Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC([SiH3])(Cl)Cl.BrC(Br)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].I[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1>CC(N(C)C)=O.C(OCC)(=O)C.[Zn].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].ClCCl.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:23]2[CH:24]=[C:25]3[CH:31]=[CH:30][NH:29][C:26]3=[N:27][CH:28]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Ic1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2cnc3[nH]ccc3c2)C1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
In an inert atmosphere, zinc dust (223 mg, 3.41 mmol) was vigorously stirred in dimethylacetamide (1.5 ml) and heated to 65° C. Subsequently, trichloromethylsilane (50 μl, 0.38 mmol) and dibromoethane (30 μl, 0.38 mmol) were added, and the reaction mixture was stirred for further 30 minutes at 65° C. 3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (462 mg, 1.89 mmol) in dimethylacetamide (2 ml) was added dropwise to the above prepared solution at 65° C. and stirred for 30 minutes. 5-Iodo-1H-pyrrolo[2,3-b]pyridine (697 mg, 2.46 mmol) in dimethylacetamide (4 ml) was added to the reaction mixture. Subsequently, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichlormethane (93 mg, 0.11 mmol) and copper(I)iodide (108 mg, 0.57 mmol) were added. The reaction mixture was heated to 85° C. for 5 hours, cooled to room temperature, diluted with ethyl acetate and filtered over Celite. The residue was extracted 3 times with water. The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:cylcohexane) to afford the title compound (104 mg, 20% yield).
Reaction SMILES: C[O:2][C:3]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:19])(=[O:18])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[S:26]([CH3:29])(=[O:28])=[O:27].[Cl-].[Li+].Cl>CN(C)C=O>[OH:2][C:3]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:18])(=[O:19])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: COc1c(C(F)(F)F)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
3-(4-methoxy-3-methylsulfonyl-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (305 mg) was dissolved in N,N-dimethylformamide (3 mL), and lithium chloride (288 mg) was added to the solution, and then the mixture was stirred at 70° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (288 mg) as a colorless crystal.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]([NH:17][CH3:18])[CH3:16])[N:14]=1)=[O:8].[F:23]C1C=C(C=CC=1)CN=C=O>>[F:23][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]([NH:17][CH3:18])[CH3:16])[N:14]=1)=[O:8]
Reactant: CNC(C)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: O=C=NCc1cccc(F)c1
Product: CNC(C)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
The 1-(3-fluorobenzyl)-3-(4-(1-(methylamino)ethyl)thiazol-2-yl)urea was prepared following the same procedure described for Intermediate 10a using 3-fluoro-benzyl isocyanate in step one.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: S=C(NCc1ccccc1)Nc1ccccc1

Procedure:
To a stirred solution of 74.6 g (0.5 mol) of benzylisothiocyanate in 500 mL toluene was added dropwise 46.6 g (0.5 mol) of aniline. The solution was refluxed 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from an appropriate solvent to yield N-phenyl-N'-benzylthiourea. Isothiocyanates which are not commercially available may be prepared from aliphatic or aryl primary amines by the following methods: Kurita and Iwakura, Org. Synth. 59, 195; Jochims, Chem. Ber. 101, 1746 (1968); or Castro, Pena, Santos, and Vega, J. Org. Chem. 49, 863 (1984).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].[NH4+].[OH-]>O>[C:27]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1(Nc2cccc(F)c2)CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(N(C(C)=O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 0.2 g (0.56 mmol) ethyl 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carboxylate in 2.6 mL (28 mmol) acetic anhydride (neat) was heated to 120° C. for 20 hr, then poured into 50 mL of a 1:1 mixture of water and concentrated NH4OH, extracted with 100 mL EtOAc, washed with water then brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge 0-5% MeOH/CH2Cl2) over 15 min) afforded ethyl 4-[acetyl(3-fluorophenyl)amino]-1-benzylpiperidine-4-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 1H); 7.20-7.31 (m, 4H); 7.06-7.15 (m, 4H); 4.25 (q, J=7.14 Hz, 2H); 3.46 (s, 2H); 2.59 (br m, 2H); 2.30-2.48 (m, 3H); 2.22 (m, 2H); 1.72 (s, 3H) 1.63 (m, 2H); 1.31 (t, J=7.15, 3H). Electrospray mass spectrum M+H=399.2
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[N+:7]([O-])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1.C(OP(OCC)OCC)C>>[CH3:1][C:2]1([CH3:20])[C:6]2[N:7]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1
Reactant: CC1(C)OC(C)(C)c2c1nnc(-c1ccccc1)[n+]2[O-]
Agent: CCOP(OCC)OCC
Product: CC1(C)OC(C)(C)c2nc(-c3ccccc3)nnc21

Procedure:
A mixture of 5.42 g. (0.02 mole) 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro[3,4-e]-as-triazine-4-oxide and 70 ml. triethylphosphite is refluxed under nitrogen for 18 hours at a bath temperature of 180°C. The solvent is removed in vacuo and the residue recrystallized from aqueous ethanol to give 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro[3,4-e]-as-triazine, m.p. 90°-91°C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CS(C)=O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To 0.170 g (0.53 mmol) of 1-benzyl-5-chloro-3-chloromethylcinnolin-4(1H)-one in 6 mL of dimethylsulfoxide was added 0.050 g (1.3 mmol) of sodium borohydride. The reaction was stirred at room temperature for 3 h and diluted with water. The resulting precipitate was collected and dried to give 0.140 g (92%) of the title compound as a fluffy cream colored solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:9][CH2:10][NH:11][C:12]1[N:17]2[N:18]=[C:19]([CH3:34])[C:20]([C:21]3[C:26]([Cl:27])=[CH:25][C:24](OS(C)(=O)=O)=[CH:23][C:22]=3[Cl:33])=[C:16]2[N:15]=[C:14]([CH3:35])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CS(C)=O>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:5][C:6](=[O:7])[C:24]1[CH:23]=[C:22]([Cl:33])[C:21]([C:20]2[C:19]([CH3:34])=[N:18][N:17]3[C:12]([NH:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:13][C:14]([CH3:35])=[N:15][C:16]=23)=[C:26]([Cl:27])[CH:25]=1
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(OS(C)(=O)=O)cc3Cl)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)c(-c2c(C)nn3c(NCCN(C(=O)OC(C)(C)C)C4CCOCC4)cc(C)nc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 176.1 %

Procedure:
A suspension of methanesulfonic acid 4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenyl ester (188 mg, 0.276 mmol) from Example 134, step B, 1,3-bis(diphenylphosphino)propane (30 mg 0.073 mmol), triethylamine (0.10 mL), and palladium(II) acetate (25 mg, 0.11 mmol) in methanol (3.5 mL)/dimethylsulfoxide (3.5 mL) was degassed with a stream of carbon monoxide and then shaken for 4 hours at 70° C. under 40 psi carbon monoxide. The mixture was filtered through Celite, diluted with ethyl acetate and washed with water, dried (Na2SO4), concentrated under reduced pressure, and chromatographed (3:1 to 1:1 hexanes/ethyl acetate) to afford the product (144 mg, 88%): +APcI MS (M+1)+592; 1H NMR (CDCl3) δ: 8.04 (s, 2H), 5.83 (br s, 1H), 3.92 (s, 3H), 2.43 (s, 3H), 2.24 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4]([O:8][C:9]([NH:11][C:12]1[C:17]([C:18]([O:20]C)=O)=[CH:16][C:15]([F:22])=[N:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[F:22][C:15]1[N:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[C:17]([C:18](=[O:20])[CH2:2][C:1]#[N:3])[CH:16]=1
Reactant: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Reactant: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)CC#N
Reaction time: 1 h

Procedure:
To 140 mL of 2.5 M n-butyllithium/hexanes in 300 mL of tetrahydrofuran at −78° C. was slowly added 14.4 g of anhydrous acetonitrile in 100 mL of tetrahydrofuran. After 30 minutes was added 32 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester in 100 mL of tetrahydrofaran. After a further 60 minutes, the reaction was quenched with 35 mL of glacial acetic acid. The reaction was diluted with equal volumes of ethyl acetate and saturated sodium bicarbonate and the aqueous phase was washed twice with ethyl acetate. The pooled organic phases were washed with saturated sodium bicarbonate, dried, and stripped of solvent. This material was further purified by passing through a plug of silica gel with a gradient of 0-5% methanol/chloroform to give a crude product that was used as is for the following step. This material can be further purified by recrystallization from chloroform/hexanes to give a white, crystalline solid: melting point 106-115° C.; mass spectrum (m/e): M+H 279.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Br
Temperature: 25 °C
Yield: 98.1 %

Procedure:
1-Bromo-2-methoxy-benzene (1.87 g, 10.0 mmol) was dissolved in chloroform (5 mL) and the solution was cooled in an ice-salt bath to −5° C. to 0° C. The cooled solution was carefully charged with chlorosulfonic acid (2.0 mL, 30.0 mmol) over 30 minutes and the mixture was allowed to warm to room temperature over 1 hour. The mixture then was poured onto chopped ice and transferred to a separatory funnel. The aqueous layer was separated and extracted (×2). The combined organic layers were dried and concentrated to give 3-bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 98%).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(#N)C.[SH2]=N>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: N=[SH2]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -1 °C
Reaction time: 0.5 h

Procedure:
A solution of 110.6 g (0.475 mol, 95% assay) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 25.2 g (0.6 mol) of cyanamide in 600 mL of acetonitrile was cooled to −5° C. To this solution was added 750 g (0.575 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 45 min with the temperature kept below 0° C. The reaction mixture was allowed to stir at −1° C. for 30 min. To the mixture was added 9.5 g (0.05 mol) of sodium metabisulfite in 25 mL of water and the two phase mixture was allowed to settle. The aqueous phase was reextracted 2×'s with 50 mL of acetonitrile. The organics were combined and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 40:54 (area) ratio of two isomers.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[C:23]([CH:24]=O)=[CH:22][N:21]=[CH:20]2)=[CH:16][CH:15]=1)#[N:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(C(Cl)Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:24][C:23]3[N:19]([CH2:18][C:17]4[CH:26]=[CH:27][C:14]([C:12]#[N:13])=[CH:15][CH:16]=4)[CH:20]=[N:21][CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCc3ccc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (0.742 g, 3.5 mmol) in CHCl2CHCl2 (15 mL) was added 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (0.812 g, 3.85 mmol), 4 Å sieves and NaBH(OAc)3 (1.11 g, 5.25 mmol). The mixture was stirred at room temperature for 16 h. and a further portion of NaBH(OAc)3 (0.55 g, 2.6 mmol) was added. After an additional 24 h the mixture was diluted with EtOAc, filtered through celite, washed with brine, dried (Na2SO4) and concentrated. The residue was stirred in 2N Hcl (50 mL) for 2 h. then extracted with ether. The aqueous layer was basified with 6N KOH and extracted 3× CH2Cl2 which was then washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. Crystallization from ether afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].Br[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:1]([CH:3]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCCBr
Reactant: CCCCC(CC)Nc1ccccc1
Product: CCCCC(CC)N(CCCC)c1ccccc1

Procedure:
N-(1-ethylpentyl)-N-butylaniline was prepared from N-(1-ethyl-pentyl)aniline and bromobutane using the same method as Example 2ii).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:40])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:36])[F:37])=[CH:18][N:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(2-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (2.249 g, 4.38 mmol) was dissolved in methanol (220 mL) and 37% formaldehyde solution (0.483 mL, 17.5 mmol) was added. After five minutes sodium tris(acetoxy)borohydride (4.641 g, 21.9 mmol) was added and stirring continued at room temperature for two hours. The volatiles were evaporated and the residue suspended in 5% aqueous sodium hydroxide (200 mL), The resuiting mixture was extracted with ethyl acetate (5×200 mL) then the combined organic phases were washed with brine (500 mL), dried over sodium sulfate and evaporated. The residue was evaporated from ether and the solvent traces removed under high vacuum to give the title compound (3) (2.196 g, 95% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (s, 1H), 7.28-7.22 (m, overlaps with CHCl3), 6.88 (dd. J=8.3, 18 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.16-3.06 (m, 4H), 2.99 (d, J=12.1 Hz, 2H), 2.48 (tt, J=10.5, 5.9 Hz, 1H), 2.34 (s, 3H), 2.07 (td, J=11.1, 4.1 Hz, 2H), 1.89-1.77 (m, overlaps with water). LCMS Method C: rt 4.94 min; m/z 528.1 [M+H]+, 550.1 [M+Na]+; m/z 526.2 [M−H]−.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 1.39 mmol) in methanol (13.9 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (40 mg, 0.20 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.49 g, 77%) as an off-white solid: HR-ES-MS m/z calculated for C23H29N4O5F [M+H]+ 461.2195, observed 461.2194; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.32-1.48 (m, 1H), 1.48-1.63 (m, 1H), 1.63-1.82 (m, 1H), 2.29 (s, 3H), 3.17-3.30 (m, 2H), 3.68-3.79 (m, 1H), 3.79-3.91 (m, 1H), 4.07 (dd, J=13.4, 3.8 Hz, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.81-4.89 (m, 2H), 4.92 (d, J=5.4 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 7.08-7.18 (m, 1H), 7.24-7.35 (m, 2H), 7.51 (d, J=2.0 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>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:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1F
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+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (302.9 mg, 0.661 mmol), 2-fluoro-3-pyridineboronic acid (102 mg, 0.727 mmol), potassium carbonate (457 mg, 3.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (38.2 mg, 0.033 mmol). The vial was flushed with Ar (g), then dioxane (3306 μL) and water (1.7 mL) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL) and brine (15 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid. Step 2: A vial was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (110 mg, 0.257 mmol), DavePhos (12.16 mg, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium(0) (11.79 mg, 0.013 mmol). The vessel was flushed with Ar(g), then lithium bis(trimethylsilyl)amide (772 μL, 0.772 mmol) (1.0 M solution in THF) and 2,2-dimethylmorpholine (61.8 μL, 0.515 mmol) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for two hours. The mixture was diluted with saturated aq. ammonium chloride solution (20 mL) and water (10 mL). The mixture was extracted with DCM (3×20 mL), leaving behing a dark oily solid. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on an 24-g Redi-Sep Gold column with 0-70% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-(2,2-dimethylmorpholino)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](OCC)=[O:14].[H-].[Na+].O>C(COC)OC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([CH:13]=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCc1ccco1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C=O)Cc1ccco1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of ethyl 3-(2-furanyl)propionate (33.77 g) and ethyl formate (22.22 g) was added dropwise with stirring to a pre-cooled (0° C.) suspension of sodium hydride (50% in oil; 8.45 g) in dimethoxyethane (70 ml) maintaining the temperature below 0° C. throughout the addition. The reaction mixture was allowed to warm to room temperature then poured on to ice and water and extracted with ethyl acetate. The aqueous layer was acidified to pH 4 and re-extracted with ethyl acetate. These second ethyl acetate extracts were combined dried (MgSO4) and evaporated at reduced pressure to yield ethyl 3-(2-furanyl)-2-formylpropionate (19.0 g).