Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[ClH:31].CON.N1C=CC=CC=1>C(O)C>[ClH:31].[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1

Procedure:
A solution of N-[(4aR,7aR)-6-(5-fluoropyrimidin-2-yl)-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (645 mg, 1.47 mmol), O-methylhydroxylamine hydrochloride (613 mg, 7.34 mmol), and pyridine (1.16 g, 14.7 mmol) in ethanol (10 mL) is stirred at 55° C. for 4 hours. The mixture is quenched with a solution of saturated sodium bicarbonate in water and extracted with ethyl acetate. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:1) to hexane/ethyl acetate (0:1). The residue is further purified by portioning between ethyl acetate and 1 N hydrochloric acid. The acidic aqueous phase is collected and the pH is adjusted to >8 with 5 N sodium hydroxide. The basic aqueous phase is extracted with dichloromethane, dried and concentrated to give the title compound as the free base. The free base is dissolved in dichloromethane. To the solution is added a saturated solution of hydrogen chloride in dichloromethane, followed by diethyl ether (10 mL). The resulting white solid is collected by filtration to give the title compound (0.40 g, 74%). ES/MS (m/e): 336 (M+H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]2)=[S:8])C.[OH-].[NH4+]>Cl>[SH:8][C:7]1[N:9]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(CNC(=S)Nc1cccc2nc(C)ccc12)OCC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2c(-n3ccnc3S)cccc2n1
Temperature: 20 °C

Procedure:
A mixture of 8.6 g (28 mmole) of N-(2,2-diethoxyethyl)-N'-(2-methylquinolin-5-yl)thiourea and 100 ml of 10% hydrochloric acid was heated on a steam bath for one hour. The solution was allowed to cool to about 20° C., and was then poured with vigorous stirring into a mixture of ice and ammonium hydroxide. The solid was separated by filtration, washed with water, and triturated with ethyl acetate to provide solid 5-(2-mercaptoimidazol-1-yl)-2-methylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH:34]1(B(O)O)[CH2:36][CH2:35]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10]([CH:34]3[CH2:36][CH2:35]3)=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:20])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OS(=O)(=O)C(F)(F)F)c12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C3CC3)c12
Yield: 91.4 %

Procedure:
To a mixture of methyl(4-(((trifluoromethyl)sulfonyl)oxy)-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (512 mg) and DMF (10 mL) were added cyclopropylboronic acid (167 mg), potassium phosphate (1238 mg), Pd(OAc)2 (21.83 mg) and tricyclohexylphosphine (82 mg) at room temperature, and the mixture was refluxed for 16 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (372 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: CC(=O)NCCN
Reactant: Clc1ncc(I)c(Cl)n1
Product: CC(=O)NCCNc1nc(Cl)ncc1I
Yield: 71 %

Procedure:
In analogy to GP 2 reaction of 2,4-dichloro-5-iodopyrimidine (1.0 g, 3.6 mmol) with N-(2-aminoethyl)acetamide (e.g. ABCR, Aldrich) (0.42 mL, 3.9 mmol) provided the desired product in 71% yield (878 mg) after trituration of the crystals obtained with diethyl ether.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(F)ccc1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
Trimethylaluminium (2M in toluene) (0.556 mL, 1.11 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (143 mg, 1.11 mmol) in toluene (10 mL), under nitrogen at 0° C. The resulting solution was allowed to stir at this temperature for a further 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AK4) (466 mg, 0.74 mmol) in toluene (5 mL) was added slowly to the mixture at 0° C. The reaction mixture was then heated to 100° C. and was stirred for 6 hours using the microwave. The reaction mixture was allowed to cool to ambient temperature, then evaporated to afford a gum. This was dissolved in EtOAc (75 mL), and washed sequentially with Rochelle's solution (20 mL), and water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane to afford the product (390 mg, 72.6%). 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 2.03 (3H, s), 3.82-3.67 (4H, m), 4.05 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.45-7.31 (8H, m), 7.50 (1H, t), 7.60 (4H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.40 (1H, d), 8.51 (1H, s), 8.56 (1H, s), 11.25 (1H, s); m/z (ES+) (M+H)+=725; HPLC tR=3.63 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15](C=O)[CH2:14][CH2:13]3)[NH:8][C:4]=2[CH:3]=1.Cl>CO>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=CN1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc2nc(SCCN3CCNCC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
1-[2-(5-Fluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.80 g, 5.8 mmol) was dissolved in methanol (20 mL), 12N hydrochloric acid (2 mL) was added thereto, followed by stirring for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and saturated ammonia-methanol was added thereto, followed by stirring for five minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform: saturated ammonia-methanol=100:3), to thereby yield 1-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine (1.33 g, yield 81%) as a brown oil.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:43])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32]C(OCC4C=CC=CC=4)=O)=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]1([O:7][C:8](=[O:43])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 114.2 %

Procedure:
To a crude product of {4-[4-(benzyloxycarbonylamino)phenoxy]pyridin-2-yl}-N-(phenoxycarbonyl)carbamic acid phenyl ester (936 mg) dissolved in tetrahydrofuran (60 ml) was added 20% palladium hydroxide on carbon (209 mg), followed by stirring under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was removed by filtration and washed with tetrahydrofuran. The solvent was removed under reduced pressure to provide a crude product of the titled compound as a brown oil (820 mg).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
53.6 g of carbobenzoxy-L-alanine are dissolved in 400 ml of dry tetrahydrofuran, the solution is treated dropwise with 30 g of thionyl chloride while cooling with ice and the mixture is stirred for 1 hour in the cold. A solution of 54 g (0.2 mol) of 2-amino-5-nitro-2'-chlorobenzophenone in 150 ml of dry tetrahydrofuran is subsequently added dropwise thereto rapidly, whereupon the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated, the residue is treated with ice and 10 percent sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate and evaporated. The residue is treated with dry ether, left to crystallize for 1 hour and then filtered while rinsing with ether/petroleum ether (1:1). After drying, there is obtained (S)-benzyl-[1-[[2-(o-chlorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl]carbamate of melting point 143°-145°; [α]25 D =18° (1 percent solution in methylene chloride).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1.Cl.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][C:5]3[CH:14]=[CH:13][C:8]4[NH:9][C:10](=[O:12])[O:11][C:7]=4[CH:6]=3)[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=c1[nH]c2ccc(CCCCl)cc2o1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(CCCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Yield: 93 %

Procedure:
A suspension of 5.5 g of 6-(3-chloropropyl)-3H-benzoxazol-2-one in 50 ml of ethanol is admixed with 5.7 g of 4-(4-fluorobenzyl)piperidine hydrochloride and 7.2 ml of triethylamine. The mixture is stirred under reflux for one hour and subjected to customary workup to give 8.5 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one, m.p. 105-107°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[N:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])=[N:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1-c1nnc(CBr)s1
Product: O=c1n(Cc2nnc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 18, 33 mg (0.11 mmol) of the compound from Example 5A were reacted with 35 mg (0.11 mmol) of the compound from Example 85A. This gave 16 mg (27% of theory) of the target compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)=[CH:10][C:9]=1[OH:8]
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2cc(CCc3ccc(N)c(O)c3)nc2c1

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine in a mixture of methanol (300 ml) and tetrahydrofuran (300 ml) was hydrogenated over 10% palladium on carbon (5.0 g) under atmospheric pressure of hydrogen gas at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give a precipitate which was collected by filtration and dried to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (20.67 g).
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[Br:14][C:13]1[C:2]([NH:1][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[C:3]([CH:10]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=1)[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN(CC)CC)c1
Reactant: CCCC(=O)Cl
Solvent: c1ccccc1
Product: CCCC(=O)Nc1c(Br)cc(C(=O)OCC)cc1CN(CC)CC

Procedure:
3 gm of 2-Amino-3-bromo-5-carbethoxy-N,N-diethylbenzylamine were dissolved in 30 ml of benzene, and the solution was heated for 30 minutes with 3 ml of butyric acid chloride at 50° C. Thereafter, the mixture was evaporated to dryness in vacuo, and the residue was purified by chromatography on silica gel (eluant: benzene/ethyl acetate = 6:1), yielding 3-bromo-2-butyrylamino-5-carbethoxy-N,N-diethylbenzylamine, which was converted into its hydrochloride, m.p. 134° C, with ethanolic hydrochloric acid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.Cl.N[C@H:24]1[CH2:28]CN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)[CH2:25]1>>[CH2:28]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1)[CH:24]=[CH2:25]
Reactant: N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Product: C=CCN[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1

Procedure:
(R)-3-Amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride can be used in the method of Example 5-1 instead of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([O:10][CH3:11])=[C:8]([S:12]([O:15][C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][C:19]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:18][C:17]=2[CH2:39][CH3:40])(=[O:14])=[O:13])[S:7][CH:6]=1)=[O:4].[OH-].[K+]>>[CH3:38][C:34]1[S:33][C:32]2[CH:31]=[C:30]3[C:25](=[C:24]([C:19]4[CH:18]=[C:17]([CH2:39][CH3:40])[C:16]([O:15][S:12]([C:8]5[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]=5[O:10][CH3:11])(=[O:13])=[O:14])=[C:21]([CH2:22][CH3:23])[CH:20]=4)[C:36]=2[C:35]=1[CH3:37])[CH:26]=[CH:27][CH:28]=[CH:29]3
Reactant: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)OC)c1OC
Agent: [K+]
Agent: [OH-]
Product: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)O)c1OC
Yield: 65.8 %

Procedure:
The title compound was prepared according to the procedure in Example 10, step 2, using 5-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-diethyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid methyl ester (0.608 g, 1.02 mmol) and 1N KOH (5.11 mL). Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil eluting with a 25, 40 & 60% EtOAc/hexane step gradient to give 0.390 g (66%) of the title compound as a white solid, mp >230° C. 1H NMR (DMSO-d6) δ 1.09 (t, 6 H), 1.58 (s, 3 H), 2.41 (s, 3 H), 2.57-2.69 (m, 4 H), 4.01 (s, 3 H), 7.18 (s, 2 H), 7.35-7.41 (m, 2 H), 7.44-7.48 (m, 1 H), 7.96 (d, 1 H), 8.49 (s, 1 H), 8.74 (s, 1 H), 13.39 (s, 1 H). IR (KBr) 2950, 1700, 1540, 1360 and 860 cm-1. mass spectrum (-ESI) m/z 579 (M-H). Anal. Calcd. for C30H28O6S3 : C, 62.05; H, 4.86; N, 0.00. Found: C, 25 62.15; H, 5.09; N, 0.06.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)c1ccncc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 143.8 %

Procedure:
A solution of 1.58 g (7.36 mmol) of ethyl 2-methyl-2-pyrid-4-ylpropionate in 30 mL of THF is cooled to 10° C. When the temperature is reached, 22.08 mL (22.08 mmol) of 1 M diisobutylaluminum hydride solution in toluene are added dropwise. The reaction mixture is allowed to warm to room temperature and is stirred overnight. 1 N hydrochloric acid solution is added to the reaction medium, which is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 1.60 g of 2-methyl-2-pyrid-4-ylpropan-1-ol, corresponding to the following characteristics:
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20]C4C=CC=CC=4)=[N:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O>[CH:1]1([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:20])[NH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCOC1CCCC1
Agent: Cl
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCOC1CCCC1
Temperature: 90 °C
Yield: 73.9 %

Procedure:
A mixture of 7-(2-cyclopentyloxyethoxy)-6-methoxy-4-phenoxyquinazoline (470 mg, 1.2 mmol) and 2M hydrochloric acid (6 ml) was heated at 90° C. for 2 hours and allowed to cool. Water was added, and the product was extracted with methylene chloride. The combined extracts were washed with aqueous sodium hydrogen carbonate, passed through phase separating paper and the solvent was removed by evaporation. Trituration with ethyl acetate give 7-(2-cyclopentyloxyethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (270 mg, 74%).
Reaction SMILES: N=C=N.ON1C2C=CC=CC=2N=N1.[CH3:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:37][CH2:38][NH:39][CH3:40])[CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:41].[O:42]1[C:46]2[C:47]([C:51](O)=[O:52])=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43]1.C(OC(=O)C)C.[ClH:60]>C(OCC)(=O)C.C1COCC1.C(#N)C>[ClH:60].[ClH:60].[CH3:40][N:39]([CH2:38][CH2:37][N:29]([CH2:28][CH2:27][CH2:26][O:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:15]([CH3:14])[C:16](=[O:41])[CH:17]=[CH:18]2)[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[C:51]([C:47]1[C:46]2[O:42][CH2:43][CH2:44][C:45]=2[CH:50]=[CH:49][CH:48]=1)=[O:52]
Reactant: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PS-Carbodiimide resin (1.3 g) and 1-hydroxy benzotriazole (HOBt) (230 mg) were added to acetonitrile and THF solution (4 ml+6 ml) of 1-methyl-6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one (304 mg) and 2,3-dihydrobenzofuran-7-carboxylic acid (164 mg). The mixture was stirred at room temperature overnight. After the reaction mixture was filtrated and condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.35 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (324.2 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1
Reactant: BrCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCCCBr)cc1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
A solution of 4-hydroxybenzoic acid methyl ester (100 g) and 1,6-dibromohexane (481 g) in N,N-dimethylformamide (500 ml) was treated with potassium carbonate (109 g) then heated at 60° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate (3 L) and washed with water (7×1 L). The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a crude oil. Hexane (˜100 ml) was added and the resulting precipitate removed by filtration and discarded and the filtrate loaded onto a silica gel column (2 kg). Elution with hexane, followed by 9:1 hexane-ethyl acetate and 8:1 hexane-ethyl acetate afforded methyl 4-(6-bromo-n-hexyloxy)benzoate (186 g) as a white solid.