Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:29])[C:27]#[CH:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH2:26][C:27]#[CH:28])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (363 mg, 1 mmol) and propargyl amine (0.2 ml, 3 mmol) in DMF (5 ml), added PyBOP (520 mg, 1 mmol) then triethyl amine (0.3 ml, 2 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C18H18BN3O5S): 399.11. MS found (ESI negative): (M−H)−=398.03. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.80 (s, 1H), 9.1 (br, 1H), 8.42 (t, J=4.8 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.13 (dd, J=8.4 Hz, 1H), 6.44 (d, J=2 Hz, 1H), 6.36 (dd, J=8.8 Hz, 1H), 4.87 (s, 2H), 3.91 (m, 2H), 3.80 (s, 2H).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: OCc1ccccc1
Agent: [Na]
Product: c1ccc(COc2nsnc2-c2cccnc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](N(OC)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]([Mg]Br)=[CH2:23]>C1COCC1>[CH:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:8](=[O:9])[CH:22]=[CH2:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To a solution of (S)-tert-butyl (3-cyclopentyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (2.5 g, 8.3 mmol) in THF (35 mL) was added vinylmagnesium bromide (16.7 mL, 33.3 mol) at 0° C. dropwise. After completion of the addition, the reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with EtOAc (2×40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1) to afford (S)-tert-butyl (1-cyclopentyl-3-oxopent-4-en-2-yl)carbamate as a yellow oil (854 mg, 38% yield).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO.O>[C:14]([C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:16])=[O:2])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])#[N:15]
Reactant: COC(=O)c1ccc(C#N)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(=O)O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Cyanoisophthalic acid dimethyl ester 203 (1.70 g, 7.76 mmol) was dissolved in methanol (100 mL) and then treated with an aqueous solution of lithium hydroxide (2.0 g, 46.5 mmol) in 50 mL of water. The basic solution was stirred at ambient temperature for 1.5 hour. It was then poured into a 10% HCl solution. The solution was extracted with ethyl acetate and the combined extracts were dried over Na2SO4. Removal of solvent gave quantitative yield of 4-cyanoisophthalic acid 204: 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J=8 Hz, 1H), 8.33 (dd, J=1.7 Hz, J=8 Hz, 1H), 8.73 (d, J=1.7 Hz, 1H).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C@@H:8]1[CH2:10][C@H:9]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1)(=O)[CH3:6].[CH3:32][NH:33][CH3:34].C(O)(=O)C.[OH-].[Na+]>CC(O)C.[Cl-].[Na+].O.O.C(O)C>[CH3:32][N:33]([CH3:34])[CH:5]([CH:8]1[CH2:10][CH:9]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)[CH3:6]
Reactant: CNC
Reactant: CC(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: CC(C1CC1c1c[nH]c2ccc(C#N)cc12)N(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
Sodium cyanoborohydride (51 mg, 0.792 mmol, 3 equiv) was added to a stirred mixture of trans-3-(2-acetyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (100 mg, 0.264 mmol), dimethylamine (2.0 M in THF, 2.64 ml, 5.28 mmol, 20 equiv), acetic acid (302 uL, 5.28 mmol, 20 equiv) and powdered 4 A molecular sieves (150 mg, actived) in 2-propanol (2.0 ml). The resulting mixture was stirred at 50° C. for 20 h. Ethanol (5 ml), water (0.5 ml), and a solution of sodium hydroxide (10 M in water, 0.6 ml) were added to the reaction. The mixture was heated with stirring at 50° C. for 1 h. The reaction contents were poured into an aqueous solution of sodium hydroxide (1 M, 25 ml) and brine (25 ml). The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (90:10:1, CHCl3/MeOH/Et3N) to provide 67 mg (100% yield) of 3-[2-(1-dimethylamino-ethyl)-cyclopropyl]-1H-indole-5-carbonitrile as a 1:1 mixture of diastereomers. viscous oil: LC-MS (column=Phenomenex Luna C18 S10, 3×50 mm, start % B=0, final % B=100, gradient time=3 min, flow rate=4 ml/min) m/e 254 (M+H)+, tR 1.19 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CO.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NC1CC1
Agent: N
Solvent: CO
Solvent: CCO
Product: OC[C@@H]1C[C@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reaction time: 18 h

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL) and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution was refluxed under nitrogen for two hours. Additional cyclopropylamine (0.66 mL) was added and reflux continued for an additional 18 hours. The solution was cooled and methanol saturated with ammonia at 0° C. (5 mL) was added. After two days at ambient temperature, volatiles were removed in vacuo and the residue chromatographed on silica gel. (±)-(1R*,2S*,3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 7% methanol-chloroform and solidified from ethyl acetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; 1H-NMR(DMSO-d6) δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH of cyclopentane), 0.80-0.50 (m, 4,2 CH2 of cyclopropyl); mass spectrum (CI): 372(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=S)[CH3:19].I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:22](=[N:21][O:20][CH2:18][CH3:19])[NH:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCONC(=S)Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCON=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol), N-ethoxy-N′-(4-fluorophenyl)thiourea (105 mg, 0.49 mmol), and sodium periodate (118 mg, 0.55 mmol) in DMF-water 1:1 (20 mL) are heated at 85° C. for 1 h. The reaction mixture is diluted with water and extracted with ether. The organic phase is dried (MgSO4) and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as pale yellow crystals.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH3:64])[N:61]([CH3:63])[C:62]=5[C:52]=4[O:51][C:50]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH3:64])[N:61]([CH3:63])[C:62]=5[C:52]=4[O:51][C:50]=3[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:47][CH:48]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1C
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: Cc1nc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2n1C
Yield: 80 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(1,2-dimethyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (26 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52-7.49 (m, 2H), 7.44-7.34 (m, 5H), 7.16-7.13 (m, 2H), 4.09 (s, 3H), 2.61 (s, 3H), 2.41-2.33 (m, 2H), 2.12-2.03 (m, 2H), 2.03-1.93 (m, 1H), 1.70-1.61 (m, 1H). LCMS (Method E): RT=2.71 min, [M+H]+=436.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:16].Cl[CH2:18][S:19]([O-:22])(=[O:21])=[O:20].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][S:19]([O-:22])(=[O:21])=[O:20])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Na+:16]
Reactant: O=S(=O)([O-])CCl
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In a 1-liter round-bottomed flask is placed 4-(4-chlorophenyl)phenol (25.5 g.), 4.0 N aqueous sodium hydroxide (39.0 ml.) and water (75 ml.). The mixture is heated to 90°-100° C., and sodium chloromethyl sulphonate (46.5 g.) is added. The mixture is heated rapidly to 160°-170° C. (bath temperature) while a current of air is passed through the flask. When most of the water has been removed the temperature of the bath is raised to, and kept at, 220°-225° C., for 90 minutes; the mixture is then cooled. The solid cakes obtained from two identical experiments are ground with water (200 ml.) in a mortar. The resulting suspension is heated to 80° C. and allowed to cool slowly, then filtered. The product is washed with water and dried to give sodium 4-(4-chlorophenyl)phenoxymethylsulphonate (58.4 g.) as a cream coloured powder pure enough for use. It may be further purified by crystallisation from aqueous dimethylsulphoxide and obtained as a microcrystalline powder not melting at 300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[CH2:17]1[O:19][CH:18]1[CH2:20][OH:21]>C(O)C>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:16])[O:12][CH2:13][CH2:14][O:15]2)=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: CC1(CCCc2ccc(N)cc2)OCCO1
Solvent: CCO
Product: CC1(CCCc2ccc(NCC(O)CO)cc2)OCCO1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 10 g (0.045 mol) of 230113 (Example 9--Step 3) in 60 ml of ethanol, are added 3.34 g (0.045 mol) of glycidol and left under stirring overnight. After concentration, the product is obtained by chromatography (silica, eluent: CH2Cl2 :97, CH3OH:3); Yield=44%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:21])[CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:22])[C:9]=2[C:8]([NH:23][CH2:24][CH2:25][NH2:26])=[CH:7][CH:6]=1.C1C=CC=CC=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH2:26][CH2:25][CH2:24][NH:23][C:8]1[C:9]2[C:10](=[O:22])[C:11]3[C:16](=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[OH:21])[C:17](=[O:19])[C:18]=2[C:5]([NH:4][CH2:3][CH2:2][N:1]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:6][CH:7]=1
Reactant: NCCNc1ccc(NCCN)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: NCCNc1ccc(NCCN=Cc2ccccc2)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A suspension of 0.0057 mole of the free base, 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxyanthraquinone (prepared as described in Example 1) in 60 ml of benzene containing 0.0057 mole of benzaldehyde is refluxed and treated as described in the general procedure for Examples 3-20, to give the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][O:25][CH3:26])=[C:18]([CH3:27])[CH:17]=2)[CH:13]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.CCOC(C)=O>[CH3:28][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]([CH3:27])[C:19]([O:23][CH2:24][O:25][CH3:26])=[C:20]([CH3:22])[CH:21]=2)[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc(/C=C/c2cc(C)c(OCOC)c(C)c2)cc(N(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of Compound 4 (1.046 g, 2.728 mmol) in THF and EtOH ( 8/4 mL) was added 2 N NaOH (2.728 mL, 5.456 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) at room temperature and diluted with EtOAc and acidified with 5% citric acid. The solution was washed with saturated brine and dried with Na2SO4. The solution was filtered and concentrated. Compound 5 (0.94 g, 97%) was obtained without further purification (TLC indicated a pure compound). 1H-NMR (500 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (s, 2H), 7.12-7.16 (m, 4H), 4.94 (s, 2H), 3.51 (s, 3H), 2.98 (s, 6H), 2.25 (s, 6H); 13C-NMR (125 MHz, DMSO-d6) δ 167.75, 154.18, 150.47, 137.92, 132.56, 131.62, 130.63, 128.12, 127.43, 126.86, 114.89, 114.16, 111.62, 98.51, 56.71, 40.03, 16.55; ESI-MS: m/z (MH+): 356.1856 (calc'd), 356.1854 (found).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C:45]([F:57])([F:56])[C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[F:44][C:45]([F:56])([F:57])[C:46]1[CH:47]=[C:48]([CH2:52][C:53]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-trifluoromethylphenyl acetic acid (76 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (106.1 mg) as an orange solid. LC/MS (ES) m/z=454.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (d, J=8.3 Hz, 1H) 7.84 (d, J=6.1 Hz, 1H) 7.69 (s, 1H) 7.57-7.67 (m, 3H) 7.52 (s, 1H) 7.36 (d, J=5.8 Hz, 2H) 7.25 (d, J=8.1 Hz, 1H) 5.79 (br. s., 2H) 4.30 (t, J=8.5 Hz, 2H) 4.05 (s, 2H) 3.27 (t, 2H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:15]([C:10]1[CH:9]=[CH:8][C:7]2[S:6][C:5]3[C:14](=[CH:1][C:2]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(=O)c1ccc2c(c1)Cc1cc(C(=O)C(C)C)ccc1S2

Procedure:
A reaction as described in example 1b by using thioxanthene, isobutyryl chloride, and aluminium chloride gives the product. The structure is confirmed by Mass [M=366] and the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.99 (d, 12H), 2.29 (hept, 2H), 2.82 (d, 4H), 4.00 (s, 2H), 7.50 (d, 2H), 7.79 (d, 2H), 7.92 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:9]=2[S:8](=[O:19])(=[O:18])[N:7]([CH2:20][CH2:21][CH2:22]OC)[CH2:6]1)[CH3:3].[BrH:25]>>[Br:25][CH2:22][CH2:21][CH2:20][N:7]1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:9]=2[S:8]1(=[O:19])=[O:18]
Reactant: CCN[C@H]1CN(CCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: Br
Agent: Cl
Product: CCNC1CN(CCCBr)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Yield: 96 %

Procedure:
A stirred solution of (+)-(R)-4-ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide hydrochloride (4.5 g, 110.7 mmol) in 48% HBr (20.0 mL) was heated at 80° C. for 72 h. The reaction mixture was concentrated in vacuo at 60° C. bath temperature to give a pale tan solid (4.8 g, 96%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Reactant: NCC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(NC(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline (0.2 g, 0.7 mmol), cyclohexanemethylamirie (0.5 ml, 3.5 mmol) and DMSO (3 ml) is heated at 110° C. for 6 hours. The reaction mixture is poured into water (50 ml), extracted with CH2Cl2 (4×25 ml), and the organic layers are combined and evaporated. The residue is slurried in ether, and a yellow solid is collected by filtration and recrystallized from ethanol/ethyl acetate to afford 200 mg of 1-ethyl-6-acetamido-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 277°-278° C.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])(O)=[O:2].OC1C2N=N[NH:36]C=2C=CC=1.N>ClCCl>[NH2:36][C:1](=[O:2])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Agent: N
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the carboxylic acid from Example 6 (0.10 g, 0.25 mmol) in dichloromethane (20 ml) were added hydroxybenzotriazole (34 mg, 0.25 mmol) and WSCDI (51 mg, 0.25 mmol). The mixture was stirred at room temperature for 10 min. Ammonia 880 (0.5 ml) was then added and stirring continued for a further 16 h. The mixture was concentrated in vacuo and the residue purified by flash chromatography on silica (eluant ethyl acetate) to give a white solid; yield 0.008 g (8%).
Reaction SMILES: ClC1C(CC2C=CC(OCC)=CC=2)=CC([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)=CC=1O.[Br:58][C:59]1[CH:64]=[C:63]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=2)[C:62]([Cl:75])=[C:61]([O:76]C)[C:60]=1[O:78]C>>[Br:58][C:59]1[CH:64]=[C:63]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=2)[C:62]([Cl:75])=[C:61]([OH:76])[C:60]=1[OH:78]
Reactant: CCOc1ccc(Cc2cc(Br)c(OC)c(OC)c2Cl)cc1
Agent: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Product: CCOc1ccc(Cc2cc(Br)c(O)c(O)c2Cl)cc1

Procedure:
Similar procedure with preparation of 77 proceeded except for using compound 160 to obtain the compound 201.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:16]([C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=[N:10][N:9]2[C:13]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])=[O:17]
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Using the procedure described in Example 20, Step A, compound 33a was prepared from compound 5e (232 mg, 1.00 mmol), 3-bromobenzonitrile (273 mg, 1.50 mmol), Pd(OAc)2 (15.7 mg, 0.0700 mmol), PPh3 (18.4 mg, 0.0700 mmol), and KOAc (294 mg, 3.00 mmol) in DMA (4 mL) at 110° C. for 16 h. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.14 (s, 1H), 8.13-8.17 (m, 1H), 8.10 (d, J=5.6 Hz, 1H), 8.03 (dt, J=8.0, 1.3 Hz, 1H), 7.76 (dt, J=8.0, 1.3 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 6.18 (d, J=5.6 Hz, 1H), 4.07-4.12 (m, 4H), 3.93-3.99 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C18H16N5O2: 334.1 (M+H). Found: 334.3.