Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:13]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[CH:6]=1.CO.Cl>O1CCOCC1>[NH2:13][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[CH2:2][OH:1]
Reactant: COc1cc(C[C@@H](CO)NC(=O)OC(C)(C)C)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C[C@H](N)CO)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial was added tert-butyl {(1S)-2-hydroxy-1-[(2-methoxypyridin-4-yl)methyl]ethyl}carbamate (0.50 g, 1.8 mmol) and methanol (2.0 mL) and 4.0 M hydrogen chloride in dioxane (5.0 mL, 20. mmol). The reaction was stirred at room temperature overnight. Direct evaporation under reduced pressure afforded the final compound. LC-MS found: 183.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16](Cl)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1Cl)[OH:9].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16]([NH:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1[NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[OH:9]
Reactant: NCCN1CCCCC1
Reactant: CN(C)CCCNN=C(O)c1cc(Cl)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(Cl)c(C(=O)O)c12
Product: CN(C)CCCNN=C(O)c1cc(NCCN2CCCCC2)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(NCCN3CCCCC3)c(C(=O)O)c12

Procedure:
Compound 7 (45 mg, 0.089 mmol) was suspended in 1-(2-aminoethyl)piperidine (0.5 ml) in a microwave reaction vessel. The tube was flushed with nitrogen, sealed and treated at 150° C. for 10 min in the microwave. The amine was then evaporated off under high vacuum. The crude mixture was purified by HPLC to obtain 8 as a blue solid. Yield 8 (6.62 mg, 0.0096 mmol, 10.8%): 1H NMR (CDCl3) δ: 1.47(m, 4H), 1.64(m, 8H), 1.90(5q, 4H, J=7.3 Hz), 2.26(s, 12H), 2.43(t, 4H, J=7.3 Hz), 2.51(m, 8H), 2.73(t, 4H, J=6.5 Hz), 3.58(m, 4H), 4.22(t, 4H, J=7.5 Hz), 8.07(s, 2H), 9.50(t, 2H, J=4.9 Hz); 13C NMR (CDCl3) δ: 24.44(2×CH2), 26.06(4×CH2, 2×CH2), 38.66(2×CH2), 40.49(2×CH2), 45.34(4×CH2), 54.57(4×CH3), 57.29(2×CH2), 57.38(2×CH2), 101.97(2×C), 118.38(2×CH), 121.07(2×C), 125.62(2×C), 148.90(2×C), 163.05(2×C═O), 165.79(2×C═O); HRMS (ES+) calcd C38H56N8O4 [M+2H]2+ 345.2285. Found: 345.2293.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C@H:12]1[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[C@H:12]1[CH:13]=[O:14]
Reactant: OC[C@H]1O[C@@H]1c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@H]1O[C@@H]1c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
A solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride is cooled to -65°-70° under argon and within a period of 2 minutes 1.5 g of dimethyl sulfoxide in 5 ml of methylene dichloride are added. After stirring for 10 minutes at -65°-70°, 1.7 g of (2R,3R)-2,3-epoxy-3-(3-trifluoromethylphenyl)-propanol in 15 ml of methylene chloride are added dropwise. After stirring for a further 30 minutes, 4 g of triethylamine are added dropwise, the temperature rising to -40°. The temperature is allowed to rise to 0° and the reaction mixture is poured onto phosphate buffer (pH 8). The organic phase is separated off and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed twice with brine, dried over sodium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) yields the title compound in the form of a colourless oil; IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm-1. Rf =0.36 (hexane/ethyl acetate 3:2). [α]D20 (chloroform, 0.20%)=-17.5°±5°.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14].BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCC(CN)NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CCC(CNc1nc(Cl)ncc1Br)NC(=O)OCc1ccccc1

Procedure:
benzyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate is synthesized by treating 5-Bromo-2,4-dichloropyrimidine with benzyl N-[1-(aminomethyl)propyl]carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) (M+H) 413
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Product: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1
Yield: 30 %

Procedure:
Beginning with 0.189 gm (0.90 mMol) 1-(4-indolyloxy)-3-chloropropane and 0.300 gm (0.90 mMol) 4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 0.137 gm (30%) of the title compound was recovered as a white solid by the procedure described in Example 1.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5C5C=CC=CC=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1([CH:47]2CC[CH2:49][NH:48]2)C=CC=CC=1>>[CH3:47][N:48]([CH3:49])[C@H:29]1[CH2:30][CH2:31][N:27]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:25]=2)[CH2:28]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Reactant: c1ccc(C2CCCN2)cc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CC[C@H](N(C)C)C5)c4)cc23)CC1
Yield: 18 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting (2R)—N,N-dimethyl-2-pyrrolidinamine (114 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 11 mg of the title compound (18%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=1)([CH3:8])[CH3:7])(=[O:4])=[O:3].[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:8])=[CH:18][CH:17]=4)=[O:15])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(C(C)(C)NS(C)(=O)=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C(C)(C)NS(C)(=O)=O)cc2)CC1
Yield: 76.4 %

Procedure:
Using methyl 4-(1-methanesulfonylamino-1-methylethyl)benzoate (126 mg) described in Preparation Example 71 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (101 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (162 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][N:39]([CH3:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([N:39]([CH3:47])[CH2:38][CH2:37][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][C:20]=2[O:25][CH3:26])=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc(Cl)cc2)cc1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccc(Cl)cc1
Temperature: 75 °C
Yield: 98 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added 2-[4-chloro(methyl)anilino]ethyl p-toluenesulfonate (170 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (136 mg, 98%). 1H NMR (DMSO-D6) δ 3.00 (3H, s), 3.77 (5H, m), 4.21 (2H, m), 6.81 (2H, d, J=9.0 Hz), 7.02-7.20 (5H, m), 7.58 (2H, d, J=8.6 Hz), 7.95 (3H, m), 8.39 (1H, s). Calcd. for C28H23Cl2N3O3S×3HCl: C, 50.81; H, 3.96; N; 6.35. Found: C, 50.91; H, 3.95; N, 6.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.COC(Cl)=O.C([Mg]Br)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: COc1ccc(C[Mg]Br)cc1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A 500 mL round-bottom flask is charged with 6-methoxy quinoline-N-oxide (8 g, 0.04566 mol.) and placed under nitrogen. The solid is then dissolved in anhydrous THF (100 mL) and cooled to −78° C. with a dry ice/acetone bath, whereupon some of the dissolved solid begins to precipitate. From an addition funnel, methylchloroformate (4.4 ml, 0.05694 mol.) is added dropwise. The bath is removed 10 minutes after the addition, and replaced after 20 minutes. A dropwise addition of 0.5 M anisylmagnesium bromide (112 mL, 0.0560 mol.) is then made. The bath is removed after the addition and the reaction is allowed to warm to room temperature. The reaction is quenched with 5% sodium bicarbonate solution. The THF is removed in vacuo and the resulting mixture is diluted with water and extracted with methylene chloride. The extracts are collected and dried with anhydrous sodium sulfate and concentrated. The crude product is purified by flash chromatography (2-5% EtOAc/dichloromethane) to yield 6.30 g (52%) of the desired product. 1H NMR: ∂ 8.03-8.11 (m, 4H), 7.78 (d, J=8.8 Hz, 1H), 7.37 (dd, J=9 Hz, 3 Hz, 1H), 7.03-7.07 (m, 3H), 3.94 (s, 1H), 3.88 (s, 1H). LCMS: 2.188 min, 266 (M+).
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[N:42]1[CH2:46][C@H:45]([OH:47])[C@@H:44]([OH:48])[CH2:43]1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([Cl:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:26].C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Cl:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:41]([N:42]3[CH2:43][C@H:44]([OH:48])[C@@H:45]([OH:47])[CH2:46]3)=[C:40]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)[CH:39]=2)=[CH:33][CH:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.451 mmol) and PdCl2(PPh3)2 (15.84 mg, 23 μmol) were added to a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 77.1, 110 mg, 0.226 mmol) and Na2CO3 (0.451 mL, 0.903 mmol) in DME (1.5 mL)/EtOH (0.3 mL) in a vial, which was sealed, purged with argon and the RM was subjected to MW irradiation at 125° C. for 30 min. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc). The resulting intermediate was dissolved in DCM (2 mL), treated TFA (0.314 mL, 4.07 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8) to give the title product as a white solid. HPLC (Condition 7) tR=6.105 min, UPLC-MS (Condition 8) tR=0.91 min, m/z=465.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.56 Hz, 2H) 3.24-3.38 (m, 2H) 3.81-3.91 (m, 2H) 4.99 (br.s, 1H) 5.04 (br.s, 1H) 6.26-6.36 (m, 1H) 6.72-6.87 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.47-7.94 (m, 5H) 10.10 (s, 1H) 12.75-13.04 (m, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.S(Cl)([Cl:32])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:32])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
To 0.05 mol of 4-(4-(2-quinolinylmethyloxy)styryl) benzoic acid in dichloromethane solution (500 ml), chilled in an ice bath, is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 4-(4-(2-quinolinylmethyloxy)styryl)benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)ccc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4-(Trifluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (0.7 ml, 7.9 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-4-bromophenol (0.8 g, 4.25 mmol) dissolved in DCM (20 ml) and added Pyridine (0.4 ml, 5.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (1.06 g, 5.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.15 (bs, 1H), 9.75 (s, 1H), 8.13 (d, J 8.1, 2H), 7.92-7.87 (m, 3H), 7.20 (dd, J 2.5, 8.6, 1H), 6.88 (d, J 8.6, 1H).
Reaction SMILES: [O:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([C:25](=[O:26])[CH2:24][C:23]([CH3:29])([CH3:28])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:1][CH2:2][CH2:3]1)=[O:26]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCNCCOCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCN(C(=O)CC(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,13,19-pentaoxa-4,16-diazacycloheneicosane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:23]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[C:18]3[CH:17]=[N:16]2)=CC=1.[Li+].[OH-].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.CCOCC>[C:37]1([C:22]2[C:23]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[C:18]3[CH:17]=[N:16][NH:15][C:19]3=[N:20][CH:21]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
TFA (3 mL) was added to tert-butyl 4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.7 g, 3.40 mmol, see Example 1) in DCM (10 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness and dried under vacuum for 3 hours. TFA (13.1 mL, 170 mmol) was then added, and the mixture was heated at 65° C. for 1 hour. The reaction was then concentrated to dryness. The resulting residue was added to THF (10 mL), an aqueous LiOH solution (6.81 mL, 2M) and Boc2O (2.23 g, 10.2 mmol) and stirred at room temperature for 3 days. Ether (50 mL) was then added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.1 g, 85%) as a solid. MS APCI (+) m/z 380.1 detected.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:16]([CH2:23][CH2:24][CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (0.73 g) obtained in Example 43a) and ethyl 3-keto-n-hexanoate (0.77 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (1.13 g, 98%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].C(O)C.[CH2:17]([O:24][C@@H:25]([CH3:31])[CH2:26][C:27](=[O:30])[CH2:28]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[CH2:28][C:27](=[O:30])[CH2:26][C@@H:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:31])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[C@@H](CC(=O)CBr)OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl acetoacetate (1.0 g, 7.7 mmol) in ethanol (30 mL), 20% sodium ethoxide/ethanol solution (3.1 mL, 7.7 mmol) was gradually added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Thereafter, under ice-cooling, a solution of the above (4S)-4-(benzyloxy)-1-bromopentan-2-one (2.1 g, 7.7 mmol) in ethanol (6.0 mL) was gradually added, and the mixture was stirred at room temperature for 3 hours. After the reaction, ethanol was distilled off under reduced pressure and 1N hydrochloric acid (0.20 L) was added to acidify it. After it was extracted with ethyl acetate and successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure. It was purified by silica gel column chromatography (ethyl acetate/hexane, 1:3, v/v) to give the title compound (1.6 g, 65%) as an oil.
Reaction SMILES: [CH3:1][NH2:2].C([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:11][CH:12]=2)[CH2:7]1)(=O)C>CO>[ClH:19].[CH3:1][NH:2][S:16]([C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][NH:6][CH2:7]2)=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: CN
Solvent: CO
Product: CNS(=O)(=O)c1ccc2c(c1)CNCC2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methylamine in methanol (2 M, 20 mL) was added to 2-acetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (2 g). The mixture was stirred at rt for 16 h. Excess methylamine and methanol were evaporated under vacuum and hydrochloric acid (10%, 30 mL) was added to the residue. The mixture was heated at reflux for 3 h and the aqueous solution was evaporated under vacuum. The residue was trituiated with ethyl acetate (2×20 mL) to afford 7-methylaminosulfonyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (1.9 g).