Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[O:20][N:19]=[C:18]([CH3:21])[C:17]=4[CH:22]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][OH:34])[NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:31][N:30]([CH2:32][CH2:33][OH:34])[C:26]=3[CH2:27][CH3:28])[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[O:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)=[CH:4][CH:3]=1
Reactant: NNCCO
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3onc(C)c3c2)C1c1ccc(Cl)cc1
Product: CCc1c2c(nn1CCO)C(=O)N(c1cc(C)c3onc(C)c3c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 79 using 5-(4-chlorophenyl)-1-(3,7-dimethylbenzo[d]isoxazol-5-yl)-4-propionylpyrrolidine-2,3-dione (Step 9.1) and 2-hydrazinylethanol. tR: 1.04 min (LC-MS 2); ESI-MS: 451 [M+H]+ (LC-MS 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[N+:18]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:21](=[O:23])[CH3:22])[C:7]3[C:16]([S:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)([O-:20])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1cc([N+](=O)[O-])ccc1N2
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of 3,7-dinitrophenothiazine (MW 289.27, 24.0 g, 82.96 mmol), acetic anhydride (MW 102.09, 151 g, 1.48 mol) and pyridine (100 cm3) was stirred at reflux for 18 hours. The warm solution was then cooled to room temperature and poured carefully over ice water. The precipitate formed was filtered to give the title compound (MW 331.26, 21.14 g, 63.81 mmol, 77%) as a sand coloured solid which was recrystallised from acetone to give light yellow needles.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:24][CH2:23][CH2:21][OH:22])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: NCCO
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1NCCO

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 59 mg; 0.20 mmol) and ethanolamine (0.20 mL; 3.3 mmol) under microwave irradiation according to the procedure described in Example 14 Step 2 provided after purification by reverse phase HPLC, 5-(2-hydroxy-ethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (26 mg, 41%) as a white powder. ES-HRMS m/e calcd for C17H27N4O2 (M+H+) 319.2129, found 319.2127.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[C:10]([C:15](=[O:17])[NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[N:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1cccnc1)c1nccnc1C(=O)O
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)c2nccnc2N(C(=O)OC(C)(C)C)c2cccnc2)n1
Temperature: 25 °C

Procedure:
3-(tert-Butoxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-carboxylic acid (405 mg, 80%, 1.02 mmol), 2-amino-4-methylthiazole (129 mg, 1.12 mmol), N,N-diisopropylethylamine (0.23 ml, 1.33 mmol) and TBTU (430 mg, 1.33 mmol) were dissolved in 1 ml DMF and stirred over night at room temperature. The reaction mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with 2N NaOH-solution, water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->40:60 gradient). The desired compound was obtained as a yellow foam (195 mg, 46%), MS: m/e=413.3 (M+H+).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])C=CN=[CH:2]1.[CH:33]1(N)C[CH2:34]1>N1C=CC=CC=1.CCOCC>[CH:2]1([NH:1][C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:20])([F:21])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])[CH2:34][CH2:33]1
Reactant: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)n3ccnc3)c2)C(F)(F)F)c2ccccc21
Reactant: NC1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)NC3CC3)c2)C(F)(F)F)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of imidazol-1-yl-{5-[2,2,2-trifluoro-1-hydroxy-1-(1-methyl-1H-indol-3-yl)ethyl]indazol-1-yl}-methanone (0.145 mmol) in 1 mL of pyridine was added cyclopropylamine (1.45 mmol). The mixture was stirred overnight, diluted with ether, washed with water and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide the title compound, m.p. 116° C.-118° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][Br:15])[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:9]([CH2:13][CH2:14][Br:15])[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: BrCCc1cccc(Br)c1
Product: O=S(=O)(Cl)c1ccc(Br)cc1CCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorosulfonic acid (17 mL) was added dropwise to 1-bromo-3-(2-bromo-ethyl)-benzene (5 g, 19 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h then an additional 3 h at rt. The mixture was poured into an ice-water slowly and extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure to give 4.3 g of crude 4-Bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride which was used directly for next reaction. MS (ESI) 342.9 (M−Cl+OH)−.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:13]1[CH:12]=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1ccc(OCC2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)CCc1ccc(OCC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Intermediate 2 (1.31 g) in acetonitrile (50 ml) was added with N-bromosuccinimide (hereinafter abbreviated as “NBS”, 979 mg, KANTO), stirred at room temperature for 2 hours, then warmed to 40° C., and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (200 ml) and washed successively with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Compound No. A-1, 1.69 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=1)[NH:11][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:9]2)C.C1(=O)CCCC1>>[CH:16]1([NH:15][C:13]2[CH:14]=[C:6]([CH2:5][CH2:4][OH:3])[CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:9]3)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Solvent: O=C1CCCC1
Product: OCCc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Yield: 80 %

Procedure:
2-[7-(Cyclopentyl)amino-2-phenyl-1H-indol-5-yl]acetic acid ethyl ester prepared in Example 31 and cyclopentanone were reacted according to the same procedure as Example 29 to give the title compound (257 mg, Yield 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([CH3:20])[CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)cc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
0.27 g (0.0009 mol) of 1,3-dimethyl-5-(4-nitrobenzenesulphonyl)-benzene was suspended in 40 ml of ethanol, treated with 0.03 g of Pd/C (10%) and stirred in a H2 atmosphere at room temperature under normal pressure for 2 hrs. Then, the catalyst was filtered off, the filtrate was freed from solvent and the residue was chromatographed on silica gel with ethyl acetate/hexane 2:1. There was obtained 0.157 g (73%) of 4-(3,5-dimethylbenzenesulphonyl)-phenylamine as white crystals; m.p.: 178-179° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][Si:9]([CH3:12])([CH3:11])Cl.C[Si](C)(C)NCCN[Si](C)(C)C>ClCCl>[CH2:1]([O:7][Si:9]([CH3:12])([CH3:11])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)NCCN[Si](C)(C)C
Solvent: ClCCl
Product: CCCCCCO[Si](C)(C)C
Yield: 59 %

Procedure:
To hexan-1-ol (5.1 g, 0.05 mole) in dichloromethane (50 ml) were added trimethylchlorosilane (1.81 g, 0.0166 mole) and N,N'-bis(trimethylsilyl)ethlenediamine (3.44 g, 0.0166 mole). The mixture was stirred under reflux for 30 minutes, filtered and the solvent removed. The residue, hexanoxytrimethylsilane, was obtained in 59% yield (5.15 g).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C@H:38]3[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([O:48][C:49](=[O:51])[CH3:50])[C@H:41]([O:52][C:53](=[O:55])[CH3:54])[C@@H:40]([C:56]([O:58][CH3:59])=[O:57])[O:39]3)=[C:33]([NH:60][C:61](=[O:82])[CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][CH:69]3[C:81]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[C:75]4[C:70]3=[CH:71][CH:72]=[CH:73][CH:74]=4)=[O:66])[CH:32]=2)=[O:28])[CH2:25][CH2:24][O:23]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[OH:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C@H:38]3[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([O:48][C:49](=[O:51])[CH3:50])[C@H:41]([O:52][C:53](=[O:55])[CH3:54])[C@@H:40]([C:56]([O:58][CH3:59])=[O:57])[O:39]3)=[C:33]([NH:60][C:61](=[O:82])[CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][CH:69]3[C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][C:75]=4[C:76]4[C:81]3=[CH:80][CH:79]=[CH:78][CH:77]=4)=[O:66])[CH:32]=2)=[O:28])[CH2:25][CH2:24][O:23]1
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(COC(=O)N3CCOC3CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(COC(=O)N3CCOC3CCCO)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a mixture of the silyl ether 13 (52 mg, 0.042 mmol) in THF (2 mL) and pyridine (2 mL) was added HF-pyridine complex (400 μL). The reaction mixture was stirred for 3 h and was poured into saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine and dried over sodium sulfate, before being filtered and concentrated. The resulting oil was purified via radial chromatography on a 1 plate eluting with 5% methanol in dichloromethane to give 36 mg (86%) of a solid residue: 1H NMR (CD3OD); δ1.55 (bs, 2H), 1.68 (m, 1H), 1.87 (m, 1H), 1.95 (s, 3H), 2.01 (m, 6H), 2.67 (oct, 2H, J=6.8 Hz), 3.30 (m, 1H), 3.50 (m, 3H), 3.65 (m, 1H), 3.69 (m, 3H), 3.82 (q, 1H, J=8.0 Hz), 4.01 (m, 1H), 4.23 (m, 1H, J=7.0 Hz), 4.25-4.40 (m, 2H), 4.47 (d, 1H, J=10.0 Hz), 5.0-5.15 (m, 3H), 5.19 (t, 1H, J=9.8 Hz), 5.28 (dd, 1H, J=6.0, 9.6 Hz), 5.39 (d, 1H, J=7.6 Hz), 5.49 (m, 3H), 7.11 (m, 2H), 7.17-7.32 (m, 3H), 7.34 (t, 2H, J=7.4 Hz), 7.62 (d, 2H, J=7.6 Hz), 7.77 (d, 2H, J=7.6 Hz), 8.07 (s, 1H); LC-MS m/z (ES+), 927.87 (M+Na+)+, 9.79 min.
Reaction SMILES: CC1C=CC=CC=1B(O)O.N[C:12]1[N:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:18]=2)[N:13]=1.[I:31]I.[I-].[Cs+].N(OCCC(C)C)=O>COCCOC.[Cu](I)I>[I:31][C:12]1[N:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:18]=2)[N:13]=1
Reactant: COc1cc2nc(N)ncc2cc1-c1ccccc1C
Reactant: II
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: Cc1ccccc1B(O)O
Solvent: COCCOC
Product: COc1cc2nc(I)ncc2cc1-c1ccccc1C
Temperature: 80 °C
Reaction time: 7 h
Yield: 184.5 %

Procedure:
In a similar manner to Example 4, 2-amino-7-methoxy-6-(2-methylphenyl)quinazoline was obtained using Compound A2 and 2-methylphenylboronic acid. The obtained 2-amino-7-methoxy-6-(2-methylphenyl)quinazoline (4.38 g, 16.5 mmol) was dissolved in DME (165 mL) and the solution was added with iodine (1.05 g, 8.3 mmol), cesium iodide (4.3 g, 16.5 mmol), isoamyl nitrite (13.3 mL, 99 mmol) and copper iodide (3.1 g, 16.5 mmol), followed by stirring at 80° C. for 7 hours. After an insoluble matter was filtered off from the reaction mixture, the solvent was evaporated under reduced pressure. The residue was added with aqueous saturated sodium thiosulfate solution and 28% aqueous ammonia and the obtained crystal was collected by filtration to obtain 2-iodo-7-methoxy-6-(2-methylphenyl)quinazoline (5.76 g, 93%) as a crude product. In a similar manner to Reference Example 4 and Example 19, Compound 174 was obtained using the above-obtained 2-iodo-7-methoxy-6-(2-methylphenyl)quinazoline and 4-heptylamine.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC1OCCC1.C1COCC1>[C:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CC(C)(C)Oc1ccc(OCCO)cc1
Temperature: 60 °C
Yield: 92.6 %

Procedure:
[2-(4-Tert-butoxyphenoxy)ethoxy](tert-butyl)dimethylsilane (1.7 g, 5.24 mmole) was taken up in 2-MeTHF (10 mL). To this was added 1M TBAF (16 mL, 16.00 mmole) in THF then the mixture was heated to 60° C. After 4 hr the mixture was cooled to RT and concentrated. The residue was taken up in H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 30% EtOAc/hexanes) gave the title compound (1.02 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 6.94-6.90 (m, 2 H); 6.83-6.79 (m, 2 H); 4.07-4.02 (m, 2 H); 3.97-3.91 (m, 2 H); 1.30 (s, 9 H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:16]1([C:2]2[C:3]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:4]=3[S:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1
Reactant: COC(=O)c1sc2cc(F)ccc2c1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1sc2cc(F)ccc2c1C1CC1
Temperature: 100 °C

Procedure:
A mixture of methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate 65a (0.613 mmol, 150 mg), cyclopropylboronic acid 65b (0.92 mmol, 79 mg), Pd(OAc)2 (0.09 mmol, 20 mg), SPhos (0.215 mmol, 88 mg), and K3PO4 (1.23 mmol, 0.26 g) in toluene (2 mL) was heated to 100° C. for 3 h in a sealed reaction vessel. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 65c.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9]1=[O:34])[CH2:4][CH3:5])[CH3:2].[CH3:35][C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[CH2:4]([N:3]([CH2:6][CH2:7][N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:45]3[CH2:46][CH2:47][N:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=4)[CH2:43][CH2:44]3)=[CH:17][CH:18]=2)[CH2:11][CH2:10][C:9]1=[O:34])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)CCN1C(=O)CCC1c1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Cc1cccc(N2CCNCC2)c1
Product: CCN(CC)CCN1C(=O)CCC1c1ccc(CCCCN2CCN(c3cccc(C)c3)CC2)cc1

Procedure:
N-(2-(N,N-diethylamino)ethyl)-5-[4-(4-(p-toluenesulfonyloxy)butyl)phenyl]pyrrolidin-2-one and 1-(3-methylphenyl)piperazine are reacted together to give N-(2-(N,N-diethylamino)ethyl)-5-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=12.[ClH:24].C([OH:27])C>>[ClH:1].[ClH:24].[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=1[C:2]2=[O:27]
Reactant: CCO
Reactant: Cc1nn(-c2ccncc2)c2nc3cc(F)c(F)cc3c(Cl)c12
Agent: Cl
Product: Cc1nn(-c2ccncc2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.80 g, 2.42 mmol) in ethanol (40 mL), 6N hydrochloric acid (2 mL, 12.0 mmol) was added, and the mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried and recrystallized from ethanol to give the title compound (0.51 g, 55% yield).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].[N:9]([O-])=[O:10].[Na+]>C(O)(=O)C.O>[N:9]([N:3]1[CH2:4][CH2:5][S:1][CH:2]1[C:6]([OH:8])=[O:7])=[O:10]
Reactant: O=C(O)C1NCCS1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCSC1C(=O)O
Reaction time: 5 h

Procedure:
To a suspension of thiazolidine-2-carboxylic acid (39.9 g, 0.30 mol) in 1,000 ml of acetic acid was added a solution of 31.0 g (0.45 mol) of sodium nitrite in 500 ml of water over 13 minutes at room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure. Acetone (500 ml) was added to the residue and the precipitate was filtered through a pad of Celite. The pad was washed with acetone (500 ml). The filtrate was concentrated under reduced pressure to dryness and crude 3-nitrosothiazolidin-2-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [N+:1]([CH:4]1[CH2:8][N:7]([CH2:9][CH3:10])[N:6]([CH2:11][CH3:12])[CH2:5]1)([O-])=O.C(O)C>C1(C)C=CC=CC=1.[Ni]>[NH2:1][CH:4]1[CH2:8][N:7]([CH2:9][CH3:10])[N:6]([CH2:11][CH3:12])[CH2:5]1
Reactant: CCN1CC([N+](=O)[O-])CN1CC
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN1CC(N)CN1CC
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of approximately 3.0 g (0.016 mole) of 4-nitro-1,2-diethyl-pyrazolidine in 100 ml of toluene was added 60 ml of anhydrous ethanol and 2 g Raney nickel (washed three times with anhydrous ethanol). The mixture was added and hydrogenated for three hours at about 30 psi. The mixture was filtered to give a light yellow solution. The solvents were evaporated at reduced pressure giving the colorless liquid, 1.95 g of the title product, b.p. 113°-115° C./40 mm. The dimaleate salt melted at 119°-120° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25]C[C@H]1CCCN1>>[OH:25][CH2:2][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: OC[C@H]1CCCN1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3CO)n2)c1

Procedure:
B24 was prepared following the procedure reported for B1 using Al and (R)-2-(hydroxymethyl)pyrrolidine. MS (ES) C15H20N6O3S requires: 364. found: 365 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (7.18 g, 52.7 mmol) in diethyl ether (100 ml), sodium borohydride (3.98 g, 105 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-chlorophenyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate (10.13 g, 26.33 mmol) in diethyl ether (50 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-3/1) to give the objective substance.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]2[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=2)=[N:2]1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]2[CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=[CH:17][N:16]=2)=[N:2]1
Reactant: O=C(NCCNc1nsc2ccccc12)c1cc(Cl)ccn1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)c1cc(N2CCOCC2)ccn1

Procedure:
A mixture of N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chloropicolinamide (50 mg) in morpholine (1 mL) was microwaved at 160° C. for 30 min. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 1% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to give N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-morpholinopicolinamide as a white solid. 1H NMR (300 MHz, DMSO-d6): 8.80 (broad s, 1H), 8.20 (m, 1H), 8.10 (m, 1H), 7.91 (m, 1H), 7.30-7.60 (m, 3H), 7.00 (m, 1H), 3.60-3.80 (m, 4H), 3.30 ppm (m, 8H). MW=383 confirmed by LC-MS, tr=8.06 min (Method Y) MH+=384.