Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67]O)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52].C(N(CC)CC)C>ClCCl>[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:16][CH3:17])=[CH:14][CH:13]=3)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
To 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (472 mg, 2 mmol, 2 eq) was added polymer-bound triphenyl-phosphine (667 mg, 2 mmol, 2 eq) and dichloromethane (10 mL). The mixture was placed under nitrogen, cooled in an ice bath, diisopropyl azodicarboxylate (0.394 mL, 2 mmol, 2 eq) was added drop-wise, stirred for 1.5 hr. A solution of 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (247 mg, 1 mmol, 1 eq) and triethylamine (0.279 mL, 2 mmol, 2 eq) in dichloromethane (2 mL) was added drop to portion wise and the reaction allowed to warm to room temperature overnight (20 hr). The reaction was filtered over Celite, adsorbed onto silica gel, and purified by flash chromatography with a gradient from 1-15% ethyl acetate in hexanes to yield 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester white/clear solid (288 mg, 62%). LC-MS (ES) calculated for C27H25F2NO2, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[CH3:29]CN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CO>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([O:19][CH3:29])=[O:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)(C)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropanoic acid (3 g, 7.75 mmol), EDCI (1.8 g, 9.3 mmol) and HOAT (0.2 g, 1.6 mmol) in CH2Cl2 (60 mL) was added CH3OH (5 mL). The reaction mixture was stirred at room temperature for 1 hour and then diluted with 20 mL of CH2Cl2. The organic phase was separated, washed with water (20 mL) and concentrated in vacuo. The crude product was purified by a column chromatography on silica gel (PE/EtOAc=2:1) to afford the title compound as a yellow oil (3 g, 96.5%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40]([N:6]3[CH2:7][CH2:8][N:9]([C:11](=[O:24])[C:12]4[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=4)[CH2:10][CH:5]3[CH2:4][O:3][CH3:2])=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(-c2nc(C(=O)O)cs2)cc1OC
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl) piperazine hydrochloride obtained in Reference Example 6 (0.50 g), 2-(3,4-dimethoxyphenyl)thiazol-4-carboxylic acid (0.37 g), triethylamine (0.42 g) and N,N-dimethylformamide (5 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.46 g). The reaction mixture is stirred at 0° C. for one hour and there poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent: AcOEt) to give 1-[2(3,4-dimethoxyphenyl) thiazol-4-ylcarbonyl]-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine. Recrystallization from EtOH gives colorless needles, m.p. 149-151° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.C(O)(C(F)(F)F)=O>[S:30]([N:25]1[C:26]2[C:22](=[C:21]([CH2:20][N:3]3[C:4]4([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)[CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)([C:33]1[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116 %

Procedure:
To a stirred solution of tert-butyl 2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.12 g, 0.21 mmol) in dichloromethane (5.0 mL), TFA (0.5 mL) was added at 0° C. and the reaction mixture was stirred for 16 h at rt under a nitrogen atmosphere. The reaction mixture was concentrated to yield the title compound as colourless oil (0.11 g, 95%) which was used in the next step.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][C:33]1[NH:34][C:35]([CH2:38][NH2:39])=[N:36][N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[NH:34][C:33]([CH3:32])=[N:37][N:36]=1)=[O:4]
Reactant: Cc1nnc(CN)[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), (5-methyl-4H-1,2,4-triazol-3-yl)methanamine (11.70 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide 2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.022 mmol, 31.7% yield) as a single enantiomer. LCMS=526.4 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.51-7.76 (7 H, m), 5.21 (1 H, s), 4.46-4.66 (2 H, m), 2.52 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:21]
Reactant: COC(=O)c1cccnc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(chloromethyl)pyridine-3-carboxylate (20.73 g, 112 mmol) was taken up in dichloromethane (225 mL) and mCPBA (27.5 g, 123 mmol) was added. The resulting solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the products extracted into dichloromethane (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (silica, 0-20% methanol/ethyl acetate) gave the title compound as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 8.50 (dd, 1H), 7.75 (dd, 1H), 7.53 (dd, 1H), 5.07 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[CH2:34][N:27]3[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:33]4[C:25]([C:21]4[NH:20][CH:24]=[CH:23][N:22]=4)=[N:26]3)[C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1
Reactant: COc1cc(N2CCN[C@@H](C)C2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. (S)-1-(4-Chloro-2-fluoro-5-methoxy-phenyl)-3-methylpiperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (29 mg): 1H NMR (CDCl3, 400 MHz) 8.79 (dd, 1H), 8.55 (dd, 1H), 7.27-7.21 (m, 3H), 7.07 (d, 1H), 6.43 (br. d, 1H), 5.46-5.37 (m, 2H), 4.83 (br. s, 0.3H), 4.51-4.48 (m, 0.6H), 4.28-4.21 (m, 0.6H), 3.86 (s, 0.9H), 3.85 (s, 2.1H), 3.79 (br. s, 0.3H), 3.67 (br. s, 0.3H), 3.33-3.21 (m, 2.5H), 2.95-2.93 (m, 0.9H), 2.83-2.76 (m, 1.6H), 1.48-1.40 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10](F)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.COB(OC)OC.C(#N)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(OC)c21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 2.83 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.72 g of anhydrous piperazine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 15 ml of acetonitrile was refluxed with heating for 4.5 hours. The reaction solution was cooled to room temperature, 30 ml of water was added therein, and separated crystals were filtered and dried to obtain 2.00 g of the objective compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O.C(N(CC)CC)C.C(Cl)[Cl:25]>P(Cl)(Cl)(Cl)=O>[Cl:25][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: ClCCl
Reactant: Oc1ncnc2ccc(OC(F)(F)F)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation D4, Step 5: A suspension of 6-(trifluoromethoxy)quinazolin-4-ol (515 mg, 2.23 mmol) in phosphorous oxychloride (1.9 mL) was treated with triethylamine (3 mL, 21.1 mmol), and the mixture was heated at reflux for 2 h. The resulting solution was cooled to room temperature, and stripped 3× from methylene chloride to remove residual phosphorous oxychloride. The residue was dissolved in 100 mL methylene chloride, 100 mL saturated sodium bicarbonate was carefully added, causing vigorous gas evolution, and the mixture was stirred for 10 min, until gas evolution had ceased. The layers were separated, and the organic phase was washed with saturated sodium bicarbonate (2×30 mL), followed by brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% EtOAc/heptane, to yield 377 mg of 4-chloro-6-(trifluoromethoxy)quinazoline as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1 H), 8.16 (d, J=9.23 Hz, 1 H), 8.10 (s, 1 H), 7.83 (dd, J=9.23, 2.20 Hz, 1 H). MS (ES+)=249 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:37]=[CH:36][CH:35]=[C:30]([C:31](OC)=[O:32])[CH:29]=1>O1CCCC1>[CH3:25][O:26][C:27]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:32])=[O:38]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Yield: 15.9 %

Procedure:
Under the conditions of example 1B, 652 mg of 2-bromo-6[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 3 ml of tetrahydrofuran is mixed with 2.75 ml of n-butyllithium (1.6 molar in hexane) and 427 mg of isophthalic acid dimethyl ester in 3 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 130 mg of an oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol/H2O=85/15. 58 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1.Cl[C:25]1N=C2C(N=C(C3(O)COC3)N2CC)=C(N2CCOC[C@@H]2C)N=1.CCCCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH2:11][CH3:25])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1
Reactant: CCn1c(C2(O)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCn1c(C2(F)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(2-chloro-8-(3-fluorooxetan-3-yl)-9-methyl-9H-pur-in-6-yl)-3-methylmorpholine, using (S)-3-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)oxetan-3-ol as the starting material. LC-MS m/z (method C)=356/358 [M+H]+, RT=2.62 min; TLC (1:1 heptane:ethyl acetate): Rf=0.58.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:5]1([CH2:16][N+:13]([O-:15])=[O:14])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: C[N+](=O)[O-]
Solvent: O
Product: Cc1ccc2c(c1)C(O)(C[N+](=O)[O-])C(=O)N2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
5-methyl isatin (0.08 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 50° C. for 24 hours. The product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (100 mg, 0.204 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.07 ml, 0.408 mmol) and ethyl 5-bromopentanoate (0.06 mL, 0.408 mmol). The reaction mixture was heated to 80° C. overnight then was allowed to cool and the solvent evaporated. Purification of the residue by flash chromatography, eluting with (40-100% ethyl acetate in cyclohexane) gave the title compound as an off white solid (70 mg).
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[OH:27]>C1(C)C=CC=CC=1>[OH:27][C:16]1[CH:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:2][CH3:1])=[O:13]
Reactant: CN
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2CCOCC2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a cooled (0° C.), stirred solution of methylamine in dry tetrahydrofuran (1.27 mL of 2.0 M solution; 2.52 mmol) was slowly added a solution of trimethylaluminum in dry toluene (1.27 mL of 2.0 M solution; 2.52 mmol) via syringe under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stir for 2 hours. To the resulting solution, a solution of the 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (100 mg; 0.42 mmol) in dry toluene (4.0 mL) was added via cannula and the resulting solution was heated to reflux for 2 hours. After cooling to room temperature, the reaction was quenched with the careful addition of 1 N aqueous hydrochloric acid to pH 4. The mixture then was extracted with EtOAc (3×10 mL), and the combined organic layers washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from CH2Cl2—hexanes to provide the amide (93 mg; 93%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]12([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>C1(C)C=CC=CC=1>[C:7]12([N:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:1](=[O:5])[C:2]3=[O:3])[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]3)[CH2:14]1)[CH2:16]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a N2 atmosphere was added 1.97 g (15.6 mmol) of oxalyl chloride to 3 ml of dry toluene which was cooled to 0° C. To this solution was added 3.55 g (15.6 mmol) of N-1-adamantylaniline in toluene (8 ml). The reaction was allowed to stir for 30 min. at 0° C. and then heated at 65° C. for 3 hours. Additional solvent (10 ml) was added and the reaction was kept at 65° C. for 72 hours. The solvent was removed and the residue was allowed to stir at 160° C. for 5 hours. The crude reaction mixture was allowed to cool and was chromatographed on silica gel using 6:1 hexane:EtOAc to afford crude product, which was triturated with isopropyl ether (IPE) to generate 164 mg (4.4%) of 1-adamantylisatin combined with product contaminated with significant amounts of impurities.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1([CH:20]=[CH:19]N=[C:17]([CH:21]([OH:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:16]1)C(NC1C=CC=CC=1)=O.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C.P(Br)(Br)Br>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:35]2[N:32]=[C:33]([C:34]3[CH:34]=[CH:33][N:32]=[CH:35][CH:36]=3)[O:29][CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:17]=2[CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccccc1)C1(Cl)C=CN=C(C(O)c2ccc(Cl)cc2)C1
Agent: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C2OC(c3ccncc3)=Nc3ccc(Cl)cc32)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To chloroform (300 ml), 4-chloro-2-(4-chloro-α-hydroxybenzyl)-isonicotinanilide (12.4 g) and triethylamine (5.0 ml) were added. With stirring and under cooling with ice, phosphorus tribromide (9.1 g) was added slowly, and the stirring was continued for 1 hour. Following another 3-hour stirring at room temperature, the reaction mixture was poured into water. The chloroform layer was thoroughly washed with water and subsequently dried. The chloroform was completely distilled off under vacuum. Upon recrystallization from a mixed solvent of ethyl acetate and n-hexane, the titled compound was obtained in an amount of 10.1 g (yield: 85%). m.p. 140°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Yield: 29.5 %

Procedure:
To a stirred mixture of (E)-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (9.87 g, 0.034 mol) in carbon tetrachloride (60 mL) under a nitrogen atmosphere was added N-bromosuccinimide (9.08 g, 0.051 mol) and benzoyl peroxide in water (75%, 1.09 g, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (3.70 g, 29%) as a yellow oil.