Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([O:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)=[N+:2]=[N-:3]>C1(C)C(C)=CC=CC=1>[C:13]1([C:12]2[N:3]=[N:2][N:1]3[C:11]=2[CH2:10][O:9][C@H:8]2[CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C@H:4]32)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](OCC#Cc2ccccc2)C1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1C[C@@H]2OCc3c(-c4ccccc4)nnn3[C@H]2C1
Yield: 56.7 %

Procedure:
Example 55 can be prepared in the same manner as example 46 from (3S,4S)-tert-butyl 3-azido-4-(3-phenylprop-2-ynyloxy)pyrrolidine-1-carboxylate (120 mg, 0.35 mmol) and xylene (6 ml), afforded the titled compound (68 mg, 57%) as white solid. M.p. 236-237° C.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:35][C@@H:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]1[N:28]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:25]=[CH:26][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:12]([O:23][CH3:24])[CH:13]=2)[C:16]1=[O:17]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1C=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@@H]1CCCC[C@H]1O)C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methoxybenzoate (0.16 g), trans-2-aminocyclohexanol hydrochloride (0.07 g), triethylamine (0.06 ml) and anhydrous magnesium sulfate (0.10 g) in THF (3.50 mL) was stirred at room temperature for 2 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.50 mL) and THF (3.50 mL), sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[CH2:32][CH:31]([NH:33][CH2:34][CH2:35][OH:36])[CH2:30][CH2:29][CH2:28][C:27]=2[C:37]=1[O:38][CH3:39]>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]3[CH2:32][CH:31]([NH:33][CH2:34][CH2:35][OH:36])[CH2:30][CH2:29][CH2:28][C:27]=3[C:37]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (100 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford an off-white foam (97 mg, 58%). Mp: 80-1° C. LCMS (m/e) 560 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 8.60 (d, J=8 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.65 (m, 1H), 7.52 (s, 1H), 7.30 (m, 1H), 6.87 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.66 (m, 2H), 3.00-2.82 (m, 5H), 2.76 (m, 2H), 2.09 (m, 1H), 1.86 (m, 4H), 1.60 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH:26]([OH:29])[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:30][O:31][N:32]=[C:33]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1O.N(C(OCC)=O)=NC(OCC)=O>CCOCC.C1COCC1>[CH3:30][O:31][N:32]=[C:33]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:29][CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:27][CH3:28]
Reactant: CCC(O)c1ccccc1
Reactant: CON=C(c1ccccc1O)n1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(Oc1ccccc1C(=NOC)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
Triphenylphosphine (1.05 g), 1-phenylpropyl alcohol (0.54 g) and THF (20 ml) were added to 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.43 g), and diethyl azodicarboxylate (0.70 g) was added under ice-cooling over 10 minutes. Then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (100 ml) was added, the mixture was washed with water (80 ml) twice, and the ether layer was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give α-(1-imidazolyl)-2-(1-phenylpropyloxy)benzaldehyde O-methyloxime (0.63 g) as a colorless oil.
Reaction SMILES: Cl.C1(CC([NH:11][CH:12]2[C:33](=[O:34])[N:14]3[CH:15]([C:20]4[N:24]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:23]=[N:22][N:21]=4)[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]23)=O)C=CC=CC=1.[K+].[Br-]>>[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]3[N:24]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[N:23]=[N:22][N:21]=3)[C:16]([CH3:18])([CH3:19])[S:17][C@H:13]12
Reactant: CC(C)(C)C(=O)OCn1nnnc1C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)C(=O)OCn1nnnc1C1N2C(=O)C(N)[C@H]2SC1(C)C
Yield: 90 %

Procedure:
The title compound is prepared as its hydrochloride, in 90% yield, from 6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]-tetrazol-5-yl)penam, using the method of Example CLXXVI. The infrared spectrum (KBr disc) shows absorptions at 1780 cm31 1 (β-lactam) and 1740 cm-1 (ester). The NMR spectrum (DMSO-d6) shows absorptions at 6.71 ppm (singlet, 2H, pivaloyloxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen 5.83 ppm (doublet, 1H, C-5 hydrogen), 5.20 ppm (doublet, 1H, C-6 hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[C:26](OC)(=[O:29])[CH2:27][CH3:28].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:26](=[O:29])[CH2:27][CH3:28])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: CCC(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: -72 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (7.2 g) in tetrahydrofuran (80 ml) at -78° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -71° C., n-butyllithium (8 ml of a 2.5M solution in hexanes). A solution of methyl propionate (3.2 ml) in tetrahydrofuran (10 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -72° C. Upon completion of the addition the mixture was stirred at -72° C. and then allowed to warm to room temperature over a period of 1.5 hours. After stirring overnight at room temperature water (100 ml) was added and the mixture extracted twice with ethyl acetate (200 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a brown gum which was purified by column chromatography on silica gel (500 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave a brown solid which was further purified by column chromatography on silica gel (60 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 143° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CC1(C)OB(c2ccn[nH]2)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: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccn[nH]2)CC1
Yield: 66.9 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 1H-pyrazole-5-boronic acid pinacol ester (19 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%), LC-MS (ESI) Rt 1.06 min, m/z 306 (100%, [M+H]+); m/z (ESI) C14H17ClN5O requires 306.1116 found [M+H]+ 306.1114.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@:8]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][C:10]2([O:14][C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:11]2)[CH2:9]1.F[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42])[C:36]#[N:37]>C(#N)C>[CH3:7][C@:8]1([CH2:30][NH:31][C:39]2[CH:38]=[C:35]([CH:34]=[CH:33][C:40]=2[N+:41]([O-:43])=[O:42])[C:36]#[N:37])[CH2:29][CH2:28][CH2:27][C:10]2([O:11][C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14]2)[CH2:9]1
Reactant: C[C@]1(CN)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@]1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 40 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of acetonitrile (2049 mL) in a 3 L flask was heated to 40° C. Next, potassium carbonate (198 g, 1434 mmol), 1-[(2R,3R,7S)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methanamine (242 g, 717 mmol) and 3-fluoro-4-nitrobenzonitrile (119 g, 717 mmol) were added slowly. The mixture was allowed to stir at 40° C. for 2 h, and then cooled to RT. Stirring was continued at RT overnight. The next day, the slurry was filtered and the solids were washed with acetonitrile (500 mL). The filtrate was concentrated to afford the crude product (while keeping the temperature ˜60° C. during concentration). To the thick dark residue was added MeOH. The solution was heated to 60° C. on the rotovap and concentrated to a minimal volume. To the residue was added ˜500 mL of MeOH slowly with heating to avoid rapid crystallization, and the solution was heated to reflux. Once at reflux, an additional 250 mL MeOH was slowly added. The resulting slurry was allowed to stir at reflux for about 60 min, then heating was stopped and the slurry was allowed to cool to RT and stirring was continued for 3 days. The slurry was cooled to ˜10° C. with an ice/water bath. Stirring was continued for ˜2 h, and then the slurry was filtered and washed with cold MeOH (100 mL). The solids were dried under reduced pressure to give the desired product as a bright orange solid (245 g, 70.7% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1CCCNCC1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: CCOc1cc(N2CCCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 58 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and methylhomopiperazine was used in place of N-methylpiperazine. In this manner, 94 mg (58%) of the captioned compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C(O)C1CCCC1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C2CCCC2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (76 mg, 0.2 mmol), cyclopentyl carboxylic acid (27 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 30 min. The crude was purified by HPLC to give title compound (20 mg, 21%) as a brown solid as TFA salt. 1H NMR (CD3CN, 400 MHz) δ 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m, 2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, 3H), 3.74-3.80 (m, 2H), 3.82-3.96 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, J=9.09 Hz, 11), 7.55 (d, J=2.53 Hz, 1H), 7.57 (s, 1H), 7.76 (dd, J=2.78, 9.35 Hz, 1H), 8.38 (s, 1H). Exact mass calculated for C22H2979BrN4O3 476.1. found 477.3 (M+H 79Br, 100), 479.3 (M+H 81Br, 98).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCCN4C(=O)c5ccccc5C4=O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and N-(3-hydroxypropyl)phthalimide were processed as described in Example 61G to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([Mg]Br)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].Cl>CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:15]([OH:16])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Cl:12])[CH3:2]
Reactant: CCOc1cccc([Mg]Br)c1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Solvent: CCOCC
Product: CCOc1cccc(C(O)c2ccccc2Cl)c1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To an ether solution of 3-ethoxyphenylmagnesium bromide [prepared from 3-ethoxybromobenzene (6 g, 30 m mol), magnesium (0.8 g, 33 m mol) and ether (30 ml)], an ether solution (30 ml) of 2-chlorobenzaldehyde (2.8 g, 20 m mol) was added dropwise with stirring and under cooling with ice. After 30 minutes, 1 N hydrochloric acid (50 ml) was added thereto. The ether layer was separated and the aqueous layer was extracted with ether (20 ml). After the combined ether layer was washed with a saturated aqueous solution of sodium chloride (15 ml) and dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (60 g) using hexane-ethyl acetate (5:1). The resulting fraction containing the desired compound was distilled to obtain the desired compound (3.4 g, 64%) as a colorless oily material (178-179° C./1 mmHg).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][O:38][CH3:39])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:34]([O:33][CH:29]([O:30][CH2:31][CH3:32])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][O:38][CH3:39])[CH3:36])[CH3:35]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)COC
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](COC)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 46.4 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-methoxy-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-25) 58 mg (0.15 mmol) to obtain the title compound 19 mg (23%).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)([O-])C.[K+].[C:33]([O:37][C:38]([N:40]1[CH2:44][C:43](=O)[CH2:42][C@@H:41]1[C@H:46]1[O:50][C:49]([CH3:52])([CH3:51])[N:48]([C:53](=[O:55])[CH3:54])[C@H:47]1[CH2:56][C:57]1[CH:62]=[C:61]([F:63])[CH:60]=[C:59]([F:64])[CH:58]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([O:37][C:38]([N:40]1[CH2:44]/[C:43](=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])/[CH2:42][C@@H:41]1[C@H:46]1[O:50][C:49]([CH3:51])([CH3:52])[N:48]([C:53](=[O:55])[CH3:54])[C@H:47]1[CH2:56][C:57]1[CH:58]=[C:59]([F:64])[CH:60]=[C:61]([F:63])[CH:62]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Place under argon a suspension of n-hexyltriphenylphosphonium bromide (0.420 g, 1 mmol) in 10 mL of dry THF. Add potassium tert-butoxide (0.112 g, 1 mmol). Stir the mixture for 1 h. Add a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.1 mmol) in 5 mL of dry THF. Stir the mixture overnight. Add water, extract with diethyl ether, dry over MgSO4, concentrate under reduced pressure and purify (silica gel chromatography, eluting with ethyl ether:hexane mixtures) to give the title compound (0.04 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.C=O.[C:52](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=3)[N:9]=[C:10]([CH:42]3[CH2:47][CH2:46][N:45]([CH3:52])[CH2:44][CH2:43]3)[C:11]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(Cn2nc(C3CCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (20.0 mg, 0.0301 mmol), formaldehyde (0.905 mg, 0.0301 mmol), sodium triacetoxyborohydride (6.39 mg, 0.0301 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature for 2 days. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (16.3 mg, 79.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 678 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:5]1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:9][C:8]1[N:4]([CH2:3][C:2]([F:23])([F:22])[F:1])[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 15 b]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-(2,2,2-trifluoro-ethyl)-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CON(C)C(=O)c1c(O)cccc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc(F)c2C(=O)N(C)OC)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide (4.320 g, 21.689 mmol) in acetone (50 mL) were added 4-methoxy benzylchloride (3.74 g, 23.858 mmol), potassium carbonate (4.50 g, 32.534 mmol), and potassium iodide (360 mg, 2.169 mmol). The mixture was stirred at reflux for 15 hrs. After cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 2-fluoro-N-methoxy-6-[(4-methoxybenzyl)oxy]-N-methylbenzamide as a pale yellow oil (6.926 g, yield; quant.).