Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:17]=[N:1][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COc1c(F)cc(F)cc1C=O
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1c(F)cc(F)cc1C=Nc1cccc2nc(C)ccc12
Yield: 87.2 %

Procedure:
To 2.0 g (12.6 mmol) 5-amino-2-methylquinolin and 2.2 g (12.6 mmol) 3,5-difluoro-2-methoxybenzaldehyde in 38 ml toluene are added 0.1 ml acetic acid and 5 g molecular sieve. The mixture is heated over 5 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene. 3.43 g of [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine are obtained as a yellow solid. 1.93 ml (22.3 mmol) 1,1,1-trifluoroepoxypropane in 40 ml THF and 10 ml hexane are cooled to −100° C. and 14 ml of a 1.6 M n-butyl lithium solution in hexane are added over 2 hours while the temperature does not exceed −96° C. 10 Minutes after complete addition 3.44 g (11.2 mmol) [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine in 50 ml THF are added over 1.5 hours while the temperature temperature does not exceed −95° C. After one hour at −100° C. the reaction mixture is warmed to 0° C. over two hours. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (isopropanol in hexane 5% to 20%) yields 1.68 g of the desired epoxide.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:6])C.[OH-].[Na+]>O1CCOCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:5]([CH3:6])[C:4]([OH:16])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)OCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(OCc1ccc(F)cc1)C(=O)O
Yield: 98.5 %

Procedure:
To a round bottom flask equipped with stir bar was added 2-(4-fluoro-benzyloxy)-propionic acid ethyl ester (0.380 g, 1.68 mmol), dioxane (6 mL) and 1N aqueous sodium hydroxide (1.76 mL, 1.76 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The isolated residue was treated with 2N aqueous hydrochloric acid (10 mL) then extracted with dichloromethane (4×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to isolate desired product as clear oil (328 mg, 99%). Isolated material was used as such in the next step. 1 NMR (300 MHz, CDCl3): δ 11.5 (br, 1H), 7.35 (m, 2H), 7.03 (m, 2H), 4.65 (d, 1H), 4.48 (d, 1H), 4.10 (q, 1H), 1.50 (d, 3H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Product: CC1Cc2ccc(-c3cnc(C#N)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (Frontier, Cat. No. C2065). LCMS (M+H)+: m/z=442.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(CC)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(CC)cc2)cc1)C(=O)O
Reaction time: 8 h
Yield: 107.8 %

Procedure:
Ethyl 2-ethoxy-3-{4-[2-(4-ethylphenyl)ethoxy]phenyl}propanoate (0.48 g, 1.3 mmol) was dissolved in dioxane (5 ml). Lithium hydroxide monohydrate (0.2 g, 4.76 mmol) in water (5 ml) was added. The mixture was stirred overnight and then acidified with 1M hydrochloric acid, pH ˜3-4. Dioxane was removed by evaporation in vacuum. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.48 g desired product was obtained, yield 100%.
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[NH4+]>O>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C([O-])CCCCC(=O)O
Agent: [NH4+]
Solvent: O
Product: O=C(O)CCCCC(=O)O
Temperature: 200 °C
Yield: 82.3 %

Procedure:
A 300 mL Parr autoclave was charged with 80 g of synthetic monoammonium adipate and 124 g of water. The autoclave was sealed and the contents stirred and heated to about 200° C. (autogenic pressure was about 203 psig). Once the contents reached temperature, water was then fed to the autoclave at a rate of about 2 g/min and vapor was removed from the autoclave at a rate of about 2 g/min with a back pressure regulator. Vapor exiting the autoclave was condensed and collected in a receiver. The autoclave was run under those conditions until a total of 1210 g of water had been fed and a total of 1185 g of distillate collected. The contents of the autoclave (209 g) were partially cooled and discharged from the reactor. The slurry was allowed to stand with stirring at room temperature over night in an Erlenmeyer flask. The slurry was then filtered and the solids rinsed with 25 g of water. The moist solids were dried in a vacuum oven at 75° C. for 1 hr yielding 59 g of adipic acid product. Analysis via an ammonium ion electrode revealed 0.015 mmole ammonium ion/g of solid. The melting point of the recovered solid was 151-154° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[Cl:19][C:20]1[C:24](Cl)=[N:23][S:22][N:21]=1>C1(C)C=CC=CC=1.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>[Cl:19][C:20]1[C:24]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[N:23][S:22][N:21]=1
Reactant: Clc1nsnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1cccs1
Yield: 54 %

Procedure:
0.92 g (0.00246 mol) of 2-(tributylstannyl)thiophene and 0.12 g (0.0001 mol) of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 0.33 g (0.00213 mol) of 3,4-dichloro-1,2,5-thiadiazole in 4 mL of toluene under nitrogen and heated at reflux. After 3 and 6 h respectively, 0.04 g (2 times 2.5×10−5 mol) of tetrakis (triphenylphosphine)palladium(0) were added. After 24 h of reflux (quantitative HPLC: 54% of product formed, all the stannane was consumed), the reaction medium was diluted with 5 mL of ethyl acetate and vigorously stirred with 10 mL of a 1M aqueous solution of KF for 2 h. After filtration through celite, the aqueous phase was re-extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: Cc1cc(CC2NC(=O)OC2c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CC(N)C(O)c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Yield: 83.3 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one (3.0 g, 7.48 mmol) in ethanol (30 ml) was added 8N aqueous sodium hydroxide solution (4.7 ml, 37.4 mmol), and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (2.34 g, 83%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[S:6][CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[CH2:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:26]([NH:25][CH2:24][C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([F:20])[CH:22]=2)=[O:27])[S:6][CH:7]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: COc1ccc(CNc2nc(CCl)cs2)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CCl)cs2)c(OC)c1
Reaction time: 8 h

Procedure:
The 4-(chloromethyl)-N-(2,4-dimethoxybenzyl)thiazol-2-amine was dissolved in DCM (50 ml) and 3-fluorobenzylisocyanate (1.2 eq.) was added and stirred overnight. The mixture was concentrated and the residue was purified on a column using 0-100% gradient of EtOAc and hexanes to give the title compound.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[NH:11]([C:13]1[N:14]=[C:15]([NH2:31])[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[NH2:12]>CC(O)C>[OH:22][C@@H:21]1[C@H:23]([OH:24])[C@@H:25]([CH2:26][OH:27])[O:28][C@H:20]1[N:19]1[CH:18]=[N:17][C:16]2[C:29]1=[N:30][C:13]([N:11]1[CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=[N:12]1)=[N:14][C:15]=2[NH2:31]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)O
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:45])[CH3:44]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:45][CH2:43][CH3:44])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: CCN
Product: CCNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and ethylamine.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30](I)[CH2:31]CC>>[CH2:28]([C:18]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:12][CH:13]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CCCCI
Product: CCCCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 5 from 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole and butyl iodide. MS (ESI) m/z 435 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:33]([CH2:34][O:35][CH2:36]1)[CH2:32][C:31]1[O:30][N:29]=[CH:28][C:27]2=1>>[CH3:18][O:17][C:15]([C:14]1[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]=1[CH2:19][N:37]1[CH:33]2[CH2:34][O:35][CH2:36][CH:26]1[C:27]1[CH:28]=[N:29][O:30][C:31]=1[CH2:32]2)=[O:16]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: c1noc2c1C1COCC(C2)N1
Product: COC(=O)C1=C(CN2C3COCC2c2cnoc2C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (200 mg) and 5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a (100 mg). 20 mg of the title compound was isolated as yellow powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11].[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21]>[Pd](Cl)Cl.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([C:21]#[C:20][CH2:19][CH2:18][OH:22])=[CH:15][CH:16]=1)=[O:11]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCCO)s1
Reaction time: 0.17 h

Procedure:
To a 20-mL vial for microwave reaction, were added a mixture of palladium chloride (57 mg, 0.32 mmol), triphenylphosphine (104 mg, 0.32 mmol), copper iodide (243 mg, 1.28 mmol), triethylamine (8.08 g, 80 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (1.77 g, 8 mmol) and anhydrous acetonitrile (10 mL). To the stirred mixture, were added copper iodide (243 mg, 1.28 mmol) and but-3-yn-1-ol, 1 (588 mg, 8.4 mmol), and the vial was sealed and put into the microwave reactor at 100° C. for 10 min. After evaporation of solvent under reduced pressure, MeOH (20 mL) was added followed by silica gel (5 g). The resulting plug was loaded on to a silica gel column (3.5×12 cm) and eluted with hexane followed by 20% EtOAc in hexane. Fractions with an Rf=0.42 (hexane/EtOAc 4:1) were pooled and evaporated to afford 1.17 g of 2 as yellow oil. 1H NMR (DMSO-d6): δ 2.59-2.63 (t, J=6.4 Hz, 2H), 3.56-3.59 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 4.95-4.98 (t, J=5.6 Hz, 1H), 7.27-7.28 (d, J=4.0 Hz, 1H), 7.69-7.70 (d, J=4.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][N:11]([CH3:15])[C:12](=[O:13])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (1.22 g) in pyridine (5 mL) was added dimethylcarbamyl chloride (1.0 mL) and the mixture was stirred at 60° C. overnight. Thereto was added diluted HCl and ethyl acetate and stirred. The organic layer was extracted by diatomaceous earth column. The organic layer was concentrated and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give 4-formylphenyl dimethylcarbamate (1.67 g, yield: 86%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([N:12]([C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH:11][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH3:17]
Reactant: COC(=O)C1CCCC1=O
Reactant: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)NN(C(=O)OCC)C1(C(=O)OC)CCCC1=O
Reaction time: 0.5 h
Yield: 130.9 %

Procedure:
To a solution of methyl 2-oxocyclopentanecarboxylate (15.6 mg, 0.11 mmol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diethyl azodicarboxylate (45.5 μL, 0.10 mmol) at room temperature. After stirring for 0.5 hr, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (41.4 mg, yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[N:30]=[C:31]=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N=C=O)cc32)cc1
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(NC(=O)N4C=CC(=O)C[C@H]4c4ccc(F)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (58 mg, 0.30 mmol) was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.16 ml of a 2.5M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 5-Bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (1 eq, 146 mg) was added and the mixture was allowed to stir for 1 hour at −40° C., then warmed to warm to room temperature and stirred for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 1:1 hexanes/ethyl acetate) to give (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide (140 mg, 65.1%) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[CH:4][C:5]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1

Procedure:
tert-butyl 4-(2-chloro-5-(4-((dimethylamino)methyl)benzamido)-4-nitrophenyl)piperazine-1-carboxylate was stirred in TFA/DCM (50%) for 1 h. After solvent was removed, the residue was dried in vacuo overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:25][C:26](=O)[NH:27][C:28]1[N:29]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C:26]([NH:27][C:28]3[N:29]([C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)[N:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=3)=[O:25])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)ccn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Heat a solution of 4-(4-amino-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 20, 1 g, 3.41 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 38, 1.38 g, 3.41 mmol), and diisopropylethylamine (1.2 mL, 6.82 mmol) in DMSO (15 mL) at 60° C. for 5 d. Cool the resulting mixture to room temperature and partition between water and ethyl acetate using saturated aq. sodium chloride solution to aid phase separation. Extract the aqueous layer with ethyl acetate, wash the combined organic layers twice with water, dry over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate in dichloromethane to give 877 mg (43% yield) of 4-{4-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. LCMS ES+(m/z) 549 [M+H].