Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[N:20]=[CH:21][CH:22]=[N:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 70.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinoxalin-5-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-8) 586 mg (0.80 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 288 mg (71%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([NH:20][C:21]1[CH:30]=[C:29]([O:31]C)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[C:12]([NH:20][C:21]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
0.94 g of aluminum chloride was added to 7 mL of toluene solution containing 0.67 g of methyl 2-(benzamido)-4-methoxybenzoate at room temperature and stirred at 80° C. for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added and a solid substance was separated by filtration to obtain 0.23 g of methyl 2-(benzamido)-4-hydroxybenzoate as white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:6]=1)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2ccccn2)nn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1nc(-c2ccccn2)nc1C=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
The acetal from step 2, 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]pyridine (11.06 g, 0.042 mol) was dissolved in 1.5 equiv of 2 N HCl (aq) and stirred at 40-50° C., overnight. The mixture was concentrated, yielding a viscous oil, which was then basified to pH 10 using saturated aqueous Na2CO3. The mixture was then extracted using ethyl acetate (4×200 mL), the organic layer dried over Na2SO4, filtered and concentrated, to a yellow solid. The solid was dissolved in a minimal amount of hot ethyl acetate, scratched and diluted with hexanes to recrystallize the product, affording 3.6 g (45%) of the desired aldehyde as a yellow powder. 1H NMR (300 MHz, CDCl3): δ 4.28 (s, 3H), 7.46 (m, 1H), 7.82 (m, 1H), 8.15 (m, 1H), 8.78 (m, 1H), 10.08 (s, 1H). MS (APCI) calcd for C9H8N4O: 188.07, found (M+H+): 189.3.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[CH2:12][N:11]([C:13](OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC1[N:43]=[CH:42][N:41]=[C:40]([NH:44][C:45]2[S:46][C:47]([C:50]#[N:51])=[CH:48][N:49]=2)[CH:39]=1.C(N(CC)CC)C>>[C:50]([C:47]1[S:46][C:45]([NH:44][C:40]2[N:41]=[CH:42][N:43]=[C:13]([N:11]3[CH2:10][CH2:9][N:8]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12]3)[CH:39]=2)=[N:49][CH:48]=1)#[N:51]
Reactant: CC(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)C1CN(c2cc(Nc3ncc(C#N)s3)ncn2)CCN1C(=O)OCc1ccccc1
Temperature: 150 °C

Procedure:
47-2 (0.24 g, 0.78 mmol) was first treated with 3 mL of trifluoroacetic acid for 30 minutes at 25° C. and then the reaction was evaporated to dryness. The residue was dissolved in n-butanol and 35-1 (0.18 g, 0.78 mmol) and triethylamine (0.39 g, 3.88 mmol) were added. After heating at 150° C. for 18 hours, the reaction was cooled and the product was filtered off, washed with n-butanol, ethyl ether and then dried to afford the product 47-3. Hi-Res MS: calc: 507.1921 found: 507.1914. 1H-NMR (DMSO-d6): 12.15(s, 1H); 8.39(s, 1H); 8.25(s, 1H); 7.33(m, 5H); 6.11(s, 1H); 5.14(m, 2H); 4.47(m, 2H); 3.85(m, 2H); 3.69(m, 2H); 3.25(m, 1H); 3.17(m, 1H); 0.93(m, 6H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1ccc2c(c1)-c1nc(SCC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 69 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 69%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:36]2([CH:42]=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]([C:36]5([CH:42]=[O:43])[CH:37]=[CH:38][CH:39]=[CH:40][CH2:41]5)[CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO3 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenylmethanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141° C.
Reaction SMILES: [Br:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[CH3:11].[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.N12CCCN=C1CCCCC2>C(#N)C>[Br:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[C:4](=[O:10])[C:3]=1[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(Br)n(C)c(=O)n(COCC[Si](C)(C)C)c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of C2 (21.9 g, 99.8 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (20 g, 120 mmol) in acetonitrile (400 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.3 g, 120 mmol), and the reaction mixture was stirred at 60° C. for 18 hours. Additional 2-(trimethylsilyl)ethoxymethyl chloride (5 g, 30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g, 30 mmol) were added, and stirring was continued at 60° C. for 18 hours. After the mixture had been concentrated in vacuo, the residue was diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were concentrated; purification using chromatography on silica gel (Gradient: 20% to 50% ethyl acetate in petroleum ether) afforded the product as a colorless oil. Yield: 22.5 g, 64.4 mmol, 64%. 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 2H), 3.61-3.72 (m, 5H), 2.13 (s, 3H), 0.93-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][S:2]1=[O:12].[Cl:13][C:14]([SH:17])([Cl:16])[Cl:15]>C(Cl)Cl>[Cl:13][C:14]([Cl:16])([Cl:15])[S:17][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][S:2]1=[O:12]
Reactant: O=C1NS(=O)Oc2ccccc21
Reactant: SC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2OS(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A 300-ml flask equipped with a stirrer and thermomether was charged with 5.0 g (0.03 mol) of 1,2,3-benzoxthiazin-4-(3H)-one 2-oxide, 5.3 g (0.03 mol) of perchloromethyl mercaptan, 3.1 g (0.03 mol) of thiethylamine and 150 ml of methylene chloride. The resulting mixture was stirred at ambient temperature for 1 hour. At the end of this time, the reaction mixture was filtered and washed 3 times with equal amounts of water. After drying, the solvent was removed by evaporation. The crude product was passed through a 250-g silica-gel column using hexane, 10% ether/hexane, and 20% ether/hexane, respectively. Evaporation gave 4 g of 3-(trichloromethylthio)-1,2,3-benzoxathiazin-4-(3H)-one 2-oxide having a melting point of 65°-67° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)Nc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and 4-methoxyphenyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH2Cl2 1:100 the eluent. This afforded the title compound as oil. 13C NMR (DMSO-d6) δ 195.2, 158.8 (dd), 155.8 (dd), 154.6, 152.7, 149.1, 139.2, 137.6, 133.5, 132.5, 131.5, 129.5, 127.0, 126.4 (dd), 124.4 (dd), 120.4, 120.2, 119.9, 118.5, 114.9, 114.0, 112.0 (dd), 111.9, 105.1 (dd), 55.2, 19.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:30][CH3:31])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h
Yield: 57 %

Procedure:
The compound from step C (1 g, 2.4 mml) and EtI (42 mg, 2.6 mmol) were dissolved in anhydrous DMF (10 mL) Then NaH (144 mg, 3.6 mmol, 60%) was added to the mixture slowly at 0° C. After 30 minutes, the reaction mixture was quenched by saturate NH4Cl (10 mL), extracted with EA, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=20:1 to 5:1 to give the title compound (0.608 g, 57%). LC/MS m/z=444.1[M+H]+. The two enantiomers were separated by SFC chiral separation.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=[O:9]>>[CH:1]([NH:4][C:11]([CH2:10][C:8]([O:7][CH2:6][CH3:5])=[O:9])=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)C=C(CC(=O)OCC)NC(C)C
Temperature: -18 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
Isopropylamine (60 ml, 0.712 mol) was added slowly to diethyl 1,3-acetonedicarboxylate (120 g, 0.5934 mol) with stirring at -18° C. After 24 hours at room temperature, the excess amine and water were removed under rotary evaporation and finally by azeotropic distillation with benzene to give a light yellow oil. It was kugelrohr distilled to give 52 g of light yellow oil as product (30%), nD25 1.4887.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:9]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[BH4-].[Na+].O>CO>[F:26][C:23]([F:24])([F:25])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:28])([F:30])[F:29])[CH:20]=1)[CH2:16][N:8]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([CH2:3][OH:2])[N:6]=[N:7]1
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 70 °C
Yield: 75 %

Procedure:
Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester in MeOH. Add NaBH4 (2.64 g, 3 eq) and warm to reflux overnight (70° C.). Cool to RT and slowly pour into a separatory funnel containing an equal volume of water. Extract with CH2Cl2. Concentrate and recrystallize from EtOAc/Hexanes to give the 7.0 g (75%) of the title compound. MS (IS) 403.2 (M+1); 1H NMR: (400 MHz, CD3OD) δ: 8.65 (dd, J=5.2, 1.6 Hz, 1H) 8.53-8.52 (m, 1H), 7.89 (s, 1H), 7.86-7.83 (m, 1H), 7.60 (s, 2H), 7.56-7.53 (m, 1H), 5.83 (s, 2H), 4.59 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1
Yield: 45 %

Procedure:
A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger, H.; Schreiber, O. Liebigs Ann. Chem., 1961, 641, 81., 2 g, 10 mmol), 4-aminophenylethyl alcohol (1.64 g, 12 mmol) and NaHCO3 (1 g, 12 mmol) in DMF (60 mL) was heated at 150° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.36 g (45%) of the title compound as an orange oil; 1H-NMR (CDCl3) δ 9.83 (1H, br.s), 8.20 (1H, d, J=2.1 Hz), 7.94 (1H, dd, J=2.1 Hz, 9.3 Hz), 7.34 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz), 7.16 (1H, d, J=9.3 Hz), 3.91 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.57 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(C(C)C)CC)(C)C.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=1)=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 83.8 %

Procedure:
Part A: 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). After one hour the mixture is concentrated in vacuo to give an oil. This oil is crystallised from ethanol to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield). 1H-NMR (200 MHz, DMSO-d6): δ 10.90 (br s, 1H), 7.91 (br d, J=8 Hz, 2H), 7.63-7.77 (m, 4H), 7.57 (dt, J=8 Hz, J=2 Hz, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19]([C:28]([NH:30][CH3:31])=[O:29])=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[C:19]([C:28]([NH:30][CH3:31])=[O:29])=[CH:18][C:17]4=[O:32])[CH2:12][CH2:13]3)=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To 2 mL of a dichloromethane solution containing 0.15 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 11 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 88 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B1OC(=O)CN(C)CC(=O)O1)[CH2:40][CH:41]=[CH2:42].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=5[CH2:39][CH2:40][CH:41]=[CH2:42])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCCc1ccccc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Temperature: 90 °C
Yield: 85.7 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (250 mg, 0.427 mmol) in DMF (5 mL) was added 2-(2-(but-3-en-1-yl)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (147 mg, 0.512 mmol), 2M sodium carbonate (0.427 mL, 0.854 mmol), and tetrakis(triphenylphosphine)palladium(0)(35 mg, 0.030 mmol). This reaction mixture was flushed with N2 and heated at 90° C. for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water (3×), dried (MgSO4), filtered, and concentrated in vacuo to give the crude product as a brown oil. This was purified by Biotage chromatography (0-40% EtOAc/hexanes) to give 233 mg (86% yield) of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as a colorless oil. LCMS (M+H).=637.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 70%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.76 (s, 3H), 4.13 (s, 4H), 6.77-6.91 (m, 3H), 7.15-7.33 (m, 3H), 7.44-7.58 (d, J=10.0 Hz, 1H), 7.58-7.75 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:35][C:36]1[S:37][C:38]2[CH:44]=[C:43]([N+:45]([O-:47])=[O:46])[CH:42]=[CH:41][C:39]=2[N:40]=1>>[N+:45]([C:43]1[CH:42]=[CH:41][C:39]2[N:40]=[C:36]([NH:35][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[S:37][C:38]=2[CH:44]=1)([O-:47])=[O:46]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: COc1ccc(Nc2ncccc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncccc2C(=O)Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
To a stirred solution of 2-(4-methoxy phenylamino)nicotinic acid (29, 244 mg 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino-6-nitrobenzothiazole (37, 137 mg, 0.7 mmol) were added, then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5) was purified by column chromatography employing EtOAc/Hexane as an eluent.