Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=[S:26]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Yield: 82.3 %

Procedure:
2,2-Dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.4 g) and Lawesson's reagent (6.19 g, 1.0 eq.) were suspended in toluene (100 ml). The reaction mixture was refluxed for one hour. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-100%) to give 2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (3 g, 82% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[C:33](Cl)=[O:34])[CH3:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:31]=[CH:32][C:23]=3[O:22][CH2:20][CH3:21])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CCOc1ccc2ccccc2c1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-ethoxy-1-naphthoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo [4,5-c]quinolin-1-yl)butyl]-2-ethoxy-1-naphthamide as a white powder, m.p. 219° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J=5.8 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.87-7.84 (m, 1H), 7.64-7.56 (m, 2H), 7.47-7.22 (m, 5H), 6.60 (s, 2H), 4.69 (t, J=7.2 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.37 (m, 2H), 2.01 (m, 2H), 1.64 (m, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) m/e 453.2157 (453.2165 calcd for C27H27N5O2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: OCCCN1CCOCC1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(O)ccc2c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCCCN3CCOCC3)ccc2c1=O
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
7-Hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (750 mg, 2.7 mmol) was suspended in methylene chloride (40 ml) at 5° C. and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added. The mixture was stirred for 5 minutes and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes at 5° C. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The solution was then purified directly by column flash chromatography eluting with methylene chloride, and then ethyl acetate, acetonitrile/ethyl acetate (20/80), and acetonitrile/ethyl acetate/ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 7-(3-morpholinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin4-one (745 mg, 68%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:25]Br>C(Cl)(Cl)(Cl)Cl>[Br:25][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:13])=[O:14])=[CH:8][CH:9]=2
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ncc(Br)cc2c1)C(F)(F)F
Temperature: 25 °C
Yield: 26.1 %

Procedure:
To a mixture of trifluoromethanesulfonic acid quinolin-6-yl ester (3.88 g, 14 mmol) and pyridine (2.26 mL, 28 mmol) in CCl4 (50 mL) was added bromine (0.86 mL, 16.8 mmol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 1.3 g of trifluoromethanesulfonic acid 3-bromo-quinolin-6-yl ester: 1H NMR (300 MHz, CDCl3) δ: 7.62 (m, 1H), 7.68 (d, 1H), 8.20 (d, 1H), 8.36 (m, 1H), 8.98 (d, 1H); MS (m/z) 356 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)#[CH:2].[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>CN(C=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.[Cu]I>[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH:8]=4)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: C#Cc1cncc(CN2CCCC2)c1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Ethynyl-5-(pyrrolidin-1-ylmethyl)pyridine (0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (as prepared above), 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF is stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])[C:3]=1[CH2:20]OC1CCCCO1.O=S(Cl)[Cl:30].O>C(Cl)Cl>[Cl:30][CH2:20][C:3]1[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (100 mg. 0.26 mmol) was dissolved in DCM (5 mL). SOCl2 (97 μL. 1.31 mmol) and water (25 μL) were added and the reaction mixture was stirred for 1 h at RT. After removal of the solvents in vacuo the resulting title compound was used for the next reaction without purification. MS (m/z): 317.0 [M+H+].
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
0.57 g of 2'-deoxy-5-n-propyluridine, 0.6 g of triphenylphosphine and 0.69 g of sodium azide were stirred in 20 ml of dry dimethylformamide. 0.77 g of carbon tetrabromide was added over a period of 5 minutes. The mixture was stirred at room temperature for 72 hours, 20 ml of methanol were added and the mixture was stirred for a further 0.5 hour. The mixture was evaporated and the residue was stirred with a mixture of 25 ml of dichloromethane/methanol (8:2). An insoluble solid was removed by filtration and the filtrate was chromatographed on 200 g of silica gel in the same solvent mixture to give 0.41 g of 5'-azido-2',5'-dideoxy-5-n-propyluridine of melting point 177°-179° C. (decomposition).
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([SH:10])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:2][C:3]1[CH:9]=[C:8]([S:10][C:18]2[CH:17]=[CH:16][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[Cl:12])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5]
Reactant: Nc1cc(F)c(S)cc1F
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(F)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 6 h
Yield: 69 %

Procedure:
3.00 Grams of 2,5-difluoro-4-mercaptoaniline hydrochloride, 6.60 g of 3,4-dichlorobenzotrifluoride and 4.90 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 6 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 100-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 3.60 g of 2,5-difluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:19]=[C:20]([CH3:25])[C:21](C)=[CH:22][CH:23]=1)([O-:17])=[O:16]>CCOCC>[CH3:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-6-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [Na].[CH:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([C:17]#[N:18])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23]>>[CH:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([C:17](=[NH:18])[O:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: COCCO
Agent: [Na]
Product: COCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
20 ml of 2-methoxyethanol are treated portionwise at 60° C. with 0.23 g of sodium. After 30 minutes, 2.2 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile are added and the mixture is stirred at 80° C. for 1 hour. Subsequently, the 2-methoxyethanol is distilled off at reduced pressure. The residue is poured on to ice-water and the resulting mixture is extracted twice with methylene chloride. The combined extracts are washed twice with water, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with ethyl acetate and increasing amounts of ethanol as the eluent, and there is obtained 2-methoxyethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 296 (6), 237 (45), 194 (100), 178 (74), 165 (49).
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5])=[N-].[ClH:11].CCOCC>C(O)C>[Cl:11][CH2:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5]
Reactant: Cl
Reactant: [N-]=[N+]=CC(=O)c1cscn1
Solvent: CCOCC
Solvent: CCO
Product: O=C(CCl)c1cscn1

Procedure:
4-Thiazolyl diazomethyl ketone, 0.1 g, is treated in 1 ml ethanol at 0° with HCl gas for a few seconds. Dilution with ether and scratching produces a copious white ppt which is filtered and washed 3× with ether, taken up in water, the pH made to 7 with K2HPO4, and extracted 3× with ether. The ether solution is dried with MgSO4, filtered and evaporated, affording 77 mg 4-thiazolyl chloromethyl ketone. IR (CHCl3) 5.85μ. NMR (δ, CDCl3): 4.95d, J=1, CH2Cl; 8.4m, 8.95m, J=1, H-2 and H-5.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: c1cnn(C2CC2)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1cnn(C2CC2)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a golden solution of 1-cyclopropyl-1H-pyrazole (2.360 g, 22 mmol) in 100 mL chloroform, was added bromine (1.2 ml, 24 mmol) as a soln in 100 mL CHCl3 dropwise over 1.5 h. the mixture was heated in oil bath to 60 C for 2 h. The mixture was allowed to cool to RT, washed with sat NaHCO3, dried over Na2SO4, filtered and evaporated to afford the title compound as a tan liquid (3.64 g).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[S:23](Cl)(=[O:25])=[O:24]>>[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH:11][S:23]([C:15]1[S:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)(=[O:24])=[O:25])[CH3:4]
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Reactant: CCOC(=O)[C@H](C)NCCN
Agent: Cl
Product: CCOC(=O)[C@H](C)NCCNS(=O)(=O)c1nc2ccccc2s1

Procedure:
N-(2-Aminoethyl)-alanine ethylester 2HCl, prepared as described by Puschl (A. Puschl et al., Tetrahedron, 1998, 39, 4707.), was reacted with benzothiazole-2-sulfonyl chloride as per the procedure of Example 1 to give the title compound. 1H NMR (500 MHz; DMSO-d6) δ 8.27 (d, 1H), 8.18 (d, 1H), 7.69˜7.62 (m, 2H), 4.01 (q, 2H), 3.17 (q, 1H), 3.13 (t, 2H), 2.61 (m, 1H), 2.49 (m, 1H), 1.13 (t, 3H), 1.06 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH:17][CH3:18].O.[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:17]([CH3:18])[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (6.8 g, 32.69 mmol) and dimethylamine in 33 wt. % solution in water (9.25 g, 98 mmol) in methanol (200 mL) was stirred at room temperature for overnight. Sodium borohydride (1.85 g, 49 mmol) was added by portions with ice cooling. After the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 ml×3). The extract was dried over anhydrous sodium sulfate and concentrated to give crude title compound (7.0 g, yield 90%), which was used in the next step without further purification. LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][CH2:31][CH2:32]I>C(#N)C.O>[F:30][CH2:31][CH2:32][N:22]1[CH2:21][CH2:20][C:6]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1
Reactant: FCCI
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CCF)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (60 mg, 0.19 mmol) was dissolved in acetonitrile (1 mL). Potassium carbonate (82 mg, 0.9 mmol) and 1-Fluoro-2-iodo-ethane (45 mg, 0.25 mmol) were added and stirred at RT for 1 h. The reaction mixture was heated at 80° C. for 1 h. After 1 h the reaction mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtained 33 mg of desired product. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.62 (d, 2H), 7.80 (d, 2H), 7.42 (s, 1H), 7.36 (s, 1H), 7.10 (m, 2H), 5.05 (m, 1H), 4.92 (m, 1H), 4.65 (s, 2H), 3.82 (m, 3H), 3.78 (m, 1H), 3.20 (m, 2H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.O.[NH2:32][NH2:33]>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[CH:8]1[C:17]2=[N:32][NH:33][C:19](=[O:21])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nnc(C)n1C)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: Cc1nnc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of ethyl 3-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg) in 85% hydrazine monohydrate (1 mL) and methanol (3 mL) was stirred at 25° C. for 3 h. The mixture was purified by prep-HPLC to obtain the title compound as a yellow solid (40 mg, yield: 26%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.23 (s, 3H), 3.38 (s, 3H), 4.78-4.80 (d, J=11.0 Hz, 1H), 4.99-5.02 (d, J=11.0 Hz, 1H), 7.11-7.18 (m, 3H), 7.35-7.40 (m, 2H), 7.47-7.51 (m, 2H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 377 (M+1)+.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.O>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccc(-c2ccccc2)cc1)OCc1ccccc1
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a suspension of 3-(biphenyl-4-yl)propanoic acid (5 g, 22.10 mmol) and K2CO3 (6.11 g, 44.2 mmol) in DMF (22 ml), BnBr (3.94 ml, 33.1 mmol) was added. After stirred for 15 hours, additional BnBr (3.94 ml, 33.1 mmol) was added. After stirred for further 22 hours, the reaction was diluted with H2O, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was diluted with EtOAc (150 ml), and NH-silica gel was added to the suspension. The EtOAc was evaporated, and the resulted slurry was allowed to stir for 1 hour. The slurry was eluted with 10% EtOAc/heptane (150 ml) to give benzyl 3-(biphenyl-4-yl)propanoate (6.16 g); Retention time=1.71 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (t, J=7.8 Hz, 2H) 3.01 (t, J=7.8 Hz, 2H) 5.12 (s, 2H) 7.21-7.47 (m, 14H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C@H:10]([OH:16])[CH2:9]1)=O)(C)(C)C.[ClH:17].CC(OC)(C)C>CCO>[ClH:17].[CH2:12]1[C:11]2([CH2:14][CH2:15][NH:8][CH2:9][C@H:10]2[OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Product: O[C@@H]1CNCCC12CC2
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of (S)-4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (3.26 g, 14.3 mmol) in EtOH (10 ml) was treated at RT with HCl solution (4 M in 1,4-dioxane, 30 ml), then after 1 h TBME (40 ml) was added. The suspension was stirred for 1 h, then the precipitate was collected by filtration to afford the title compound (2.11 g, 90%). White solid, MS: 128.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=[C:4]([NH:25][CH2:26][C@@H:27]([OH:29])[CH3:28])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
In a two-necked round-bottom flask, [4-[2-chloro-6-(2(S)-hydroxy-propylamino)-pyrimidin-4-yl]-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile (370 mg, 0.9 mmol), 3-pyridine boronic acid (143.27 mg, 1.17 mmol), bis(triphenylphosphine)palladium (II) dichloride (18.88 mg, 0.027 mmol), and potassium carbonate (75.98 mg, 0.72 mmol) were dissolved in a mixture of acetonitrile and water (10 mL, 1:1, v/v) through which nitrogen gas was then flowed for 10 min and heated at 75° C. for 3 hours. After completion of the Suzuki coupling reaction, the reaction mixture was dissolved in water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under vacuum. The purification of the concentrate by chromatography produced the title compound (274 mg, 67.1%).