Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Brc1cccnc1
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: Cc1ccccc1
Solvent: CCO
Product: c1cncc(-c2ccc3c(c2)OCO3)c1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
A mixture of 3,4-(methylenedioxy)phenylboronic acid (500 mg, 3.0 mmol), 3-bromopyridine (290 μl, 476 mg, 3.0 mmol), 2 M Na2CO3 (3.05 ml, 6.0 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), EtOH (0.75 ml) and toluene (3 ml) was heated in a microwave reactor at 120° C. for 40 min. Another crop of 3,4-(methylenedioxy)phenylboronic acid (250 mg, 1.5 mmol) was added and the mixture heated under microwaves at 120° C. for 10 min. The reaction mixture was filtered and the layers were separated. The organic phase was extracted twice with 1 M HCl. All the aqueous phases were combined, basified with 5 M NaOH and extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 585 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:21][CH3:22])=[O:4].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:8](=[C:9]([CH2:21][CH3:22])[CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CNC
Reactant: CCc1cccc2c(-c3ccccc3)c(C(=O)OC)c(Cl)nc12
Product: CCc1cccc2c(-c3ccccc3)c(C(=O)O)c(N(C)C)nc12

Procedure:
The title compound was prepared in analogy to example 43 step E from 2-chloro-8-ethyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 43 step D) and dimethylamine (40% in water). Yellow solid. MS (ESI): 321.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19](SCC2C=CC=C(F)C=2F)[C:18]2[C:13](=[N:14][C:15]([NH2:31])=[CH:16][N:17]=2)[N:12]=1.[NH2:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35]>CN1C=CN=C1>[NH2:31][C:15]1[N:14]=[C:13]2[C:18]([C:19]([NH:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35])=[N:20][C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:12]2)=[N:17][CH:16]=1
Reactant: Nc1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2n1
Reactant: CC(N)(CO)CO
Agent: Cn1ccnc1
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)cnc12

Procedure:
A solution of the product from example 1, step (c) (0.25 g) and 2-amino-2-methyl-1,3-propanediol (0.28 ml) in N-methylimidazole (1 ml) was heated in a microwave at 160° C. for 95 minutes. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a brown oil which was purified by silica gel flash column chromatography, eluting with 10:1 dichloromethane:methanol to give the title compound as a pale brown solid (0.031 g).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:7])([O-])=O.[Cl-:24].[NH4+:25]>[Fe].C(O)C.O>[ClH:24].[ClH:24].[NH2:1][C:4]1[C:23]([N:25]2[CH2:10][CH2:9][NH:8][CH2:6][CH2:5]2)=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:7]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccccc1[N+](=O)[O-]
Reactant: [NH4+]
Reactant: [Cl-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: Cl
Product: Nc1c(C(=O)NCC23CC4CC(CC(C4)C2)C3)cccc1N1CCNCC1
Yield: 85.1 %

Procedure:
A suspension of 3-(4-{1,1-dimethylethyl}oxycarbonyl]-piperazin-1-yl)-2-nitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.8 g, Example 1b), iron powder (2.13 g) and ammonium chloride (2.04 g) in 2:1 ethanol/water (90 ml) was heated at reflux, under a nitrogen atmosphere, for 2 h. The cooled reaction mixture was filtered and the filtrate partitioned between water and ethyl acetate. The organic layer was separated and washed with water twice further, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a residue. Purification of the residue by chromatography over silica gel, eluting with 20% ethyl acetate in iso-hexane, yielded the subtitle compound as a solid (2.27 g).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:11])=[O:9])[C:4](=[O:24])O1.[CH2:26]=O.[NH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:26][N:28]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:4](=[O:24])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:15]=1
Reactant: C=O
Reactant: CN(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCCC(=O)O
Product: CN(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 9 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a colorless oil (0.01 g, 9% yield). 1HNMR (300 MHz, CDCl3) δ: 7.78 (1H, dd, J=8.06, 2.57 Hz), 7.43 (1H, dd, J=8.60, 4.94 Hz), 7.36–7.30 (1H, m), 5.08 (2H, s), 4.20 (2H, s), 3.58 (2H, t, J=5.85 Hz), 3.16 (6H, s), 2.42 (2H, t, J=6.22 Hz), 1.95 (2H, t, J=6.59).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C:8]2=[N:7][N:6]=1)([CH3:4])[CH3:3].[ClH:21].C(OCC)C.O1CCOCC1>C(Cl)Cl>[ClH:21].[ClH:21].[N:7]1[N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(C)(C)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(O)c1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.40 g, 1.417 mmol) in DCM (10 mL) at 0° C., was added 2 M HCl in diethyl ether (3.54 mL, 7.08 mmol) dropwise. The reaction was stirred overnight at RT. After 16 hours, the white precipitate was collected by vacuum filtration, washed with ether, and dried in vacuo. The residue was resuspended in 1,4-dioxane (10 mL) and 4 M HCl in dioxane (1.78 mL, 7.08 mmol) was added. The mixture was heated to 60° C. and stirred vigorously overnight. After 16 hours, the suspension was concentrated to a white powder and dried in vacuo to generate 2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-ol dihydrochloride (0.373 g, 103% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O.[CH2:18]=[C:19]([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A 500-ml flask was charged with 50 ml of toluene and 53.42 g (0.25 mol) of 4′-methyl-2-biphenylcarboxylic acid, 0.45 ml (0.025 mol) of water and 32.63 g (0.58 mol) of isobutene. To this mixture was added dropwise 7.74 g (0.05 mol) of phosphorus oxytrichloride, and the mixture was stirred for 6 hours. The reaction mixture was added to 50 ml of a 10%-aqueous sodium hydroxide and washed. The organic layer was dried over anhydrous magnesium sulfate. Thereafter, the organic layer was concentrated by distilling off toluene by using a rotary evaporator, to give 64.2 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 95% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[CH:12]=[O:13].[Cl-].[NH4+]>C(OCC)C>[OH:17][C:16]1[C:15]([CH3:18])=[CH:14][C:11]([CH:12]([CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[OH:13])=[CH:10][C:9]=1[CH3:8]
Reactant: C[Si](C)(C)CCl
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)C[Si](C)(C)C)cc(C)c1O
Temperature: 0 °C

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (1.5 g, 10 mmol) in anhydrous ethyl ether. Stir until reaction is complete. Cool the reaction mixture to 0° C. and add saturated ammonium chloride solution. Separate the ether layer, wash with water and dry (MgSO4). Evaporate to give 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl)-methyl]benzenemethanol and purify by silica gel chromatrography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[S:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:3]=1
Reactant: N
Reactant: Fc1ccc(-c2ccccc2)c(N=C=S)c1
Solvent: CCO
Product: NC(=S)Nc1cc(F)ccc1-c1ccccc1

Procedure:
Reaction of 4-fluoro-2-biphenylylisothiocyanate (12 g) in ethanol (10 ml) with 25% aqueous ammonia solution (40 ml) at ambient temperature for 8 hours gave N-(4-fluoro-2-biphenylyl)thiourea as a white solid (m.p. 185°-187° C.).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([NH:18][C@H:19]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][F:37])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([NH:18][C@H:19]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][F:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of N-[(1-phenylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (154 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treated with TFA (1 mL), and the resultant reaction mixture was stirred for one hour under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride, then triturated with ether to yield the title product as a white powder (100 mg). TLC: (methylene chloride/methanol/acetic acid, 20:1:1): Rf =0.38, MS (EI) for C25H26FN3O5 : MH+ =468; (M-H)- =466.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[N:4][C:5]([CH3:14])=[C:6]([C:12]=1[OH:13])[C:7]([O:9]CC)=[O:8].O.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[C:3]([Cl:15])=[N:4][C:5]([CH3:14])=[C:6]([C:12]=1[OH:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(C)nc(Cl)c(Cl)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(Cl)c(Cl)c(O)c1C(=O)O

Procedure:
36 g (0.14 mol) of ethyl 5,6-dichloro-4-hydroxy-2-methyl-nicotinate are boiled under reflux in 88 ml of ethanol and 175 ml of water with 24.2 g (0.43 mol) of potassium hydroxide for thirty minutes. The cooled mixture is brought to a pH of 1 with half-concentrated hydrochloric acid, while cooling with ice. The product which precipitates is isolated, washed with water and dried.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: B1CCON1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Preparation of the Compound of Formula (II) wherein R1 is CH3 ##STR13## Cis, exo-3-amino-2-hydroxybornane (1.0 g, 5.9 mmol), toluene (18 mL), and trimethylboroxine (0.56 mL) were combined at ambient temperature and stirred for 16 hr. Water, toluene and excess boroxine were distilled off until about 8 mL volume remained. The reaction was chased with toluene (3×11 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (1.10 g, 98%). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from cis, exo-3-amino-2-hydroxybornane (228 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol as a colorless oil 3.16 g (90% ee).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:19]1([O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Reactant: OC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)OC2CCCCC2)cc1)n1ccnc1
Yield: 78 %

Procedure:
1 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is converted, analogously to example 20, into the acid chloride; it is dissolved in 10 ml of methylene chloride, mixed with 360 mg of cyclohexanol and 3 ml of pyridine, after 20 hours at room temperature it is added to excess 1M hydrochloric acid and extracted with ether. The water phase is alkalized with potassium carbonate and extracted with ethyl acetate. After drying and concentration by evaporation, the residue is distilled on a bulb tube. 915 mg of the title compound is obtained as oil with a boiling point of 200° C./0.03 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylamine hydrochloride (13.5 g, 190 mmol) followed by the addition of a sodium hydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried (magnesium sulfate) to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%) as a white solid. 1H-NMR (DMSO-d6): δ 11.56 (s, 1H), 8.44 (d, 1H), 7.80 (m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); 19F-NMR (DMSO-d6): δ −113.44; MS m/z 265 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=O)C.[OH2:17].[CH3:18]O>[OH-].[Na+]>[OH:4][CH2:5][C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2
Reactant: O
Reactant: CC(=O)OCc1cc2ccccc2[nH]c1=O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(=O)c(CO)cc2c1

Procedure:
2 Grams of 3-acetoxymethylcarbostyril was dissolved in 30 ml of methanol containing 0.6 g of sodium hydroxide, then the mixture was refluxed for 3 hours. After removal of methanol by distillation, to the residue thus obtained was added water and the crystals precipitated were collected by filtration. Recrystallized from acetone to obtain 1.3 g of 3-hydroxymethyl-6-methoxycarbostyril in the form of light yellowish needle-like crystals.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]3)[N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N[C:27]([OH:31])([CH2:29][CH3:30])[CH3:28].F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1.O>[OH:31][CH:27]([CH3:28])[CH2:29][CH2:30][NH:39][C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:12]2[N:11]=[C:10]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[N:2]3)[CH:15]=[CH:14][N:13]=2)[CH2:18][CH2:19]1)=[O:24]
Reactant: CCC(C)(N)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CCNC(=O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(4-indazol-1-ylpyrimidin-2-ylamino)-cyclohexanecarboxylic acid (100 mg, 0.30 mmol), 2-amino-2-butanol (39.2 mg, 0.44 mmol), BOP (194.6 mg, 0.44 mmol), DIPEA (77.4 mg, 0.60 mmol) in THF (8 mL) was stirred at RT overnight. Water (20 mL) was added to the resulting suspension: the solids first dissolved, then precipitated with the addition of more water (100 mL). The precipitate was collected by filtration, washed with water and Et2O, and dried under reduced pressure to give trans-4-(4-indazol-1-yl-pyrimidin-2-ylamino)-cyclo-hexanecarboxylic acid (3-hydroxy-butyl)amide (78 mg) as white solid. MS=409 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1.[F-].[Cs+].[CH2:15](B1OC(C)(C)C(C)(C)O1)[CH:16]=[CH2:17]>C1COCC1.O.C(OCC)(=O)C.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>[CH2:17]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1nc([N+](=O)[O-])ccc1OC
Temperature: 66 °C
Yield: 74.6 %

Procedure:
2-Bromo-3-methoxy-6-nitropyridine (3.22 g, 13.8 mmol), cesium fluoride (6.3 g, 41.5 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.6 g, 1.38 mmol) were combined with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.55 g, 2.85 mL, 15.2 mmol) in THF (27 mL) and heated at 66° C. for 20 h. The mixture was cooled then diluted with water and ethyl acetate. The phases were separated then the organic phase was washed with water (2×) and brine, concentrated in vacuo and then purified by chromatography (silica, 10 to 50% ethyl acetate in hexanes) to give 2-allyl-3-methoxy-6-nitropyridine (2.0 g, 10.3 mmol, 75%) as a blue solid. MS (EI/CI) m/z: 194.8 [M+H].
Reaction SMILES: [C:1]([CH:3]([CH2:6][C:7](=O)[CH3:8])[C:4]#[N:5])#[N:2].Cl.CNC.[CH3:14][OH:15]>>[CH3:14][O:15][C:1]1[NH:2][C:7]([CH3:8])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO
Reactant: CC(=O)CC(C#N)C#N
Agent: CNC
Agent: Cl
Product: COc1[nH]c(C)cc1C#N
Temperature: 25 °C

Procedure:
A solution of 2-cyano-4-oxopentanenitrile (2.75 g) and dimethylamine hydrochloride (16.25 g) in 100 ml of methanol was heated at reflux for 24 h. The mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in 50 ml of H2O and extracted with EtOAc. The organic extracts were dried over Na2SO4. Silica gel chromatography afforded a white solid (0.8 g), m.p. 105° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12](CC)[CH:11](S)[CH:10]([CH2:16][NH2:17])[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([CH:21]=[O:22])C>CO>[C:1]([O:5][C:6]([N:8]1[CH:12]([O:22][CH3:21])[CH2:11][CH:10]([CH2:16][NH2:17])[O:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCC1C(S)C(CN)ON1C(=O)OC(C)(C)C
Solvent: CO
Product: COC1CC(CN)ON1C(=O)OC(C)(C)C

Procedure:
In the same manner, N-tert-butoxycarbonyl-5-aminomethyl-3-ethylthiyl-4,5-dihydroisoxazole was made by using sodium ethyl thiolate in dry DMF instead of sodium methoxide in methanol.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)(=[O:29])=[O:28])=[CH:22]2>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([S:27]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(C(F)(F)F)c5)cnc34)C[C@@H]2C1
Yield: 60 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 8-iodo-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 107 mg (60%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:36])=[N:29][C:30]([CH2:33][O:34][CH3:35])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:36])=[N:29][C:30]([CH2:33][O:34][CH3:35])=[CH:31][CH:32]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(COC)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 41.4 %

Procedure:
To a mixture of (4-benzyloxy-phenyl)-acetohydroximoyl chloride (19 mg, 0.069 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (1 mL) were added 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (8.6 mg, 0.053 mmol) described in Manufacturing Example 26-1-7 and triethylamine (15 μL, 0.11 mmol) at room temperature, which was stirred for 5.5 hours at room temperature. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate-tetrahydrofuran (3:2). The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (8.8 mg, 41%).