Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COC2C=CC([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=CC=2O1.ClC1N=C(N[CH2:35][CH:36]([OH:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(F)=CN=1.[CH2:45]1[CH2:55]OC2C=CC(N)=CC=2[O:46]1>>[CH2:55]1[CH2:45][O:46][C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH2:35][CH:36]([OH:43])[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:14]3[N:13]=[C:12]([NH2:11])[C:17]([F:18])=[CH:16][N:15]=3)=[CH:21][C:22]=2[O:26]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: OC(CNc1nc(Cl)ncc1F)c1ccccc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: Nc1nc(N(CC(O)c2ccccc2)c2ccc3c(c2)OCCO3)ncc1F

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (s, 1H), 7.48 (m, 5H), 6.89-6.71 (m, 3H), 5.41-5.38, 4.97 (dd, 1H, J=3.6 and 7.5 Hz), 4.28-4.22 (m, 4H), 3.88 (ddd, 1H, J=4.2, 7.2, and 14.1), 3.64-3.55 (m, 1H); 19F NMR (CDCl3): −47910; LCMS: ret. time: 20.47 min.; purity: 88%; MS (m/e): 383 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+:28].[CH3:29][OH:30]>O.[Fe]>[F:1][C:2]1[CH:23]=[C:22]([NH:24][C:5](=[O:4])[CH2:6][C:29]([NH:28][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:3]=2)=[O:30])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:13][C:6]=12
Reactant: CO
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccncc4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccncc4)sc23)c(F)c1)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of the 63 (660 mg, 1.80 mmol) in MeOH (15 ml) and water (3 ml) was added ammonium chloride (81 mg, 0.84 eq, 1.51 mmol) and Fe (907 mg, 9 eq, 16.2 mmol) and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to RT, filtered through celite then concentrated. The mixture was partitioned between DCM/H2O and the DCM was collected, dried over Na2SO4, filtered and concentrated to produce the amine 64 which was used directly in the next step (607 mg, 100%). To a solution of the amine 64 (607 mg, 1.80 mmol) in dry DMF (˜7 ml) was added the acid 1 (644 mg, 2 eq, 3.6 mmol), HOBT (365 mg, 1.5 eq, 2.7 mmol) and EDC (690 mg, 2 eq, 3.6 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water, the organic phase was collected, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was purified by column chromatography (EtOAc) to afford title compound 62 as a white solid (150 mg, 17% yield). 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 10.20 (s, 1H), 8.70 (m, 2H), 8.55 (d, J=5.28 Hz, 1H), 8.37 (s, 1H), 7.89 (m, 3H), 7.60 (m, 2H), 7.58 (m, 2H), 7.30 (dt, J=1.96 and 7.43 Hz, 2H), 7.07 (m, 1H), 6.70 (dd, J=0.78 and 5.28 Hz, 1H), 3.51 (s, 2H). MS (m/z): 499.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5])[CH2:26]2
Reactant: COC(=O)C(O)(c1ccco1)C1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccco1)C1CCCCC1

Procedure:
Prepared using the same method as for Intermediate I-1, but from 13.73 g (0.057 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester (Intermediate I-11) dissolved in 350 ml of toluene, 8.6 g (0.067 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.37 g (0.0342 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.33 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 97:3:0.3. Appropiate fractions were combined and evaporated to obtain the two diastereomers: I-4a and I-4b.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20]O)=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(OCC)C>[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][Br:2])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Reaction time: 2 h

Procedure:
Phosphorous tribromide (2 mL) was added to a solution of (4-benzyloxy-3,5-dichlorophenyl)-methanol (CAB02117, 5.50 g, 19.4 mmol) in dichloromethane (80 mL) at 0° C. The mixture was stirred at this temperature for 2 h, diluted with diethyl ether (150 mL), transferred into a separation funnel and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane. 1H-NMR (400 MHz, CDCl3) δ=4.39 (s, 2H, —CH2Br), 5.05 (s, 2H, —CH2Ph), 7.37 (s, 2H), 7.38-7.44 (m, 3H), 7.54-7.58 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=31.48, 75.39, 128.73, 129.68, 129.70, 129.72, 130.06, 135.46, 136.27, 151.23.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[C:45]([OH:49])=[C:44]([Br:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1.C(O)=O>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[C:45]([OH:49])=[C:44]([Br:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: O=C(O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.4 mg (0.06 mmol) LiOH in 1 mL water was added to a solution of 30 mg (0.04 mmol) of (R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 138) in 3 mL THF and the reaction solution was stirred overnight at RT. The solvent was eliminated in the nitrogen current, the residue was taken up in 1 mL water, acidified with formic acid, the precipitate formed was removed by suction filtering and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[O:8][C:9]3[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.C(N(CC)CC)C.S1C=CC=C1>C1COCC1.[Pd]>[NH2:15][C:14]1[C:9]2[O:8][C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]=3[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCc2oc3c([N+](=O)[O-])cccc3c2C1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCc2oc3c(N)cccc3c2C1
Yield: 96.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-2-methyl-6-nitrobenzofuro[3,2-c]pyridine (0.0215 mol) and triethylamine (2 g) in THF (200 ml) was hydrogenated with palladium-on-charcoal catalyst 10% (2 g) as a catalyst in the presence of thiophene 4% (2 ml). After uptake of H2 (3 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 4.2 g 1,2,3,4-tetrahydro-6-amino-2-methylbenzofuro[3,2-c]pyridine (interm. 7).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([F:14])[CH:13]=1)[NH2:10]>Cl.O>[F:6][C:7]1[CH:13]=[C:12]([F:14])[CH:11]=[C:9]2[C:8]=1[CH:1]=[CH:2][C:3]([CH3:4])=[N:10]2
Reactant: C/C=C/C=O
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Solvent: O
Product: Cc1ccc2c(F)cc(F)cc2n1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Crotonaldehyde (28 mL, 0.33 mol) was added dropwise to a refluxing solution of 3,5-difluoroaniline (10.75 g, 0.083 mol) in 5 N hydrochloric acid (450 mL) and reflux was continued for a further 0.5 h. Reaction mixture was cooled, diluted with water (200 mL) and washed with ether (200 mL). The aqueous layer was basified (pH 14) with 50% NaOH (aq) and extracted into dichloromethane (3×200 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜100 g) with 50–100% ethyl acetate in hexane gradient elution to give 5,7-difluoro-2-methylquinoline as a brown solid (6.57 g, 44%). A mixture of 5,7-difluoro-2-methylquinoline (1.0 g, 5.6 mmol) and sodium methoxide (1.62 g, 30 mmol) in methanol (50 mL), was stirred at reflux for 18 h, cooled, and most of the methanol removed in vacuo. The residue was partitioned between ethyl acetate (100 mL), and water (100 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a brown oil which was purified by chromatography on silica gel (˜60 g) with 20–30% ethyl acetate hexane gradient elution to give a yellow solid (0.57 g) which was suspended in 48% HBr (aq) (5 mL) and heated at reflux for 18 h. Reaction mixture was cooled and evaporated in vacuo to give the title compound as a brown solid (0.67 g, 46%).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]([C:5]([OH:7])=O)[CH3:4].C(N1CCOCC1)C.ClC(OCC(C)C)=O.O1CCCCC1ONC([C@H]([C@@H:51]([CH2:60][CH:61]([CH3:63])[CH3:62])[C:52]([NH:54][NH:55][CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])C/C=C/C1C=CC=CC=1)=O>O1CCCC1.C(OCC)(=O)C>[CH2:56]([N:55]([C:5](=[O:7])[C@H:3]([CH3:4])[N:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:54][C:52](=[O:53])[CH2:51][CH2:60][CH:61]([CH3:63])[CH3:62])[CH:57]([CH3:59])[CH3:58]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.233 g of N-methyl-N-tert.-butoxycarbonyl-L-alanine in 10 ml of tetrahydrofuran was cooled to −10° C. and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for a further 10 minutes at −10° C. and then treated with 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0° C. and stirring was continued for 45 minutes. The mixture was then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.608 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(N-methyl-N-tert.-butoxycarbonyl-L-alanyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]3[C:15]4[C:16](=[C:20]([C:24]([OH:26])=O)[N:21](C)[N:22]=4)[CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][N:10]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[K].[CH3:30]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[CH2:61]([NH:68][C:24]([C:20]1[C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[C:13](=[N:14][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[O:27][CH3:28])=[N:10][CH:11]=3)[C:15]=2[N:22]([CH3:30])[N:21]=1)=[O:26])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(Br)ccc1Nc1ncc2c(n1)-c1nn(C)c(C(=O)O)c1CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1Nc1ncc2c(n1)-c1c(c(C(=O)NCc3ccccc3)nn1C)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.8 %

Procedure:
A suspension of potassium 9-[(4-bromo-2-methoxyphenyl)amino]-2-methyl-2,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylic acid (0.050 g, 0.110 mmol) in anhydrous DMF (5.0 mL) was treated with DIPEA (0.056 mL, 0.033 mmol) and TBTU (0.065 g, 0.200 mmol). The mixture was then treated with benzylamine (0.015 mL, 0.011 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (0.045 mg, 77% yield) as a pale yellow solid.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[C:7]4[N:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:9]=[N:10][C:6]=4[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: OCCCO
Product: Cn1ccc2cc(-c3cc(C(F)(F)F)cc4ncn(-c5ccccc5)c34)ccc21
Yield: 83.8 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 2.5 mmol), 1-methyl-5-indolyl boronic acid (0.65 g, 3.73 mmol), 1,3-propanediol (0.9 ml, 12.4 mmol), potassium carbonate (1.71 g, 12.4 mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred at reflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in ethanol to afford the title product as an off-white solid (0.82 g, 84%) m/z, 392.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([CH3:27])[C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CCOC(C)=O.O.[CH2:37]1[CH2:41]OC[CH2:38]1>>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([CH3:27])[C:10]=1[CH:11]([OH:12])[CH2:41][CH:37]=[CH2:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(C=O)c(C)c1OCc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCC(O)c1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde (3.90 g, 12.16 mmol) was dissolved into 50 mL THF and cooled to 0° C. prior to the addition of 15 mL allyl Grignard (1.0 M in THF, 15 mmol). The pale yellow solution browned over the course of the addition. After 15 minutes at 0° C. the reaction was not complete by HPLC and an additional portion of allyl Grignard (3 mL, 1.0 M in THF, 3 mmol) was added and stirred for 0.6 h at which time the reaction was judged complete by HPLC. The reaction was treated carefully at 0° C. with 50 mL 10% aqueous NH4Cl stirred for five minutes post addition and 100 mL EtOAc added. The layers were stirred vigorously until they clarified, an additional 100 mL H2O and 100 ml EtOAc was added, the layers separated and the aqueous phase extracted 3×100 mL EtOAc. The combined organics were washed with 2×50 mL saturated aqueous NaCl and dried over Na2SO4 prior to concentration to a pale brown oil. Storage under vacuum gave a brown solid. Flash chromatography (gradient elution 0-20% EtOAc/heptane) yielded 3.91 g of 1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol as a white, waxy solid. M++H—H2O=385 m/z; 1H NMR (400 MHz, CDCl3) δ=7.55 (d, 4 H), 7.51-7.42 (m, 6 H), 5.91 (m, 1H), 5.19-5.10 (m, 3 H), 5.01 (d, 1 H), 4.90 (d, 1 H), 4.78 (s, 2 H), 3.35 (d, 1 H), 2.76 (m, 1 H), 2.55 (m, 1 H), 2.39 (s, 3 H), 2.32 (s, 3 H), 2.31 (s, 3 H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:31][C:30]([OH:33])([CH3:32])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:4][C:3]=1[F:34].[CH3:35]B1OB(C)OB(C)O1>>[F:34][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([N:28]3[CH2:31][C:30]([OH:33])([CH3:32])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)[CH:6]=[N:7][C:2]=1[CH3:35]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cnc(Cl)c(F)c2)C1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 52 using 6′-chloro-5′-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 134) and trimethyl-boroxine. HPLC (Condition 4) tR=5.26 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=477.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 2.42-2.55 (m, 3H) 3.50-3.65 (m, 4H) 5.46 (d, J=0.78 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.74 (d, J=10.56 Hz, 1H) 7.83 (d, J=8.60 Hz, 2H) 7.97-8.05 (m, 1H) 8.37 (s, 1H) 8.71-8.78 (m, 1H) 10.19 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.CN(C)C=O.[S-2:25].[Na+].[Na+]>C(O)(=O)C>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([SH:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: [S-2]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1ncc2c1ncc1c(S)nc3ncnn3c12
Reaction time: 1 h

Procedure:
5.6 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.) are dissolved in 100 ml. of dimethylformamide. 2 g. of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidified with acetic acid. 8-Ethyl-8H-pyrazolo[3',4':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-5-thiol precipitates and is filtered off.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14]/[CH:15]=[CH:16]/[CH2:17]Br.[OH2:19]>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][N:5]2[C:1](=[O:19])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrC/C=C/CBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CN1C(=O)c2ccccc2C1=O
Reaction time: 72 h
Yield: 91 %

Procedure:
Potassium phathalimide (20 g, 108 mmol) was added in portions over 2 h to a stirred solution of (E)-1,4-dibromobut-2-ene (10.7 g, 50 mmol) in DMF (100 ml) at room temperature. The mixture was stirred for a further 3 days at this temperature, then poured into water (100 ml), and the mixture was extracted with dichloromethane (5×100 ml). The organic extracts were dried, filtered and concentrated in vacuo to leave DMF (ca. 30 ml), and a white solid, which was filtered off and washed with ether (3×10 ml) to give (E)-1,4-diphathalimidobut-2-ene (15.5 g, 91% yield).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1>C(Cl)Cl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1)(=[O:8])=[O:9]
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 0.535 ml of trifluoromethanesulfonic anhydride in 3.75 ml of methylene chloride is added, via a syringe, a 0° C. solution of 0.529 g of product from Example 6 in 0.75 ml of methylene chloride and 0.243 ml of pyridine. The reaction is stirred in an ice bath for 45 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, slurried with ethyl acetate and filtered. The filtrate is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.799 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 8.9 g of 4-(p-hydroxyphenyl)-tetrahydropyran in 50 ml of ethanol was added to a mixture of 1.15 g of sodium in 100 ml of ethanol and the mixture was stirred for 2 hours at room temperature and was then cooled to 0° C. 7.82 ml of ethyl 2-bromo-propanoate were added to the mixture which was then allowed to return to room temperature and the mixture was refluxed for 5 hours. The mixture was evaporated to dryness and the residue was dissolved in a mixture of 100 ml of ether, 45 ml of water and 5 ml of 2N hydrochloric acid. The aqueous phase was removed by decanting and the organic phase was washed with 2N sodium hydroxide, was dried and evaporated to dryness under reduced pressure to obtain 7.9 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate with a boiling point of 138°-140° C at 0.05 mm Hg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]([NH2:11])[C:8]([O:10][CH3:20])=[O:9])=[CH:5][CH:4]=1
Reactant: CO
Reactant: NC(C(=O)O)c1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(C(F)(F)F)cc1
Yield: 69 %

Procedure:
4-Trifluoromethyl-α-carboxybenzylamine (1.4 g, 1.83 mmol) and thionylchloride were added to methanol (8 ml) and the mixture was refluxed for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in diethyl ether and the product was filtered off, washed with ether and dried to give the title compound 0.34 g (69%).