Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: NS(=O)(=O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 72.6 %

Procedure:
A mixture of Example 86a (0.543 g, 2 mmol), 2,4-difluorophenol (0.390 g, 3.00 mmol), and cesium carbonate (1.955 g, 6.00 mmol) in DMSO (10 mL) was heated at 110° C. for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give the title compound (0.53 g, 1.451 mmol, 72.6% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[OH:24][CH2:3][CH:2]1[CH2:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.3 %

Procedure:
A mixture of 47.1 g (0.228 mole) ethyl 3-allyl4-hydroxybenzoate, 350 ml chloroform and 79.7 g (0.462 mole) m-chloroperbenzoic acid was heated at reflux, with stirring, under nitrogen for 3.5 hours. The resulting mixture was allowed to cool to room temperature, the solvent evaporated, the residue dissolved in ethyl ether, washed with 1N sodium hydroxide, brine and dried (MgSO4). Evaporation of the ether gave 32.07 g of product as a colorless solid, m.p. 72°-77° C. which was used in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[C:18]([F:24])[CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][C:15](=[O:25])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:23]2
Reactant: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with 3-(1-benzylpiperidin-4-yl)-8-fluoro-3,4-dihydroquinazolin-2(1H)-one (1.40 g, 4.12 mmol) and methanol (25.0 mL). The suspension was heated with a heat gun to aid in dissolution. The flask was flushed with nitrogen, treated with palladium on charcoal (141 mg, 0.032 equiv.), flushed with nitrogen, then hydrogen, and vigorously stirred under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 0.99 g (97%) as a white solid which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.71 (m, 4H), 2.75 (m, 2H), 3.16 (m, 2H), 4.38 (s, 2H), 4.46 (m, 1H), 6.77 (bs, 1H), 6.81–6.89 (m, 2H), 6.95 (m, 1H). Mass spec.: 250.22 (MH)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:26])[C:15]2[C:16]3[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:26][N:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[C:16]2[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCNC1
Yield: 91.8 %

Procedure:
To a solution of (S)-4((1-benzylpiperidin-3-yl)(methyl)amino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.3 mmol) in MeOH (3 mL) was added 10% Pd/C (100 mg) and ammonium formate (179 mg, 2.8 mmol) and the reaction mixture was heated for overnight. The reaction mixture was filtered and concentrated in vacuo to afford (72 mg, 96%) of the titled intermediate which was used without purification. LC-MS: m/z [M+1]=262.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc2oc(S)nc2c1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(N3CCN(C)CC3)nc2c1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (227 mg) was dissolved in anhydrous toluene (3 ml), the resulting solution was mixed with 2-mercapto-5-methylbenzoxazole (150 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (1 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-5-methylbenzoxazole (188 mg).
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C=O.C(NCC)C>C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH3:4])[CH2:1][C:5](=[CH2:9])[C:6]([OH:8])=[O:7]
Reactant: CC(C)CC(C(=O)O)C(=O)O
Agent: C=O
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: C=C(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a stirred mixture of 14.0 g of isobutylmalonic acid and 37 mL of 37% formalin was added 9.05 mL of diethylamine at room temperature. The mixture was stirred at room temperature for 3 h and refluxed for an additional 2 h. The reaction mixture was cooled to room temperature and diluted with CHCl3, and extracted with saturated aqueous NaHCO3. The aqueous layer was acidified with 1M HCl and extracted with CHCl3. The organic extract was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 11.0 g at 98% yield of 4-methyl-2-methylenepentanoic acid as a clear liquid which was used without further purification. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ6.32 (d, J=2 Hz, 1H), 5.62 (d, J=2 Hz, 1H), 2.17 (dd, J=1, 7 Hz, 2H), 1.82 (m, 1H), 0.90 (d, J=7 Hz, 6H); 13C NMR (300 MHz) δ173.6, 139.4, 128.4, 40.7, 26.9, 22.0.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][CH:13]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@@H:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11]
Reactant: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@H](NC(=O)[C@H](N)Cc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
3(R,S)-[2(R)-(tert-Butyloxycarbonyl)amino-3-phenylpropionylamino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4.7 g) was dissolved in ethyl acetate (20 ml) and cooled to 0° C. This solution was then saturated with hydrogen chloride gas. After 1.5 h, the resulting precipitate (which was shown to be the undesired diastereoisomer, Rf=0.04 ethyl acetate), was removed by filtration and the filtrate evaporated. The solid residue was partitioned between ethyl acetate (25 ml) and 10% sodium carbonate solution (20 ml). The organic phase was separated and the aqueous extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using a gradient elution of 0-20% methanol in ethyl acetate to afford the title compound (1.66 g). Mp 100°-103° C. 1H NMR (360 MHz, CDCl3) δ 1.00-1.39 (4H, m), 1:50-1.72 (4H, m), 1.84-1.92 (1H, m), 2.00-2.07 (1H, m), 2.72-2.84 (2H, m), 3.28 (1H, dd, J=13.8 and 4.0 Hz), 3.40 (3H, s), 3.69 (1H, dd, J=9.8 and 4.1 Hz), 5.36 (1H, d, J=8.3 Hz), 7.21-7.36 (7H, m), 7.47-7.58 (2H, m), 8.66 (1H, d, J=8.3 Hz). [α]D23 +32.7° (c=0.58, CH3OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21](I)[CH3:22]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[NH:19])[S:18][CH2:21][CH3:22])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(N)=S)cc1
Reactant: CCI
Product: CCSC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 85 %

Procedure:
Using the compound obtained in Example 50 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 29 gave the titled compound (yield, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:5]([CH3:27])[NH:4][N:3]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([S:34]([N:4]2[C:5]([CH3:27])=[C:6]([CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)=[N:18][CH:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)[C:2]([CH3:1])=[N:3]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1n[nH]c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Solvent: c1ccncc1
Product: Cc1nn(S(=O)(=O)c2ccccc2)c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
To a solution of 4-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.160 g, 0.4 mmol, 1 eq) add benzenesulfonyl chloride (56 μL, 0.4 mmol) followed by pyridine (1 mL). Heat to 120° C. with stirring for 4 hr. Add water and extract 3 times with ethyl acetate (20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:DCM). Lyophilize from a 50% acetonitrile/water solution to give the title compound as a white solid (138 mg, 68%). MS (ES): m/z=507.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[C:4]([CH3:21])([CH3:20])[O:3]1.CNN>ClCCl>[CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][O:8][NH2:9])[C:4]([CH3:21])([CH3:20])[O:3]1
Reactant: CC1(C)OC(CON2C(=O)c3ccccc3C2=O)C(C)(C)O1
Agent: CNN
Solvent: ClCCl
Product: CC1(C)OC(CON)C(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
2-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (0.158 g, 0.52 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C., and charged with methylhydrazine (30 μL, 0.57 mmol). The ice bath was removed and the reaction was allowed to stir at ambient temperature for 1 hour. The reaction mixture was diluted with diethylether and the solids were filtered off and filtrate concentrated in vacuo to afford O-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine as a yellow oil (0.042 g, 46%). 1H NMR (400 MHz; DMSO-d6) δ 6.06 (bs, 2H), 3.84-3.87 (m, 1H), 3.50-3.59 (m, 2H), 1.26 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 0.94 (s, 3H); MS (APCI+)=176.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccnc1
Product: COc1ccc(/C(C#N)=C/c2cccnc2)cc1OC
Yield: 90 %

Procedure:
3-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 4.79 g, 90%).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1)(=O)=O.[OH-:23].[K+].Cl>O.C1COCC1>[C:17]1([C:8]2[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:10][C:5](=[O:23])[NH:6][N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)c1nnc(-c2ccccc2)c(-c2cccnc2)n1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1nc(-c2cccnc2)c(-c2ccccc2)n[nH]1
Yield: 92.8 %

Procedure:
To a solution of 3-(methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.035 g, 0.112 mmol) in a 1:1 mixture of H2O/THF (1.5 mL) was added potassium hydroxide (0.037 g, 0.560 mmol). The reaction was heated at reflux for 2 h. Upon completion, the reaction mixture was cooled to room temperature and neutralized with 1 M HCl, then extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated to give the title compound as a yellow solid (0.026 g) without further purification. LCMS m/z=251.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH2:17])[CH2:3][O:4][CH2:5][CH:6]([O:8][CH2:9][CH:10]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH3:11])[CH3:7].[C:18]1(=[O:24])O[C:21](=[O:22])[CH:20]=[CH:19]1.O>C1C=CC=CC=1>[C:18]1(=[O:24])[NH:16][C:21](=[O:22])[CH2:20][CH2:19]1.[CH3:1][CH:2]([NH2:17])[CH2:3][O:4][CH2:5][CH:6]([O:8][CH2:9][CH:10]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH3:11])[CH3:7]
Reactant: O=C1C=CC(=O)O1
Agent: CC(N)COCC(C)OCC(C)OCC(C)N
Solvent: O
Solvent: c1ccccc1
Product: O=C1CCC(=O)N1

Procedure:
A succinimide of a polyoxypropylenediamine of about 2000 MW(JEFFAMINE® D-2000) is prepared as follows: A mixture of JEFFAMINE® D-2000 (750g., 0.375 mole) and maleic anhydride (18.4g., 0.187 mole) was refluxed in benzene until water removal was complete (reaction temperature 145°-195° C.). The resulting product was then vacuum stripped at 180° C./3MM. The product analyzed as follows -- total amine 0.64 meq./g., primary amine 0.43 meq./g.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1>>[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[CH:43][CH:44]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(N)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-aminopyridine-5-boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=513, obsd.=513).
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]1[C:11]2[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[CH:19][CH:18]=2)[N:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([NH:9][C:10]1[C:11]2[CH2:31][NH:30][CH2:29][CH2:28][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[CH:21][CH:22]=2)[N:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCc3ccccc3)c2C1
Agent: Cl
Solvent: CO
Product: c1ccc(CNc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Temperature: 76 °C
Yield: 75.3 %

Procedure:
Hydrochloric acid (2M aq, 2 ml) was added to a solution of tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.15 g, 0.30 mmol, Example 6a) in MeOH (4 mL). The reaction was heated in an open reaction vessel to 76° C. for 1 h and the product precipitated out from the solution as it was cooled. The crude product was filtered off and washed with water. The crude salt was dissolved in water and precipitated when saturated NaHCO3 was added. The product was filtered off and purified by preparative HPLC to give N4-benzyl-N2-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.090 g, 75%). MS (ESI+)/(ESI−) m/z 399/397
Reaction SMILES: [OH-].[K+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19]([C:22]([CH3:24])=[O:23])([CH3:21])[CH3:20].C(O)(=O)C>CO.O>[F:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:24][C:22](=[O:23])[CH:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(=O)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)C=Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.1 ml of 15% strength aqueous potassium hydroxide solution are added to 64.8 g (0.3 mol) of 3-phenoxy-4fluorobenzaldehyde and 51.6 g (0.6 mol) of methyl isopropyl ketone in 90 ml of methanol and the mixture is stirred overnight at room temperature. The mixture is neutralized using 1.95 ml of glacial acetic acid, diluted using 300 ml of water and extracted a number of times using ether. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl>>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(COc2ccccc2Cc2ncc[nH]2)c(Cl)c1

Procedure:
Analogously to Example 1, 2.21 g. of (2,4-dichlorobenzyl)-[2-(1-imidazolymethyl)-phenyl]-ether, m.p. 108°-110°, is obtained from 1.74 g. of 2-(1-imidazolylmethyl)-phenol (Bull. Soc. Chim. France 1973, 1179), 300 mg. of sodium hydride suspension, and 1.41 g. of 2,4-dichlorobenzyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:23]=[C:22]2[C:9]([C:10]3[CH:34]=[C:14]([C@@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][CH:17]=[CH:18][C@@H:19]([CH3:25])[C:20](=[O:24])[NH:21]2)[N:13]=[CH:12][CH:11]=3)=[CH:8][CH:7]=1)=[O:4].C([O-])(=[O:37])C.[Na+].OO>C1COCC1.O>[OH:37][CH:17]1[CH2:16][C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:14]2=[CH:34][C:10](=[CH:11][CH:12]=[N:13]2)[C:9]2[C:22](=[CH:23][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][CH:8]=2)[NH:21][C:20](=[O:24])[C@H:19]([CH3:25])[CH2:18]1
Reactant: CC(=O)[O-]
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CC(O)C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl N-[(10R,11E,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(18),2,4,6,11,15(19),16-heptaen-14-yl]carbamate (634 mg, 1.36 mmol) 1H in THF (13.6 mL) at 0° C. was added borane tetrahydrofuran complex (4.08 mL, 4.08 mmol) dropwise. The reaction was allowed to warm up to rt and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and added sodium acetate (9.06 ml, 27.2 mmol), followed by hydrogen peroxide (4.16 mL, 40.8 mmol) dropwise. The reaction was warmed up to rt and stirred at for 8 h. The mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to yield a mixture of two products 22A and 22B (323 mg, 49%) as a light grey solid. MS (ESI) m/z: 485.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=3)=[N:18][N:17]=2)=[CH:11][C:10]=1[CH2:31][CH3:32])C1C=CC=CC=1>CC(=O)OCC.C(O)(=O)C>[CH2:31]([C:10]1[CH:11]=[C:12]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH:28]([CH3:29])[CH3:30])[CH:22]=3)=[N:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:32]
Reactant: CCc1cc(-c2nnc(-c3cc(C)nc(C(C)C)c3)s2)cc(C)c1OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(C)nc(C(C)C)c3)s2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-2-isopropyl-6-methyl-pyridine (837 mg, 1.88 mmol) in EA (30 mL) 33% HBr in acetic acid (1 mL) is added. The mixture is stirred at rt for 3 h before it is diluted with EA, washed twice with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-ethyl-4-[5-(2-isopropyl-6-methyl-pyridin-4-yl)-[1,3,4]thiadiazol-2-yl]-6-methyl-Phenol (540 mg) as a pale yellow oil; LC-MS: tR=0.92* min, [M+1]+=354.14.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: [H][H]
Reactant: CCN(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82.4 %

Procedure:
A solution of crude tert-butyl 2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (502 mg, 1.1 mmol) in MeOH (10 mL) was added to 10% Pd/C (5.2 mg) and stirred in a hydrogen atmosphere (@ ambient pressure) for 6 h. The reaction was filtered through Celite and the filtrate concentrated under reduced pressure to yield crude tert-butyl 2-((25,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (293 mg). MS (ESI+) for C17H29N3O3 m/z 324.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[NH4+].[OH-]>Br>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: COc1cc2nc(C)ccc2cc1F
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2cc(F)c(O)cc2n1
Yield: 133.7 %

Procedure:
6-Fluoro-7-methoxy-2-methylquinoline (5.2 g, 19 mmol) was heated to reflux in 48% aqueous HBr for 48 hours. After cooling, the reaction was basified (pH 8) by addition of NH4OH. The resulting solid was filtered, washed with water and dried to yield 6-fluoro-2-methylquinolin-7-ol (4.5 g, 93% yield) as a black solid.