Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)cc1
Temperature: 95 °C
Yield: 80 %

Procedure:
A mixture of Compound 3 (4.01 g, 10.1 mmol), 1-bromo-4-iodobenzene (5.73 g, 20.2 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and potassium carbonate (4.2 g, 30 mmol) in dioxane/water (60 mL/10 mL) was degassed and heated at about 95° C. overnight. After being cooled to RT, the mixture was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, then loaded on silica gel, purified by flash column (hexanes to hexanes/ethyl acetate 4:1) to give a light yellow solid washed with methanol and dried in air (3.39 g, in 80% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:14](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:14](/[CH:18]=[CH:19]\[C:20]([N:29]3[CH2:30][C:27]([F:31])([F:26])[CH2:28]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:4]=[C:3]([C:2]([F:23])([F:1])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC1(F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
A 100 mL 3-neck round-bottomed flask was charged with a solution of (Z)-3-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)acrylic acid (0.15 g, 0.429 mmol) in DCM (10 mL) and cooled to 0° C. and 3,3-difluoroazetidine hydrochloride (0.052 g, 0.558 mmol) was added dropwise. T3P (50% in EtOAc) (0.163 g, 0.514 mmol) was added dropwise followed by DIPEA (0.11 g, 0.858 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated under reduced pressure to afford 0.2 g of crude product which was purified by column chromatography (60/120 silica gel, 0-3% ethylacetate:n-hexane gradient) to afford 0.01 g of (Z)-3-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)-1-(3,3-difluoro azetidin-1-yl)prop-2-en-1-one (Yield 6.6%). 1H NMR (400 MHz, CDCl3, ppm) δ=4.307-4.425 (m, 4H); 5.523-5.443 (d, J=10 Hz, 1H); 6.387-6.404 (t, 1H); 6.500-6.509 (t, 1H); 6.765-6.790 (d, J=10 Hz, 1H); 7.704-7.715 (t, 1H); 7.811-7.845 (m, 3H). LCMS calcd for: C18H13F8N2O [M+H]+435.29. found 425.49 (retention time 3.292 min).
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.Cl>CS(C)=O.O>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:9]/[CH2:8][CH2:7][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CC/C=C/c1ccccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
A stirred suspension of sodium hydride (3.04 g; 60% in mineral oil) in dimethyl sulfoxide (100 ml) was heated at 80° C. for 40 minutes. Then the solution was cooled. To the solution was added (3-carboxypropyl)triphenylphosphonium chloride (15.9 g) portionwise at ambient temperature. After 30 minutes, 2-pyridinecarbaldehyde (3.96 g) was added at ambient temperature and then the mixture was stirred for 2 hours. Water was added to the mixture and acidified to pH 5 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and combined organic layer was washed with brine, dried, and concentrated. The residue was chromatographed on silica gel ethyl acetate:methanol=10:1) to give (4E)-5-(2-pyridyl)-4-pentenoic acid (1.6 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 68 °C
Yield: 55.3 %

Procedure:
Titanium (IV) chloride (0.36 g, 1.89 mmol) was added drop wise to a suspension of zinc powder (0.25 g, 3.78 mmol) in THF (3 ml). This solution was heated at 68° C. for one hour, then cooled to RT before rac-(3R,4S)-1-benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine (0.20 g, 0.63 mmol) in THF (2 ml) was added. The reaction mixture was then stirred at reflux over night. The reaction was cooled to RT, diluted with 300 ml of Et2O, washed with an aqueous solution of NaHCO3 and the organic phases were dried over Na2SO4. Flash chromatography (SiO2, CH2Cl2/MeOH, 9:1) yielded 0.10 g (57%) of rac-(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine as a light yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]=[CH2:19])=[C:13]([OH:20])[C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.C>C(=O)(O)[O-].[Na+]>[CH2:17]([C:14]1[CH:15]=[CH:16][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=2[C:13]=1[OH:20])[CH:18]=[CH2:19]
Reactant: C=CCc1ccc2oc(C(=O)OCC)cc(=O)c2c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCc1ccc2oc(C(=O)O)cc(=O)c2c1O
Temperature: 100 °C

Procedure:
A suspension of 2.0 parts of 6-allyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in aqueous sodium bicarbonate solution was stirred and heated at 100°C till solution was complete. The solution was treated with charcoal, filtered and acidified with dilute hydrochloric acid to give a yellow precipitate. This solid was crystallised from ethanol to give 0.84 parts of 6-allyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid as yellow needles, melting point 222°-224°C.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCC(OO)=[O:16]>C1C=CC=CC=1>[O:16]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: CCC(=O)OO
Reactant: C=CCc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: c1cc2c(cc1CC1CO1)OCO2
Temperature: 40 °C
Reaction time: 5 h

Procedure:
19.90 g (0.11 mol) of 5-(2-propenyl)-1,3-benzodioxole were initially introduced into a double-walled flask having a stirrer and reflux condenser and are warmed to 40° C. 43.58 g (0.10 mol) of a 20.58% strength solution of perpropionic acid in benzene were added dropwise, whilst stirring, and stirring was continued at this temperature for a further 5 hours. Titrimetric analysis then showed a peracid conversion of 98%. Analysis of gas chromatography gave a selectivity for the 5-(oxiranylmethyl)-1,3-benzodioxole formed of 61%.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>C1COCC1>[Br:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Ic1cnccn1
Reactant: Cc1cccc(C=O)c1Br
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2cnccn2)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-iodopyrazine (0.48 mL, 4.85 mmol) in dry THF (3 mL) was brought to 0° C. followed by the slowly addition of butylmagnesium chloride, 2.0M solution in THF (2.4 mL, 4.85 mmol). The resulting dark solution was stirred at 0° C. for 30 min then a solution of 2-bromo-3-methylbenzaldehyde (1.06 g, 5.34 mmol) in THF (2 mL) was slowly added and kept at 0° C. for 2 h. The mixture was quenched with saturated NH4Cl and extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography using gradient 1:1 hexanes/EtOAc to afford a yellow-orange oil as (2-bromo-3-methylphenyl)(pyrazin-2-yl)methanol.
Reaction SMILES: C([N:4]1[CH2:7][CH:6]([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:13]=[C:14]([C:20]5[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=5)[S:15][C:16]=4[CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH2:5]1)(C)C.[CH3:30][C:31]1([CH3:38])[O:35][C@@H:34]([CH:36]=O)[CH2:33][O:32]1.C(N(C(C)C)CC)(C)C>>[CH3:30][C:31]1([CH3:38])[O:35][C@@H:34]([CH2:36][N:4]2[CH2:5][CH:6]([C:8]3[CH:29]=[CH:28][C:11]4[C:12]5[N:13]=[C:14]([C:20]6[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=6)[S:15][C:16]=5[CH2:17][CH2:18][O:19][C:10]=4[CH:9]=3)[CH2:7]2)[CH2:33][O:32]1
Reactant: CC1(C)OC[C@H](C=O)O1
Reactant: CC(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C[C@H]4COC(C)(C)O4)C3)ccc1-2

Procedure:
The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13](F)=[C:12]([F:19])[C:11]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:41])[NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>C(#N)C>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([N:38]2[CH2:39][CH2:40][C@H:36]([NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:41])[CH2:37]2)=[C:14]([F:17])[C:15]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(OCc1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(F)c2F)C1
Yield: 63.6 %

Procedure:
A solution of 2,3,4,5,6-pentafluorobenzoic acid benzyl ester (Example 1d, 8.05 g, 26.6 mmol), triethylamine (26 mL, 186 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.6 g, 30 mmol) in acetonitrile (150 mL) is stirred at room temperature for 24 hours. The solvent is removed under vacuum and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a solid. The solid is then purified by column chromatography (1:1:6 ethyl acetate/chloroform/hexanes) to yield the title compound as a solid (7.92 g). 1H NMR (CDCl3): δ 7.48-7.30 (m, 5H, 5.35 (s, 2H), 4.77-4.50 (m, 1H), 4.37-4.19 (m, 1H), 4.01-3.63 (m, 3H), 3.59-3.46 (m, 1H), 2.29-2.09 (m, 1H), 2.01-1.82 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:46])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([N:43]([CH3:45])[CH3:44])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:45][N:43]([CH3:44])[C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:46])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N(C)C)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(N(C)C)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(2-dimethylamino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K49) (171 mg, 0.48 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (114 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)([CH2:14][NH:15][C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][C:11]1([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-(4-iodo-phenyl)-4-(isobutoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.15 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation and dried under high vacuum for 1 h to give [4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester as a reddish solid (0.058 g, ˜0.14 mmol). MS (ESI): 417.1/418.1(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].CI.[C:16]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH3:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a solution of 4-chloro-2-nitroaniline (10 mmol, 1.73 g) in DMF (10 mL) was added portionwise NaH (12 mmol, 480 mg of a 60% suspension in mineral oil) (exothermic, gas evolution). After 10 min MeI (20 mmol, 1.2 mL) was added to the reaction mixture. After 1 h the reaction mixture was poured into aqueous NaHCO3 and brine to afford the product as an orange precipitate, which was filtered, washed with water and dried in vacuo. H1 NMR (500 MHz, d6-DMSO): δ 8.22 (m, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.56 (dd, J=9.1 Hz, 2.5 Hz, 1H), 7.02 (d, J=9.4 Hz, 1H), 2.94 (d, J=5.0 Hz, 3H).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4](=[O:11])[NH:3][CH:2]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.O1CCOCC1.CN(C)C(=O)C>C(Cl)(Cl)Cl.CC(O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:8][CH2:7][C:6]3[N:1]=[CH:2][NH:3][C:4](=[O:11])[C:5]=3[CH2:10]2)=[N:14][CH:15]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: O=c1[nH]cnc2c1CNCC2
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCc3nc[nH]c(=O)c3C2)nc1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
Into a 20 ml microwave tube was combined 5,6,7,8-Tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one (0.280 g, 0.00183 mol), 2-chloro-5-methylpyridine (0.47 g, 0.0037 mol), 1,4-dioxane (2.5 mL, 0.032 mol) N,N-diisopropylethylamine (0.64 mL, 0.0037 mol) and N,N-dimethylacetamide (0.5 mL, 0.005 mol). The mixture was heated via microwave at 150° C. for 4 hours. The mixture was reduced in vacuo and taken up in chloroform:IPA (3:1) (50 ml). The organic was washed with sodium bicarbonate and brine (1×50 ml), dried over sodium sulfate, and reduced in vacuo. The mixture was purified by flash chromatography on silica gel using a methylene chloride:methanol (0-10%) gradient. The combined pure fractions were reduced in vacuo to yield a bright yellow solid (0.215 g, 47.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][C:9]2=[O:16])=[CH:5][CH:4]=1.C(OC(C)C)(=O)C.CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH3:40][O:41][NH:42][CH3:43]>CCCCCCC>[CH3:40][O:41][N:42]([CH3:43])[C:13]([C@@H:12]1[CH2:11][S:10][C:9](=[O:16])[N:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1)=[O:15]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Solvent: CN1CCOCC1
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with the title compound from Example 3 (310.0 g, 1.16 mol) and isopropyl acetate (2.4 L). The vessel was purged with nitrogen and cooled to 0° C. N-methylmorpholine (130.0 g, 1.29 mol) was added dropwise such that the internal reaction temperature never increased above 5° C. The reaction became cloudy. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwise such that the internal reaction temperature never increased above 5° C. The reaction was stirred at 0° C. for 45 minutes. N-methoxy-methanamine (78.0 g, 1.28 mol) was added dropwise, again keeping the internal reaction temperature below 5° C. The reaction was monitored by HPLC and was worked up when the ratio of the product to starting material was 4:1 (approximately 30 minutes after amine addition). The mixture was then washed with 0.1 M HCl and satd aq NaHCO3. The organic phase was separated and concentrated to a final volume of 1.0 L by distillation. Upon stirring, a precipitate began to form. A 250 mL portion of n-heptane was added, and the mixture was stirred vigorously. The solid was filtered and dried in a vacuum oven at 40° C. to afford the title compound (250 g, 70%).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:44])[CH3:43])[CH:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:43])[CH3:44])[CH:29]([O:34][Si:35]([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36])[C:30]([F:33])([F:31])[F:32])=[O:26])[C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (2.41 g) in dry tetrahydrofuran (8 mL) was added 10% (w/w) palladium-on-carbon (0.50 g) in dry tetrahydrofuran (8 mL) under nitrogen. This mixture was stirred under hydrogen at atmospheric pressure for 5 h. The catalyst was removed by filtration through a plug of diatomaceous earth and the plug was washed with ethanol. The filtrate was evaporated and dried under vacuum to give 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (1.78 g); TLC: Rf =0.06, ethyl acetate:dichloromethane (6:94); MS: m/z=512(M+1).
Reaction SMILES: [OH:1][N:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1([CH3:14])[CH3:13].[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:17]=1[C:18](Cl)=[O:19]>>[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:17]=1[C:18]([O:1][N:2]1[C:3]([CH3:14])([CH3:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]1([CH3:12])[CH3:11])=[O:19]
Reactant: CC1(C)c2ccccc2C(C)(C)N1O
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Product: Cc1cc(C)c(C(=O)ON2C(C)(C)c3ccccc3C2(C)C)c(C)c1
Yield: 92 %

Procedure:
Using this hydroxylamine compound and 2,4,6-trimethylbenzoyl chloride in a procedure otherwise similar to that for preparing the compound 101 gives a 92% yield of the compound 104 which is obtained in the form of colourless crystals; melting point: 181-183° C. (dichloromethane/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH:27]1([C:30]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:10][N:11]([C:13]4[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccccc2F)ccn1
Product: O=C1CCC(n2cc(-c3ccnc(NC(=O)C4CC4)c3)c(-c3ccccc3F)n2)=NN1
Yield: 71.5 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 50.0 mg (0.14 mmol) of 4-(2-aminopyridin-4-yl)-3-(2-fluorophenyl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 55 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 15.7 mg (0.15 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 41.9 mg of the title compound as a white powder. (Yield: 70%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]N(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (0.88 g) and DMF (8.0 ml) were added cesium carbonate (2.5 g) and methyl iodide (0.82 g) under ice-cooling, followed by stirring at room temperature for 1.5 hours. To the reaction mixture ethyl acetate and water under ice-cooling were added. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (15 ml), and the organic layer was combined and washed with a 10% aqueous citric acid solution, a saturated sodium bicarbonate solution, water, and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain methyl (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate (0.85 g).