Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[CH2:5][OH:6])[CH3:2]
Reactant: CCc1cc(C)ccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)ccc1CO
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of compound methyl 2-ethyl-4-methylbenzoate (646 mg, 3.65 mmol) in THF (6 mL) cooled to −50° C., was added LiAlH4 (277 mg, 7.30 mmol) in portions. The mixture was stirred at this temperature for 1 h. Added water (0.3 mL) slowly, followed by NaOH (aq, 10%, 0.3 mL) and water (0.9 mL), the resulting mixture was filtered and washed with THF, concentrated the filtrate to give 518 mg of the title compound (95%). 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.2 Hz), 1.54 (1H, s), 2.33 (3H, s), 2.68 (2H, q, J=7.6 Hz), 4.67 (2H, s), 7.01 (1H, d, J=8.0 Hz), 7.03 (1H, s), 7.23 (1H, d, J=7.6 Hz).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)C=CC=CC=1.Cl>C1COCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C@@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(diphenylmethylidene)-3-methoxyphenylalaninate (912 mg, 2.35 mmol), 5 M hydrochloric acid (0.471 mL, 2.35 mmol) and THF (20 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the crude product, ethyl 3-methoxyphenylalaninate which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:39][CH2:38][CH2:36][OH:37])=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)NCCO
Yield: 80.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with ethanolamine (0.15 mL, 2.5 mmol) to give the title compound as a white solid (170 mg, 80%); NMR Spectrum 1.65 (d, 3H), 3.22 (q, 2H), 3.41-3.45 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.70 (s, 2H), 7.01-7.12 (m, 4H), 7.36 (dd, 2H), 7.72-7.76 (m, 3H), 8.17 (s, 1H), 8.47 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.73 (br s, 1H); Mass spectrum MH+ 501.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19]S[CH2:21][C@H:9]23)=[CH:4][CH:3]=1.O[O:23][S:24]([O-:26])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:24](=[O:26])(=[O:23])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CSC[C@@H]32)cc1
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=S1(=O)C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 75.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (10 mg, 0.033 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at 50° C. for 2 hours. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ6-thia-cyclopenta[a]naphthalen-8-ol 14 (8.5 mg, 0.025 mmol, 77%). 1H NMR (δ, 400 MHz, MeOD) 7.47 (d, 2H, J=8.3 Hz), 6.87-6.74 (m, 4H), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 5.25 (s, 1H), 4.12-4.01 (m, 2H), 3.00 (m, 1H), 2.72 (dt, 1H, J=6.8, 12.8 Hz), 2.63-2.53 (m, 1H), 2.52-2.42 (m, 1H). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.68 min).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23]>>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])=[O:9]
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Reactant: N[C@@H]1CCCC[C@H]1O
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br

Procedure:
The title compound was synthesised in analogy to the amide coupling procedure described for the synthesis of Example 1, from 5-bromo-6-(2-methoxy-ethoxy)-nicotinic acid and trans-2-amino-cyclohexanol (commercially available). MS (m/e): 373.1 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:34]=[C:33]([C:31]3[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[O:37][CH3:38])[N:35]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3C(C)CCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (152 μL; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 23 (74 mg; 0.4 mmol, 1 eq.) and DIEA (155 μL; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of 0.625 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is washed with water, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give crystals. Recrystallization from hexane-CH2Cl2 gives 0.16 g of white crystals, m.p. 203°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][CH:31]=O)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([C@@:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([N+:30]#[C-:31])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: O=CN[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: [C-]#[N+][C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (6 mL, 159 mmol) was heated at 60° C. for 3 h, then cooled to rt. An aliquot of the resulting solution (0.623 mL) was added to a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine prepared as described in Procedure 3, 4, 5 and 6 (83 mg, 0.2 mmol) in DCE (1 mL). The reaction mixture was stirred at rt for 1.5 h, then concentrated under reduced pressure to yield a clear oil. The resulting oil was dissolved in DCM and purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide as white solid (72 mg, 81% yield). LCMS: RT=2.02 min [M-NHCOH] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). At 0° C. to a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide (72 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and POCl3 (0.016 mL, 0.18 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc (15 mL). The organic layer was washed with sat. NaHCO3 and sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene as a white solid (60 mg, 87% yield). LCMS: RT=2.10 min [M-NC] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.65 (m, 2H), 5.74-6.01 (m, 1H), 6.84 (d, J=7.03 Hz, 2H), 6.94 (d, J=7.03 Hz, 3H), 7.04-7.10 (m, 2H), 7.16-7.26 (m, 3H), 7.32 (dd, J=9.01, 5.05 Hz, 2H).
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[CH:10][N:9]=[C:8]3[N:12]([CH3:21])[N:13]=[C:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[C:7]=23)[CH2:3]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:26]2[CH:27]=[CH:28][C:23]([C:19]3[N:18]([CH3:20])[N:17]=[CH:16][C:15]=3[C:14]3[C:7]4[C:8](=[N:9][CH:10]=[N:11][C:6]=4[N:4]4[CH2:3][CH:2]([F:1])[CH2:5]4)[N:12]([CH3:21])[N:13]=3)=[CH:24][CH:25]=2)[CH2:31][CH2:30]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: Cn1cc(-c2nn(C)c3ncnc(N4CC(F)C4)c23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CC(F)C4)c23)c1-c1ccc(C2CC2)cc1
Temperature: 100 °C

Procedure:
4-(3-Fluoroazetidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (C11) (300 mg, 1.04 mmol), 1-bromo-4-cyclopropylbenzene (617 mg, 3.13 mmol), and potassium carbonate (289 mg, 2.09 mmol) were combined in 1,4-dioxane (7 mL). Palladium(II) acetate (98%, 50.2 mg, 0.219 mmol) was added, and the reaction mixture was heated at 100° C. for 48 hours. Solids were removed via filtration, and the filtrate was concentrated in vacuo. Purification using silica gel chromatography [Gradient: 25% to 50% (10% methanol in ethyl acetate) in heptane] provided the product as a glass. Yield: 205.3 mg, 0.509 mmol, 49%. LCMS m/z 404.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 0.61-0.66 (m, 2H), 0.91-0.97 (m, 2H), 1.81-1.89 (m, 1H), 3.77-3.95 (br m, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 4.07-4.26 (br m, 2H), 5.15-5.36 (m, 1H, JHF=57.5 Hz), 7.05 (br d, J=8.2 Hz, 2H), 7.23 (br d, J=8.4 Hz, 2H), 7.71 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].FC(F)(F)C(O)=O.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(OCC)C>[C:15]([O:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])(=[O:18])[CH2:16][CH3:17]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CCC(=O)Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
L-Serine (5.25 g, 50 mmol) was added with stirring to trifluoroacetic acid (35 ml) and the resultant was decanted from the insoluble material. Propionyl chloride (5.66 ml, 64.0 mmol) was then added to the solution and the mixture was stirred for 1 h at room temperature. Upon the addition of diethyl ether (6 ml), a white solid precipitated which redissolved upon stirring. The reaction vessel was sealed and left to stand overnight in a refrigerator. Further diethyl ether (30 ml) was added to the cold solution with stirring. The resultant fine white precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to afford 6.43 g (32.5 mmol, 65%) of 2020370, m.p. 148-150° C. (dec.). 1H NMR (300 MHz, d6-DMSO) δ 0.96 (t, J 7 Hz, 3H), 2.29 (m, 2H), 4.21 (br s, 1H), 4.39 (m, 2H), 8.75 (br s, 3H). 13C NMR (75.5 MHz, d6-DMSO) δ 8.7, 27.2, 52.0, 61.3, 168.9, 174.0. m/z 162.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:6]=1[CH2:7][N:8]1[CH2:12][C@H:11]([CH:13]([CH3:15])[CH3:14])[NH:10][C:9]1=[O:16].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C@@H:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:5]=2[O:4][CH3:3])[C:9]1=[O:16])[CH3:29]
Reactant: COc1ccc(CN2C[C@H](C(C)C)NC2=O)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1C(C)C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60%, 380 mg) was added to a solution of (4S)-1-(2,4-dimethoxybenzyl)-4-(propan-2-yl)imidazolidin-2-one (2.4 g) in DMF (35 mL), and the mixture was stirred for 20 min. Ethyl bromoacetate (1.14 mL) was added thereto, and the mixture was stirred at 90° C. for 1 hr. Additional ethyl bromoacetate (1.14 g) and sodium hydride (60%, 380 mg) were added thereto, and the resulting mixture was further stirred at 90° C. for 1 hr. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford ethyl[(55)-3-(2,4-dimethoxybenzyl)-2-oxo-5-(propan-2-yl)imidazolidin-1-yl]acetate (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N+:10]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C)c1N

Procedure:
A solution of 1-methoxy-3-methyl-2-nitrobenzene (15.04 g, 0.09 mol) in ethanol (250 ml) was hydrogenated over 10% palladium on charcoal (4 g) at atmospheric pressure and at room temperature, for 18 h. The catalyst was removed by filtration, and the filtrate evaporated under reduced pressure to leave the title compound (D28) as an amber oil, which crystallised on standing (11.18 g, 91%).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccc(Cl)cc1
Yield: 63.1 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (10 mmol) and 4-chlorobenzylamine (11 mmol) and proceeding according to the abovementioned method A2, 3-(4-chlorobenzylamino)methylenedihydrofuran-2-one (1.5 g, 73%) is produced in the form of a white powder.
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][C:29](OC)=[O:30])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO>O1CCCC1>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)CSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
0.21 g of sodium borohydride was added to a solution of 1.98 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(methoxycarbonylmethylthio)pentanamide [prepared as described in step (b) above] in 40 ml of tetrahydrofuran, and 8 ml of methanol were added dropwise to the mixture, whilst ice-cooling; it was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 1.51 g (yield 63%) of the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](O)=[O:4].CC(OC(C)=O)=O>>[CH3:1][CH:2]1[CH:6]([CH3:10])[C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: CC(C(=O)O)C(C)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)OC(=O)C1C

Procedure:
2,3-Dimethyl succinic anhydride was prepared as described in Sutton, et al. OPPI 24 (1992) 39. Briefly, 7.1 g 2,3-dimethyl succinic acid and 6.9 ml acetanhydride were slowly heated up to 50° C. for 3 hours. Then acetanhydride was removed by distillation. The product was recrystallized from ethanol abs. and characterized by the melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-chloro-4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[Cl:19].[F:24][C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([Cl:19])=[CH:17][C:16]2[N:20]=[C:27]([C:26]([F:31])([F:30])[C:25]([F:33])([F:32])[F:24])[NH:21][C:15]=2[CH:14]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(C(F)(F)F)c1

Procedure:
A solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, crude) in pentafluoropropanoic acid (20 ml) was stirred overnight at 80° C. in an oil bath and then quenched with ice-water (50 ml). The pH value of the solution was adjusted to 8 with sodium carbonate and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a off-white solid (76.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1c(F)cccc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,6-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CS[C:21]1[NH:26][C:25](=[O:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:23][N:22]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:21]1[NH:26][C:25](=[O:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:23][N:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Product: O=c1[nH]c(NCCCN(Cc2ccccc2)c2ccccn2)ncc1Cc1ccc(Cl)cc1

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino]pyridine (1.45 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (1.33 g) were fused together on an oil bath at 160° C. for 3 hr. On cooling, the residue was crystallised from ethanol and then chromatographed (silica gel, chloroform). Fractions containing the required product were stripped and the residue recrystallised from ethanol to give 2-[3-(N-benzyl-N-pyrid-2-ylamino) propylamino]-5-(4-chlorobenzyl)pyrimid-4-one 0.25H2O, 0.9 g (39%) mp 80°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:36][C:37]([N:39]1[CH2:48][CH2:47][C:42]2([O:46][CH2:45][CH2:44][O:43]2)[CH2:41][CH2:40]1)=[O:38]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][C:42]4([O:46][CH2:45][CH2:44][O:43]4)[CH2:47][CH2:48]3)=[O:38])[N:9]=2)[CH:7]=1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (4.65 g, 11.5 mmol) and cesium carbonate (10.08 g, 30.94 mmol) was added N,N-Dimethylformamide (40 mL) and stirred at room temperature for 5 minutes. To this was added 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one (5.34 g, 20.2 mmol) in N,N-Dimethylformamide (4.5 mL) and stirred at room temperature for 3 and a half hours. LC/MS (method 31) shows reaction complete. The reaction was then filtered and the filtrate was concentrated under reduced pressure to give a red oil. This was then dissolved in 30 mL dichloromethane and purified by ISCO using a silica column and eluting with 0-100% Ethyl acetate in heptane in 5 minutes followed by 0-15% Methanol in dichloromethane to give 5.16 g (8.78 mmol) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow foamy solid. LC/MS (method 39) [M+H]+=589.2, RT=1.91 min.