Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15]>COCCO>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[NH:10][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: Nc1cccc(CO)c1
Solvent: COCCO
Product: O=c1cc(Nc2cccc(CO)c2)[nH]c(=O)[nH]1
Yield: 86 %

Procedure:
6-chlorouracil (1 mmol) and meta-aminobenzyl alcohol (2.0 mmol) were dissolved in 10 ml 2-methoxyethanol to form a reaction mixture. The mixture was then stirred at reflux for 10 hours to form 6-(meta-hydroxymethyl anilino)uracil with a yield of 86%. The hydroxy group was displaced by a bromo group by reacting the hydroxymethyl anilino-uracil (0.5 mmol) with 30% HBr in acetic acid (10 ml), thus forming 6-(meta-bromomethyl anilino)uracil with a yield of 90%. The bromo group was further replaced by a thiocyanate group by reacting 0.4 mmol 6-(meta-bromomethyl anilino)uracil with 2 mmol KSCN to form 6-(meta-mercaptocyanomethyl anilino)uracil (MMCMAU) with a yield of 80%. mMCMAU was then hydrolyzed to 6-(meta-thiomethyl anilino)uracil in 5 mL of 2N NaOH. The final product, 6-(meta-disulfidemethyl anilino)uracil, was formed quantitatively by reacting 6-(meta-thiomethyl anilino)uracil with methyl methane thiosulfonate in 2 molar excess.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=CC(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cccc(C=CCO)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
3-(3-Methylphenyl)acrylic acid (3.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained colorless oil was dissolved in tetrahydrofuran (60 ml), 1M diisobutylaluminum hydride/toluene solution (38 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated Rochelle salt water, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (2.45 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:2]1([NH:1][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 9.3 g (0.10 Mole) of aniline (IIIa) and 8.3 g (0.10 Mole) pyridine in 100 mL CH2Cl2 at 0° C. under an argon atmosphere was added a solution of 15.5 g (0.10 Mole) phenylacetyl chloride (IIa) in 25 mL CH2Cl2 over a 30 minute period. The solution was allowed to warm to 25° C. over 1 hour and was quenched into 200 mL H2O. The aqueous layer was washed with two 100 mL portions of CH2Cl2 and the combined organic layers were washed with two 100 mL portions of 10% HCl solution. The organic extract was dried over MgSO4, filtered, concentrated, and crystallized from CH2Cl2 /hexane to give 20.07 g (95%) of colorless needles. mp. 115°-116° C. δ1H-NMR (CDCl3) ppm 7.0-7.6 (m, 11 H); 3.67 (S, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].Cl[C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:7])[C:3]1[S:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][N:4]=1
Reactant: CN(C)C(=S)NN
Reactant: CCOC(=O)C(=O)Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nnc(N(C)C)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 4,4-dimethyl-3-thiosemicarbazide (2.0 g, 16.8 mmol) and ethyl chloro-oxo-acetate (2.3 g, 16.8 mmol) were mixed under an inert atmosphere and cooled to 0° C. in an ice bath. Sulfuric acid (2 mL) was added slowly. After the effervescence ceased, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 3 hours. To the white heterogeneous mixture, ethyl acetate (100 mL) was added and the organic layer was washed twice with 2% sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residual solid was dissolved in ethyl acetate and the desired compound was precipitated with ether to yield the ethyl 5-(dimethylamino)-1,3,4-thiadiazole-2-carboxylate (IIIc) (1.9 g, 9.4 mmol). The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65° C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired β-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the β-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65° C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36 mmol) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[C:6]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[C:5]2[OH:27].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:7](=[O:21])[C:6]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[C:5]2[O:27][CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: COc1ccc(Cn2c(=O)c(-c3cccs3)c(O)c3cc(Br)ccc32)cc1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c(-c3cccs3)c(OCC3CCOCC3)c3cc(Br)ccc32)cc1
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-4-hydroxy-1-(4-methoxybenzyl)-3-(thiophen-2-yl)quinolin-2(1H)-one (1.2 g, 2.8 mmol) in tetrahydrofuran (0.3 M, 10 mL) at room temp was added potassium carbonate (1.2 g, 8.4 mmol). 4-bromomethyl tetrahydropyran (1.0 g, 5.6 mmol) was added to this solution mixture. The reaction mixture was left stirring overnight. The crude reaction mixture was poured into 1 N sodium hydroxide (100 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 7:3 hexanes/ethyl acetate) to yield 6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-1-(4-methoxybenzyl)-3-(thiophen-2-yl)quinolin-2(1H)-one as an orange oil. LCMS (M+H)=539.8.
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][CH:42]1[CH:59]([C:60]([OH:62])=O)[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)=[O:40])([CH3:37])([CH3:36])[CH3:35].N1CCCC1>CN(C=O)C>[C:34]([O:38][C:39](=[O:40])[NH:41][CH:42]1[CH:59]([C:60]([N:3]2[CH2:4][CH2:6][CH2:9][CH2:7]2)=[O:62])[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)CN1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)N3CCCC3)CN1CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
N-Ethyldiisopropylamine (96 mg, 0.74 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 103 mg, 0.27 mmol) were added at r.t. to a suspension of (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (100 mg, 0.25 mmol) in N,N,dimethylformamide (2 mL), then after 45 min pyrrolidine (19 mg, 0.27 mmol) was added. The homogeneous solution was stirred 90 min at r.t., then partitioned between hexane/ethyl acetate 1:1 and water. The organic layer was washed with brine, dried (MgSO4), and evaporated, and the residue chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 80:1:0.2) to produce the title compound (58 mg, 51%). Light yellow solid, MS (ISP) 460.5 (M+H)+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[C:13]1([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][CH2:20][CH2:21][C:22]([N:3]2[CH2:4][CH2:5][S:1][CH2:2]2)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CSCN1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCSC1
Temperature: 25 °C
Yield: 88 %

Procedure:
5.5 mmol of thiazolidine and 5.5 mmol of triethylamine were dissolved in 10 ml of methylene chloride. To the solution 5 mmol of 4-phenylbutanoyl chloride was added dropwise under ice-cooling with stirring. The mixture was left to raise to room temperature and further heated under refluxing for 2 hours. The resulting reaction mixture was washed with 1N hydrochloric acid, brine, and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated by distillation and the residue was purified by column chromatography on silica gel to obtain 1.14 g of colorless crystals of N-(4-phenylbutanoyl)thiazolidine (yield: 88%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[N:29]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:37]([C:34]4[CH:35]=[C:36]5[C:31]([CH:30]=[N:29][NH:28]5)=[CH:32][CH:33]=4)=[O:38])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5cn[nH]c5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 1H-indazole-6-carboxylic acid (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25% acetonitrile/75% water (0.1% TFA V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide (45 mg, 36%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J=6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.63-7.44 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 4.62-4.25 (m, 2H), 3.96-3.66 (m, 10H), 2.35-2.11 (m, 3H). LC-MS: 516.9 [M+H]+, tR=1.38 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.76 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20](OCC)=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([CH2:20][OH:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: -20 °C
Yield: 15.4 %

Procedure:
To a solution of ethyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (300 mg, 0.89 mmol) in dry THF (9 mL) was added lithium aluminum hydride (1.07 mL, 1.07 mmol, 1.0 M in THF) dropwise at −40° C. under nitrogen. The resulting solution was allowed to slowly warm to −20° C. over the course of 1 hour after which time the reaction was quenched with saturated aqueous ammonium chloride (3 mL) and diluted with ethyl acetate (40 mL). The suspension was filtered through Celite, the filtrate washed with saturated aqueous sodium chloride (20 mL) and then dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material thus isolated was chromatographed over silica gel eluting with MeOH:CH2Cl2 0%→1%→2%) to furnish 40.6 mg (15.5%) of [1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazol-5-yl]methanol EXAMPLE 5. 1H NMR (400 MHz, CDCl3): δ=9.46 (s, 1H), 7.76 (s, 1H), 7.67 (t, J=2.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.47-7.45 (m, 1H), 7.44-7.41 (m, 2H), 7.39-7.35 (m, 2H), 6.16 (d, J=1.2 Hz, 1H), 4.75 (s, 2H). MS (ES+): m/z 296.17 (100) [MH+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1cccc(C=O)n1
Product: Cc1cccc(C=C2C(=O)Nc3cccc(CCO)c32)n1

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one (89 mg, 0.5 mmol) was condensed with 6-methyl-2-pyridinecarbaldehyde (61 mg, 0.5 mmol) using method B to give 4-(2-hydroxyethyl)-3-(6-methylpyridin-2-ylmethylene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.O>CN(C=O)C>[CH2:19]([O:18][CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=[C:29]2[C:28]([F:27])([F:39])[F:38])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:20]
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)OCC
Temperature: 60 °C

Procedure:
Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (371 mg, 1 mmol) was dissolved in DMF (5 ml) and K2CO3 (552 mg, 4 mmol) was added followed by 2-trifluoromethyl benzimidazole (204 mg, 1.1 mmol). The reaction mixture was heated to 60° C. for 17 hrs. After the completion of the reaction, water was added and the product was extracted with Et2O. The product was purified by column chromatography on silica gel using ethyl acetate and hexanes as solvent (333 mg, 70%).
Reaction SMILES: O[C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C#N)c1ccc(O)nn1
Agent: [Na+]
Agent: [OH-]
Product: CC(C#N)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.5 g (10 mmol) of 2-(6-hydroxy-pyridazin-3-yl)-propanenitrile are mixed with 5 g of phosphorus oxychloride and the mixture is stirred at 80°-90° C. for 45 minutes. The mixture is poured onto 30 g of ice, adjusted to pH 6 using 2N NaOH and extracted using ether. After removal of the solvent, an oil remains which solidifies on standing. Yield: 1 g (59.7% of theory); m.p.: 65° C. from hexane.
Reaction SMILES: [CH3:1][C@@H:2]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.CN>CO>[CH3:1][C@@H:2]([O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: CN
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor was charged with 14 g (36 mmol) of (R)-1-methyloctyl-4′-acetoxybiphenyl-4-carboxylate and 150 ml of toluene, 5.7 g of a methanol solution containing 40% methylamine (73 mmol % of methylamine) was dropwise added, and a mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([N+:28]([O-])=[O:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([NH:28][OH:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c([N+](=O)[O-])nccc23)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c(NO)nccc23)CC1

Procedure:
A solution of the nitro-isoquinoline from step B (0.81 mmol, 1.86 mmol) and Pd/C (10%, 0.081 g) in methanol (50 mL) was stirred under hydrogen overnight, filtered and evaporated to give a crude oil. Chromatography on silica eluting with a gradient of 20% to 70% of EtOAc/Hexane gave an oil. (0.43 g, 55%). LCMS (+APCI) m/z 423 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[N:13]=[C:14]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[S:15][C:16]=3[C:17]([O:19]CC)=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O1CCCC1.CO.[OH-].[Li+].Cl>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[N:13]=[C:14]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[S:15][C:16]=3[C:17]([OH:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 83.9 %

Procedure:
Ethyl 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (58.0 mg, 0.000148 mol) was placed in a 50 ml round bottom flask equipped with a stirbar. Tetrahydrofuran (2.25 mL, 0.0277 mol) and methanol (0.50 mL, 0.012 mol) were added and the mixture was stirred to give a clear solution. A solution of lithium hydroxide in water (2.0M, 0.750 mL, 0.00150 mol) was added in a single portion, resulting in a pale yellow solution which was stirred at room temperature under an atmosphere of nitrogen for 15 minutes. The reaction was then heated at reflux for 2.5 hours, cooled to rt, and diluted with water (˜25 ml) to give a clear slightly gray solution, which was allowed to stir at room temperature overnight under an atmosphere of nitrogen. 1 N HCl (˜1.8 ml) was slowly added to the stirring solution to lower the pH to ˜3 (pH paper) whereupon a white precipitate formed. The mixture was stirred for ˜15 minutes, at which point the solid was collected on a fritted funnel, washed with water, and dried on the funnel with house vacuum under a stream of nitrogen for several hours to yield 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (110) (45 mg, 84% yield) as a slightly gray powder. LC/MS (FA) ES+ 363; 1H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 6.76-6.64 (m, 3H), 4.17 (s, 4H), 4.08 (s, 2H), 3.77-3.61 (m, 4H), 3.51-3.34 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH2:12][CH2:11]2)=[O:5].[Cl:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:19][C:8]1[CH:9]=[C:10]2[C:14](=[C:6]([C:4](=[O:5])[C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])[CH:7]=1)[NH:13][CH2:12][CH2:11]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccccc1F)c1cccc2c1NCC2
Solvent: ClCCl
Product: O=C(c1ccccc1F)c1cc(Cl)cc2c1NCC2
Yield: 84 %

Procedure:
44 g (182 mmol) of 7-(2-fluorobenzoyl)indoline and 800 ml of methylene chloride are poured into a reactor equipped with a central stirrer, a condenser provided with a calcium chloride guard tube, a dipping thermometer, a nitrogen inlet and a pressure-equalizing dropping funnel. 27.9 g (182 mmol) of N-chlorosuccinimide are added gradually and the mixture is stirred over a warm temperature. The mixture is washed with saturated sodium bicarbonate solution and then with water, dried and evaporated. It is chromatographed on silica, eluting with methylene chloride. 42 g (84% yield) are obtained. The product is obtained in the form of a foam which has no definite melting point. TLC: H2CCl2Rf=0.70.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.[CH2:28](O)/[CH:29]=[CH:30]\[CH3:31].[Cl-].[Na+]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:28]/[CH:29]=[CH:30]\[CH3:31])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C/C=C\CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C/C=C\COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1.17 h

Procedure:
To a solution of 1-(t-butoxycarbonyl)-3-piperidinecarboxylic acid (60.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (55.2 g) in chloroform (600 ml) was added 4-dimethylaminopyridine (35.2 g), and the mixture was stirred for 70 minutes. To the mixture was added (Z)-but-2-en-1-ol (26.8 ml), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water (300 ml) and saturated aqueous sodium chloride solution (100 ml), and the mixture was extracted with chloroform. The separated organic layer was concentrated under reduced pressure, and to the resulting residue were added ethyl acetate and n-hexane. The mixture was sequentially washed with 3.5% aqueous potassium bisulfate solution three times and saturated aqueous sodium chloride solution twice. To the separated organic layer was added silica gel (200 ml), and the mixture was stirred and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (68.3 g).