; H, 2.99.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Reactant: OB(O)c1ccccc1OCc1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C
Yield: 41 %

Procedure:
2′-Bromobiphenyl-3-carboxylic acid ethyl ester (153 mg, 0.5 mmol) and 2-benzyloxyphenylboronic acid (125 mg (0.55 mmol) were dissolved in 1:1 toluene:ethanol (5 ml) under nitrogen. Potassium carbonate (552 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) were added and the mixture heated at 90° C. for 3 h. After cooling, the solvent was evaporated. The residue was partitioned between diethyl ether and water and the organic phase washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was flash chromatographed (silica gel, 2-10% EtOAc-isohexane) to give the title compound as a clear oil (84 mg, 41%). LC/MS Rt=4.09 [(M−OEt)H+]=363.1.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](C)=O)=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[CH:6][C:7]=1[SH:8]
Reactant: COc1cc(C)cc(S(C)=O)c1F
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(C)cc(S)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a mixture of 2-fluoro-1-methoxy-5-methyl-3-(methylsulfinyl)benzene (486 mg) and CH3CN (20 mL) was added TFAA (1.02 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (3.5 mL) and TEA (3.5 mL) at 0° C. The solution was stirred at room temperature for 1 h, and concentrated in vacuo. The residue was diluted with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (214 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC(C2CC(=O)C(=[CH:30][N:31]([CH3:33])[CH3:32])C(=O)C2)=CC=1>>[CH3:30][N:31]([CH:33]=[C:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15])[CH3:32]
Reactant: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Product: CN(C)C=C1C(=O)CC(c2ccc(F)cc2)CC1=O
Reaction time: 0.17 h

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)cyclohexane-1,3-dione (1.0 g, 4.85 mmol), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was run at ambient temperature for 10 min.
Reaction SMILES: B(Br)(Br)[Br:2].[F:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH2:8]O>>[F:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH2:8][Br:2]
Reactant: Cc1ccc(F)c(CO)c1
Reactant: BrB(Br)Br
Product: Cc1ccc(F)c(CBr)c1
Temperature: 7.5 °C

Procedure:
An oven dried round bottom flask is charged with boron tribromide (13 mL, 140 mmol) and is cooled to −30-45° C. 2-Fluoro-5-methyl-benzyl alcohol (6.5 g, 46 mmol) is then added slowly after which time the reaction is allowed to warm to room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=2)[CH3:9])[CH:2]=1.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH3:9])=[N:11][CH:12]=2)=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: CC(Oc1cccnc1)c1ccc(C(=O)O)cn1
Reactant: Cc1cc(C)c(CN)c(O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccnc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
To a solution of 6-(1-(Pridin-3-yloxy)ethyl)nicotinic acid (150 mg, 0.61 mol) was dissolved in dichloromethane (20 mL), H-benzo[d][1,2,3]triazol-1-ol (124 mg, 0.92 mmol), 1-(3-dmethylaminopropyl)-3-ethylcarbodiimide hydrochloride (176 mg, 0.92 mmol) and triethylamine (3 mL, 1.84 mmol) were added. After stirring at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (93 mg, 0.61 mmol) was added. The mixture was stirred at room temperature for 18 hours. Once the start material was consumed, water (30 mL) was added. The mixture was extracted with dichloromethane (40 mL). The organic layer was separated and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-(pyridin-3-yloxy)ethyl)nicotinamide (50 mg, 21.5%).
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14]C([O-])(C)C.[K+].CI>C(Cl)Cl>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH3:14])([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC(C)CC1=CCC(C)(C=O)C(C)C1
Temperature: -3 °C
Yield: 99.4 %

Procedure:
4-Isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (8 g, 44 mmol) was dissolved in methylene chloride (400 ml) and cooled to −3° C. with stirring and under nitrogen. KOtBu (6.7 g, 58 mmol) and MeI (19 g, 130 mmol) were added sequentially and the suspension stirred for 30 min before being allowed to return to room temperature. After stirring for a further 3 h the reaction crude was poured onto brine (400 ml), stirred for 10 min and the phases allowed to separate. The upper aqueous phase was extracted with methylene chloride (150 ml) and the organic phases combined, dried (Na2SO4) and concentrated in vacuo to give 8.5 g of an orange oil (8.5 g). The oil was purified by flash chromatography (MTBE/hexane 1:9) and combination of pure fractions gave 3c as a 7:3 mixture of diastereomers (7 g, colorless oil, 80% yield). 1 g of the oil was distilled to give a sample for olfactory assessment. (0.52 g, colourless oil, >99% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:12]([F:11])([F:39])[F:38])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:12][C:13]1[CH:14]=[C:15]([C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (10.6 g, 54 mmols), tert-butyl(1R)-1-(3-hydroxyphenyl)ethylcarbamate (13.7 g, 58 mmols), potassium carbonate (8.7 g, 63 mmols) and N,N-dimethylformamide (150 ml) was stirred at 100° C. for 1 hour. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography, and the resulting crystal was re-crystallized from hexane/ethyl acetate to give a crystal of tert-butyl(1R)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (12.9 g, 60%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[NH:15][C:16](=O)[C:17]4[CH:22]=[CH:21][NH:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Br)(Br)([Br:26])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Br:26][C:16]1[C:17]2[CH:22]=[CH:21][NH:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c(Nc2ccc(N3CCOCC3)cc2)nc2[nH]ccc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1nc(Nc2ccc(N3CCOCC3)cc2)nc2[nH]ccc12
Temperature: 25 °C

Procedure:
A mixture of 2-[(4-morpholin-4-ylphenyl)amino]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one A (312 mg, 1 mmol), phosphorous oxybromide (717 mg, 2.5 mmol), and diisopropylethylamine (130 mg, 1 mmol) in anhydrous toluene (15 ml) was heated at reflux under N2 overnight. The mixture was cooled down to room temperature, and the solid was filtered, washed with sat. NaHCO3, water, and dried over MgSO4. The solvent was removed in vacuo to give the product 4-bromo-N-(4-morpholin-4-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine B (284 mg, 76%) as a black solid. This was clean and used as such without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (3.00 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (5.41 g; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].Cl>C(O)C.O>[NH2:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[CH:2]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (4.00 g., 21 mmol) and diethyl oxalate (7.3 mL, 54 mmol) in absolute ethanol is added dropwise to a solution of sodium ethoxide (0.1 mol) in absolute ethanol. The mixture is heated at reflux temperature for 1.5 h, cooled to ambient temperature, poured into water, acidified to pH 3 with 6N HCl and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford an oily residue. The residue is dissolved in ethanol, treated with concentrated HCl heated at reflux temperature overnight, cooled to 0° C. for several hours and filtered. The filtercake is dried to afford the title compound as an orange solid, 2.95 g (61% yield), mp 195°-198° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](N(CC)C(C)C)(C)[CH3:29].BrCC>C1COCC1>[CH2:28]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 100 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 3 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was be shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM and washed with 1N aqueous NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Treatment with 1 equiv. 2M HCl in dioxane and concentration in vacuo gave 16 mg of its hydrochloride salt. Yield 27%, ES MS (+) m/z 405