Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2OCC[O:9]2)[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[CH:22](OC)(OC)OC>>[NH:20]1[C:17]2[CH:18]=[CH:19][C:14]([O:13][C:3]3[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=3[Cl:1])=[CH:15][C:16]=2[N:21]=[CH:22]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1N
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)c(Cl)c1

Procedure:
Crude 4-{[2-chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-1,2-benzenediamine was heated to reflux in 5 mL of trimethyl orthoformate for 2 hours. The reaction mixture was then concentrated and purified by preparative HPLC, with conconiment loss of the dioxolane protecting group. The HPLC fractions were combined and diluted with 1N NaOH, extracted with ethyl acetate, dried over MgSO4 and concentrated to give 4-(1H-benzimidazol-5-yloxy)-3-chlorobenzaldehyde. (M+1) 272.9, 1.65 min (LC/MS method B)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][N:19]([CH3:38])[C:20]1[CH:37]=[CH:36][C:23]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]2)=[CH:22][CH:21]=1>CCCCCC.CS(C)=O>[CH3:38][N:19]([CH3:18])[C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C@@H:28]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:27]2)=[CH:36][CH:37]=1
Reactant: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (160 mg, 4.0 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (12 ml). After stirring at room temperature for 30 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (790 g, 4.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes and then at 50° C. for 60 minutes. A solution of (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxypyrrolidine (378 mg, 1.21 mmol) in dimethyl sulfoxide (7 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was poured into ice/water. After the extraction with ethyl acetate, the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with hexane and ethyl acetate (3:1) and finally with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (196 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[C:33](OC(=O)C)(=O)[CH3:34]>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:20])[C:3]=1[OH:21])[O:19][C:33]([CH3:34])=[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH:8]2[OH:18]
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)c(C)c2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(C)Oc3c(cc(Cl)c(O)c3C)C2O)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(5-chloro-2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) in an. DMF (7 ml) was added K2CO3 (3 eq). Acetic anhydride (3 eq) was added dropwise to the solution, which was then refluxed under nitrogen whilst stirring for 5 h. The solution was taken up in water and extracted using ethyl acetate, dried over MgSO4 and concentrated in vacuo to give 6-chloro-3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol as a crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][C:15](=[O:17])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2sccc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of step b) (˜165 mmol) was dissolved in 1 L of DCM. DMF (100 uL) was added followed slowly by oxalyl chloride (21.7 mL, 247 mmol). After 1 hour the reaction was concentrated to dryness and the crude material was re-dissolved in DCE (1 L). AlCl3 (55 g, 410 mmol) was carefully added and the reaction was stirred at room temperature for ½ hour. The crude reaction was quenched with ice, diluted with EtOH (300 mL), washed with water (3×), and dried over MgSO4. The title product was purified by silica gel chromatography (30% EtOAc in Hexanes) to give 10.5 g of the subtitle compound as an off-white solid. MS: ESI (positive): 240 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].[CH:10]1[CH:15]=C[NH+]=CC=1.[Br:16][Br-]Br>C(O)(=O)C>[Br:16][CH:3]([CH:2]([CH3:9])[CH3:1])[C:4](=[O:8])[C:5]([O:7][CH2:15][CH3:10])=[O:6]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(Br)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
To a solution of 4-methyl-2-oxopentanoic acid (5 g) in acetic acid (40 ml) was added pyridine hydrobromide perbromide (12.3 g) and the mixture stirred at 20° C. for 18 hr, then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with water (100 ml), separated by hydrophobic frit and evaporated. The residue was taken up in ethanol (100 ml) and treated with concentrated sulphuric acid (1 ml) and heated at reflux for 18 h, then concentrated in vacuo to approx 30 ml. The mixture was diluted with water (250 ml) and extracted with diethyl ether (100 ml), dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (5.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=[O:9])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=[O:9])=[CH:4][C:3]=1[O:12][CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=CC=O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=CC=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
4-Hydroxy-3-methoxycinnamaldehyde (0.6 g) was added to the mixture of benzyl chloride (1 mL), K2CO3 (1 g), and NaI (1 g) in acetone (20 mL). The resulting mixture was stirred at room temperature for 24 hrs. The solid were removed by filtration and washed with acetone. After evaporation of solvent, the crude product was purified by gradient chromatography to give a yellowish solid. Yield 85%.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([O:8][C:9]([O:11]C(OC(C)(C)C)=O)=O)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([N:2]([CH3:1])[NH2:3])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCO
Product: CN(N)C(=O)OC(C)(C)C

Procedure:
10 mL of methyl hydrazine was dissolved in 90 mL of ethanol, and under stirring at ice-cooling, a solution of 41 g of di-tert-butyldicarbonate in 90 mL of ethanol was added dropwise over 45 minutes. After stirring at room temperature for 7 hours, the solvent was evaporated, to afford 24.7 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.C(=O)(O)[O-].[Na+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].CN(C=O)C>O>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([Br:1])=[CH:3][C:4]=1/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(F)c(Br)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Br)c(F)cc1N
Temperature: 100 °C
Yield: 77.3 %

Procedure:
To a vial was added, 4-bromo-5-fluoro-2-iodoaniline (5.67 g, 17.95 mmol), PdOAc2 (0.201 g, 0.897 mmol), sodium bicarbonate (3.77 g, 44.9 mmol), ethyl acrylate (2.049 ml, 18.85 mmol) and DMF (12.0 ml). The reaction was heated for 3 hour at 100° C. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was triturated with heptane overnight and then filtered to afford (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate (4.00 g, 13.88 mmol, 77% yield) as a light yellow solid. m/z (ESI) 288.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:24](Br)[C:25]#[CH:26]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:26][C:25]#[CH:24])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Reactant: C#CCBr
Solvent: CS(C)=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7 g (7.7 mmole) the product of step A, 1.1 g (8.0 mmole) KCO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 184° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:16][CH3:17])=[N:8][N:9]3[C:14]([I:15])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([S:16][CH3:17])=[N:8][N:9]3[C:14]([I:15])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:24][CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH2:2][CH2:3]1
Reactant: CSc1nn2c(I)cccc2c1NCC1CC1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (70 mg) in tetrahydrofuran (2.5 mL) was added tetrahydropyran-4-carbaldehyde (56 mg) at room temperature, and then sodium triacetoxyborohydride (103 mg) was gradually added. After 1 hour, saturated aqueous sodium bicarbonate was added, extraction was performed with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford a crude product of the title compound (50 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][CH2:10][CH2:11]Br>CC#N>[Br:9][CH2:10][CH2:11][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrCCBr
Reactant: Nc1cccc(Cl)c1
Solvent: CC#N
Product: Clc1cccc(NCCBr)c1
Temperature: 80 °C
Yield: 9.8 %

Procedure:
A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73 g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated on rotavap and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to isolate N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid. To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46 mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). The resulting mixture was stirred at 70° C. for 2 days. It was partitioned in EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAC (50 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolated (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 74.4%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:15])[CH2:13][C:12](=[O:14])[O:11][C:9]1=[O:10].[C:16](C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].[N+](=C)=[N-].CCOCC.[NH4+].[Cl-]>C1COCC1.C(O)(=O)C>[CH3:7][C:8]([CH3:15])([CH2:9][OH:10])[CH2:13][C:12]([O:11][CH3:16])=[O:14]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: C=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)CO
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To a suspension of LAH (lithium aluminum hydride) (4.9 g, 0.129 mol) in THF (300 mL) maintained at -78° C. was added during 45 min a solution of 2,2-dimethylsuccinic anhydride (16.5 g, 0.129 mol) in THF (350 mL). After 45 min of vigourous stirring the reaction mixture was warmed to -60° C. and pourred into 1M aqueous sodium potassium tartrate (500 mL) and stirred for 2 h at r.t. The mixture was then acidified with acetic acid (150 mL) and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The residual oil was dissolved in ether and a solution of diazomethane in ether (about 300 mL, 0.15 mol) was added until the yellow color remained. An aqueous solution of NH4Cl was added and the ester was extracted with EtOAc and dried over MgSO4. The oil was purified by flash chromatography with 2:3 EtOAc:hexane to yield the title compound (13.5 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)CCCCl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester (1.0 g, 3.16 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 4-Chlorobutyryl chloride (0.446 g, 3.16 mmol) was dissolved in THF (10 mL) and added dropwise to the mixture over 5 min. The mixture was stirred at 0° C. for 0.5 h. and then at 23° C. for 1 h. The solvent was removed in vacuo and the concentrate chromatographed over silica gel (1:4 to 1:0 EtOAc:hexane gradient) to give the title compound (1.33 g, 100%) as a pale yellow foam.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]4[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:27]=4[N:28]=3)=[CH:18][CH:17]=2)=[CH:14][N:13]=[CH:12]1.O>CS(C)=O>[OH:10][CH2:9][CH2:8][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:25]1[C:26]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:27]=2[N:28]=[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]3[O:11][CH:12]=[N:13][CH:14]=3)=[CH:21][CH:20]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: OCCNc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 70 °C
Yield: 76.7 %

Procedure:
2-(Phenylamino)ethanol (0.051 g, 0.37 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.37 mmol, Example 1b) in DMSO (3 mL). The reaction mixture was heated in a microwave reactor at 70° C. for 3 h. Water (1 mL) was added to the solution and the precipitate was washed with water and filtered to give tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, 77%). No further purification. MS (ESI+)/(ESI−) m/z 529/527
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:19]
Reactant: COC(=O)Cc1nc(-c2ccc(Br)cc2)oc1C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1nc(-c2ccc(Br)cc2)oc1C
Temperature: 50 °C
Yield: 46 %

Procedure:
[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (11.6 g, 37.4 mmol) is dissolved in anhydrous tetrahydrofuran (150 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (28 mL of 2M soln., 56.1 mmol) is slowly added to the solution at room temperature. This is then heated to 50° C. for 6 hours. The solution is allowed to cool to room temperature and methyl iodide (7.0 mL, 112 mmol) is added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acid methyl ester (5.57 g, 17.19 mmol) is isolated in 46% yield after column chromatography. The racemic 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl)-propionic acid methyl ester is resolved on a Chiralcel OJ column (4.6×250 mm). Eluted with 40% isopropanol in heptane with 0.2% dimethy-ethylamine at 1 mL per minute with detection at 260 nM and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 99.4% ee).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][OH:12])=[C:4](O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][CH2:11][O:12]2
Reactant: OCCCc1c(O)cccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cccc2c1CCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a solution of 3-chloro-2-(3-hydroxypropyl)phenol (0.56 g; 3 mmol) and triphenylphosphine (1.02 g; 3.90 mmol) in tetrahydrofuran (42 mL) was added diisopropyl azadicarboxylate (0.766 mL; 3.90 mmol), the reaction mixture was stirred at room temperature for 4 h and the volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-80%) in heptane furnished 0.121 g (24%) of 5-chlorochroman.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.O.[OH-].[Li+]>CO>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCCCC2)c1C(F)(F)F
Temperature: 80 °C
Yield: 86.3 %

Procedure:
Cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.265 g, 0.91 mmol) was dissolved in methanol (1.4 mL). Water (1.4 mL) and lithium hydroxide (0.029 g, 1.21 mmol) were added and the mixture was heated at 80° C. for 1.5 hours. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added to the residue and then removed in vacuo to ensure complete removal of the methanol. 6N HCl was added to the aqueous residue to pH 2-3, resulting in precipitation of a solid. The solid was collected by filtration, washed with water and dried under high vacuum at 100° C. to give 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.206 g, 86%). Mass spectrum: m/z: 263.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:18][C:17]([Cl:33])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Cl:33][C:17]1[CH:18]=[C:19]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.9 %

Procedure:
To a solution of 4-[5-chloro-3-(3-trifluoromethyl-benzoylamino)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.40 g, 2.89 mmol) in methylene chloride (100 mL) is added hydrogen chloride (3.00 mL, 12 mmol) as a 4.0 M solution in 1,4-dioxane. The mixture is stirred at room temperature for 2 days during which time a solid precipitates from solution. The off-white solid is collected by filtration, washed with methylene chloride and dried on the filter pad to afford 1.20 g of N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-3-trifluoromethyl-benzamide in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccc(F)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 3-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide. LC/MS m/e obsd. (ESI−) [(M−H)−] 443.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:18][CH2:19][N:20]=[N+:21]=[N-:22])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].N1NN=C(COC2C=CC(N3C=NN=N3)=NC=2)C=1>>[C:12]([O:18][CH2:19][N:20]1[C:10]([CH2:9][O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:22]=[N:21]1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C#CCOc1cccnc1C
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Product: Cc1ncccc1OCc1cnnn1COC(=O)C(C)(C)C

Procedure:
The title compound was synthesized using 2-methyl-3-(prop-2-ynyloxy)pyridine and azidomethyl pivalate in a manner similar as that described in Intermediate 13, Step 3.