Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(CCO)(CCO)CCO.Cl.[CH:12]([NH2:15])([CH3:14])[CH3:13].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[CH2:32]([CH:39]1[CH2:43][O:42][C:41](=[O:44])[N:40]1[C:45]([C@@H:47]1[CH2:52]CC(=O)C[C@H:48]1[C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CS(C)=O>[NH2:15][C@@H:12]1[CH2:14][CH2:52][C@@H:47]([C:45]([N:40]2[C@H:39]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:43][O:42][C:41]2=[O:44])=[O:46])[C@H:48]([C:54]2[CH:55]=[CH:56][C:57]([Br:60])=[CH:58][CH:59]=2)[CH2:13]1
Reactant: CC(C)N
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OCC2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: Cl
Solvent: OCCN(CCO)CCO
Solvent: CS(C)=O
Product: N[C@@H]1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Br)cc2)C1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of aqueous triethanolamine (684 mL, 100 mM) was added isopropylamine hydrochloride (102.6 g), pyridoxal phosphate (Vitamin B6; 1.14 g), and the enzyme ATA24 (22.8 g) [ATA-024 is also known as CDX-010 and purchased from Codexis, Inc., Redwood City, Calif., USA.] The mixture was treated with DMSO (228 mL) and heated to 45° C. using a Multimax (Mettler Toledo). The pH was adjusted to 8.6 when 4-benzyl-3-{[(1R,2R)-2-(4-bromophenyl)-4-oxocyclohexyl]carbonyl}-1,3-oxazolidin-2-one (5.7 g, 12.49 mmol) was added as a solution in DMSO (228 mL) by syringe pump over 3 h. An additional amount of the enzyme ATA24 (2 g) was added in 10 mL of buffer and allowed to react for approximately 4 h. An additional amount of the enzyme ATA24 (3 g) was added in 30 mL of buffer and the reaction aged overnight. The reaction was treated with aq. 6 N HCl to lower the pH to 2, and then aged for about 30 min. The reaction was then filtered and the enzyme precipitate was rinsed with 250 mL of 10% DMSO/pH 2.5 H2O (3×). The filtrate was extracted with MTBE (1 L), and the aqueous layer was separated, brought to pH 9.5 and subsequently extracted with MTBE (1 L). The organic layer was separated, washed with pH 11 brine (2×250 mL), dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 478 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=1[F:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.O>[Si:31]([O:30][CH2:29][CH2:28][O:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[F:20])=[C:2]([F:1])[CH:7]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc2F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate (1.0 equiv.) and potassium carbonate (4.0 equiv.) in DMF (0.4 M) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2 equiv.). After stirring for 72 hours at rt the heterogeneous solution was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield methyl 6-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinate in 74% yield. LC/MS=442.1 (M+H), Rt=1.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O.OS(O)(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: COC(=O)Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 107.8 %

Procedure:
To a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) in dichloroethane (100 ml) was added MeOH (15:6 ml, 383 mmol) and H2SO4 (1 ml) at room temperature. After 20 minutes stirring, the mixture was heated at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extract was concentrated in vacuo to give methyl 3-chlorophenylacetate (25.4 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ 3.60 (s, 2H), 3.70 (s, 3H), 7.15–7.26 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][N:27]([CH3:43])[C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH3:26][N:27]([CH3:43])[C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][N:29]=1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N(C)C)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 50 mg, 0.125 mmol) and 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 38 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: tR 2.68 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.46 (s, 2H), 8.20 (s, 1H), 8.09-8.02 (m, 1H), 7.91-7.84 (m, 1H), 7.38 (s, 1H), 4.60-4.51 (m, 1H), 3.56 (s, 3H), 3.13 (s, 6H), 1.97 (s, 3H), 1.49-1.44 (m, 6H))
Reaction SMILES: [C:1]1([CH:7](O)[CH:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:15]CC.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]1([CH:7]=[CH:8][CH:9]([OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC(O)c1ccccc1
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C=Cc1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
1-Phenyl-2-buten-1-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether. The combined extract was dried over anhydrous potassium carbonate. Evaporation of the solvent followed by Kugelrohr distillation at 30° C. for 30 minutes afforded 131.73 g (96.8%) of the desired 4-phenyl-3-buten-2-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O.[O:7]=[CH:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])O.N#N>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:17]1[O:18][C@H:9]([CH2:8][OH:7])[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@H:15]1[OH:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COCCN
Agent: N#N
Solvent: O
Product: COCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
N-(2-methoxyethyl)-glucosylamine (sugar adduct) is prepared starting with 1728.26 g of 50 wt.% 2-methoxyethylamine in water (11.5 moles, 1.1 mole equivalent of 2-methoxyethylamine) placed under an N2 blanket at 10° C. 2768.57 grams of 50 wt. % glucose in water (10.46 moles, 1 mole equivalent of glucose), which is degassed with N2, is added slowly, with mixing, to the methoxyethylamine solution keeping the temperature below 10° C. The solution is mixed for about 40 minutes after glucose addition is complete. It can be used immediately or stored 0° C.-5° C. for several days.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Pd]>[C:14]([O:13][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][C@@H:6]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:5][C@@H:4]1[NH2:1])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1N
Yield: 67.5 %

Procedure:
(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)-1-(tert-butyldiphenylsilyloxymethyl)cyclohexane (2.59 g) was dissolved in methanol (50 ml), and 10% palladium on carbon (200 mg) was added to stir the mixture for 20 hours in a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:20→1:10) to obtain (1S,2S,4R)—N1-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediamine (1.66 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H) 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.26 (m, 1 H), 1.14 (m, 7 H), 0.82 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). mp 93-95° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCCCCCN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CCO
Product: CCCCCCNc1cc(Cl)nc(N)n1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
50 g of 2-amino-4,6-dichloropyrimidine were suspended in 350 ml of absolute ethanol in a reactor. 181.5 ml of hexylamine (reagent A) were added in a single portion and the mixture was refluxed for 3 h. The medium was evaporated under vacuum. The oil obtained was taken up in 600 ml of water with stirring for 1 h, 30 min. The precipitate was filtered off, washed and dried in a heated desiccator. 43.5 g of the expected compound were thus obtained, for a yield of 62%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2.C(N(CC)CC)C>C(O)C>[C@H:25]12[CH2:31][C@H:28]([N:29]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH2:30]1)[CH2:27][O:26]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 150 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (56 mg, 0.15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (22 mg, 0.16 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (59 μL, 0.45 mmol) and was then heated in the microwave reactor for 15 minutes at 150° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile to provide 3-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenol. MS (ES+): 386.3 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a mixture of NaH (60%, 4.92 g, 0.205 mol) in DMF (60 mL) is added 5-benzoxyindole at 0˜5° C., then stirred 30 min. ethyl 2-bromopropionate is added dropwise, the mixture is allowed to warm to room temperature and heated at 70° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate yields the title compound (29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])(=O)C.[Na+]>C(O)C.C(OCC)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aniline (0.096 mole), ethyl bromoacetate (0.096 mole) and sodium acetate (0.096 mole) in ethanol (150 ml) were refluxed for four hours and stirred at room temperature for 18 hours. The ethanol was removed by a rotary evaporator to give an oil. The oil was dissolved in ethyl ether (200 ml), filtered and the solvent removed by a rotary evaporator. The dark oily residue crystallized from cold hexane. Structural assignment was supported by NMR and the compound is used as is to prepare title compound of Example 1.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)[CH3:3].[OH-].[Na+].[BH4-].[Na+]>C(O)C.O>[CH3:3][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)C(c1cccc(F)c1)C1CCC(CO)CC1
Reaction time: 8 h

Procedure:
The aldehyde 34 (7.11 g, 27 mmol) was dissolved, under argon, in ethanol (120 ml), water (60 ml) and 1N NaOH (27 ml, 27 mmol) and stirred for 30 minutes at RT. A solution of NaBH4 (2.04 g, 54 mmol) in water (200 ml) was then slowly added dropwise and the mixture was stirred overnight. Ethanol was removed in vacuo, the aqueous residue was extracted three times with ethyl acetate (100 ml each time), and the organic phase was washed with water (100 ml) and saturated NaCl solution (100 ml), dried (Na2SO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.O>[C:2]([NH:5][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.3 %

Procedure:
2-Methylpropan-2-amine (5.8 g, 80 mmol) and K2CO3 (11 g, 80 mmol) were dissolved in a mixed solvents of THF and H2O (V:V=1:5, 30 ml). Benzenesulfonyl chloride (7.06 g, 40.0 mmol) was added drop wise at 0° C. to the above solution. After being stirred overnight, the resulting mixture was extracted with ethyl acetate (3×100 mL), washed with 1 N HCl (50 mL), sat. NaHCO3 (50 mL), sat. NaCl (50 mL), and dried over Na2SO4. After concentration, the residue was purified by silica gel chromatography eluting with a 0-10% gradient of EtOAc in petroleum ether to afford N-tert-butylbenzenesulfonamide (6.0 g, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3): δ 7.93-7.91 (m, 2H), 7.54-7.47 (m, 3H), 5.06 (br, 1H), 1.22 (s, 9H)
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([C:25]([O:27]CC)=[O:26])[CH:20]=2)[CH2:15][CH2:14]1.O.Cl>C1COCC1>[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]1[CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.0 mL (36.0 mmol) of a 4M NaOH solution were added to 5.50 g (14.9 mmol) ethyl 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate, 25 mL water in 150 mL THF. After 3 h stirring at RT the THF was eliminated i. vac. The aqueous residue was combined with 9 mL of a 4M hydrochloric acid solution. After 3 h stirring at RT the precipitate was suction filtered and dried in the CAD at 60 C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1cc(N2CCOCC2)nc(-c2ccccc2)n1
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)c1
Yield: 9.1 %

Procedure:
A mixture of 4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol), m-anisidine (20 μl, 0.181 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 5 days. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (50 ml), which was washed with water (2×25 ml), aqueous saturated NaCl, and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo and isolated as a yellow solid (6 mg, 9%). 1H NMR (CDCl3): 8.40–8.37 (m, 2H), 7.46–7.43 (m, 3H), 7.31–7.25 (m, 2H), 7.00 (t, J=2.3 Hz, 1H), 6.91 (dd, J=1.7, 8.0 Hz, 1H), 6.70–6.67 (m, 2H), 3.83 (s, 3H), 3.81–3.63 (m, 8H).
Reaction SMILES: [SH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl.Cl[CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:21]([N:20]1[CH:19]=[N:18][N:17]=[C:16]1[CH2:15][S:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12])[CH2:22][CH3:23]
Reactant: Nc1ccc(S)c(C(F)(F)F)c1
Reactant: CCCn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnnc1CSc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
4-mercapto-3-trifluoromethylaniline (1.0 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (1.1 g) and potassium carbonate (1.4 g) were added to N,N-dimethylformamide (35 ml), and the mixture was stirred overnight at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) to give 4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]-3-trifluoromethylaniline (1.4 g) as pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]([OH:44])[CH:39]([CH3:43])[C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[CH:34][C:35]([C@@H:38]([OH:44])[C@H:39]([CH3:43])[C:40]([OH:42])=[O:41])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(C(=O)O)C(O)c1ccc(C=O)cc1
Product: C[C@H](C(=O)O)[C@H](O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 3-(4-formyl-phenyl)-3-hydroxy-2-methyl-propionic acid according to the procedure of Example 66. MS (ES) m/z 583.0.