Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH2:5]
Reactant: [H][H]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O

Procedure:
In a mixture of 50 ml of methanol and 5 ml of acetic acid was dissolved 3 g of benzyloxycarbonyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester and after addition of 500 mg of palladium black, the mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and to the residue was added 100 ml of ethyl ether-petroleum ether (1:5). The mixture was allowed to stand in a refrigerator overnight and the resulting precipitate was collected by filtration and dried. Yield 1.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8]2.[Br:17]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>CO>[Br:17][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11]2
Reactant: BrBr
Reactant: COc1cccc2ccc(C(F)(F)F)nc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2ccc(C(F)(F)F)nc12
Reaction time: 2 h

Procedure:
The intermediate 8-methoxy-2-(trifluoromethyl)quinoline (2.21 g, 9.7 mmol) in MeOH (15 mL) was treated with a 1.5 N solution of bromine in MeOH (7.8 mL, 11.7 mmol) over a 15 min period. This mixture was stirred 2 h then treated with a 1 N aqueous solution of Na2S2O3 (30 mL) and EtOAc (300 mL). The phases where separated and the organic portion washed with brine, a saturated aqueous solution of NaHCO3, and again with brine. The organic phase was dried with Na2SO4, filtered, and evaporated to afford titled compound as a light brown solid. 1H NMR (CDCl3) 8.70 (dd, J=8.8, 0.6, 1H), 7.86 (d, J=8.8, 1H), 7.85 (d, J=8.4, 1H), 7.02 (d, J=8.4, 1H), 4.10 (s, 3H). LC/MS (Method B) 3.82 min, [M+1]+ 305/307.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](C2C=CC=CC=2)(O)[C:7]([OH:9])=[O:8])=[CH:2]1.CC(=O)OCC.[BrH:23]>C(O)(=O)C>[Br:23][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccsc1
Reactant: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(Br)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (thiophen-3-yl)mandelic acid (8.60 g, 54.4 mmol) was dissolved in 100 ml of 30% HBr in acetic acid. The solution was stirred for 18 hours at RT. The clear black solution was poured onto 2.5 L of ice water and immediately extracted with Et2O (4×400 ml). The ether was dried over Na2SO4 and treated with decolorizing carbon. The Et2O was evaporated and the residue was azeotroped with toluene to remove residual acetic acid. The crude solid product was recrystalized from hexanes to yield 9.07 g. (75.%). EA, MS(FD).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17].[H-].[Na+].[CH2:21]([O:23][CH2:24]Cl)[CH3:22]>CN(C)C=O.CCCCCC>[CH2:21]([O:23][CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([O:15][CH:16]([CH3:18])[CH3:17])=[C:7]1[C:12]([NH2:14])=[O:13])[CH3:22]
Reactant: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOCn1c(C(N)=O)c(OC(C)C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
5-Methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide (328 mg, 1.32 mmol) in 5 mL of dimethylformamide is added to a suspension of sodium hydride (60% by weight) (67 mg, 1.67 mol) in 5 mL of dimethylformamide. After 1.5 hours the mixture is cooled to 0° C. and chloromethyl ethyl ether (160 μL, 1.72 mmol) is added dropwise, and the solution is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The reaction mixture is diluted with 1:1 hexane:ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Chromatography eluting with 1:1 ethyl acetate:hexane gives 240 mg (51%) of 1-ethoxymethyl-5-methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide; mp 110°-112° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3ncc([N+](=O)[O-])n3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (1.09 g, 3.68 mmol), iron powder (623 mg, 11.05 mmol) and NH4Cl (995 mg, 18.41 mmol) in a mixture of EtOH (10.0 mL) and water (5.0 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (30 mL) was added followed by 1M NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.78 min; [M+H]+=267.30.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:17]=1[CH2:18][C:19](Cl)=[O:20]>>[CH2:8]([N:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH:2]([NH:1][C:19]([CH2:18][C:17]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1)=[O:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCN(CC)CCC(N)c1ccccc1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Product: CCN(CC)CCC(NC(=O)Cc1ccc2ccccc2n1)c1ccccc1
Yield: 95.9 %

Procedure:
The procedure of Example 1 was repeated using 618 mg (3.0 mmol.) of N-(3-amino-3-phenylpropyl)-N,N-diethylamine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.08 g (yield: 100%) of the subject compound as a pale yellow oily product.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.[ClH:23]>CO>[ClH:23].[N:16]1([C:12]2[CH:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(N2CCOCC2)c1
Agent: Cl
Solvent: CO
Product: CC(N)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84.4 %

Procedure:
To a solution of [1-(3-morpholin-4-yl-phenyl)ethyl]carbamic acid tert-butyl ester (1 g, 3.27 mmol) in methanol (3 mL) was added hydrochloric acid (1.0 M in ethyl ether) (13.1 mL, 13.1 mmol) and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under vacuum to provide the title compound as pale yellow solid (0.67 g, quantitative yield) which was used for next step without any further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO>[CH3:27][O:26][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:28][CH3:29])[N:4]=[C:3]([CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Solvent: CO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.5 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline-3-carboxylate (2.0 g), morpholine (2.5 g) and methanol (30 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane was added to the residue. The mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The resulting crystals were separated by filtration and recrystallized from ethanol to give ethyl 6,7-dimethoxy-4-(4-methoxyphenyl)-2-morpholinomethylquinoline-3-carboxylate (1.65 g, 74%). Colorless prisms, mp. 165°-166° C.
Reaction SMILES: [I:1]I.[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[N:4]1>C(#N)C.C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([I:1])=[CH:20][CH:21]=3)[CH2:11]2)=[N:4]1
Reactant: II
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccccc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(I)cc1
Reaction time: 24 h
Yield: 73.4 %

Procedure:
Iodine (0.67 g, 2.64 mmol) was added portionwise to a stirred solution of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one (0.7 g, 2.53 mmol) and silver trifluoroacetate (0.727 g, 3.29 mmol) in acetonitrile (4 ml) and chloroforrn (6 ml). The mixture was stirred for 24 hours in the dark. The mixture was filtered and the filtrate evaporated. The residue was extracted with EtOAc and the extract washed with water, dilute ammonia (0.1 ml of 0.88SG ammonia in 25 ml water), water and brine, dried (Na2SO4) and evaporated to give the title product as a solid (0.749 g, 73%)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:4][CH:5]=[C:6]([Sn](C)(C)C)[N:7]=1.[Br:13]C1SC=C(Br)N=1.O>CN(C=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[S:4][CH:5]=[C:6]([Br:13])[N:7]=1
Reactant: Brc1csc(Br)n1
Reactant: CN(C)c1nc([Sn](C)(C)C)cs1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(Br)cs1
Temperature: 155 °C
Yield: 89 %

Procedure:
Synthesis of 2-Dimethylamino-4-trimethylstannylthiazole 386 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in DMF (0.1 M) and heated at 150-160° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-dimethylamino-4-bromothiazole 385, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 89% yield.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C@@H:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2<2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.O>ClCCl>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([CH:2]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:1])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)N1CCC(CN)(c2ccccc2C)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(N)C1(c2ccccc2C)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Subsequently, the resulting 4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine was dissolved in dichloromethane (10 ml), added with ethyl chloroformate (0.18 ml) and triethylamine (0.26 ml) and stirred at room temperature for 30 minutes. After the reaction mixture was added with water (10 ml) and the layers were separated, the aqueous layer was further extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1) to obtain 372 mg of the title compound. Yield: 51% (for the two steps).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([NH:30][CH:31]2[CH2:38][C@H:37]3[N:39]([CH3:40])[C@H:33]([CH2:34][CH2:35][CH2:36]3)[CH2:32]2)=[O:29])=[CH:26][C:25]=1[F:43].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:42]=[CH:41][C:27]([C:28]([NH:30][CH:31]5[CH2:38][C@H:37]6[N:39]([CH3:40])[C@H:33]([CH2:34][CH2:35][CH2:36]6)[CH2:32]5)=[O:29])=[CH:26][C:25]=4[F:43])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN1[C@@H]2CCC[C@H]1CC(NC(=O)c1ccc(N)c(F)c1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4C[C@H]5CCC[C@@H](C4)N5C)cc3F)ncc21
Temperature: 160 °C
Yield: 47.5 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 97 mg, 0.3 mmol) and 4-amino-3-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 88 mg, 0.3 mmol) were combined with p-toluenesulphonic acid monohydrate (143 mg, 0.75 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 30 minutes at 160° C. The cooled reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX-3 (5 g) cartridge pre-wet with methanol. The cartridge was washed with methanol (2×10 mL) and product eluted with 7 N methanolic ammonia (20 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (82 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][N:19]3[CH2:18][C@@H:17]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@H:16]23)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][N:19]3[CH2:18][C@@H:17]3[CH2:25][NH:26][CH2:27][C@H:16]23)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(Br)cc(c43)[C@H]2C1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c(Cl)c1

Procedure:
Using 2,4-dichlorobenzeneboronic acid and following the procedures described in EXAMPLE 20, (±)-cis tert-butyl 2-bromo-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-2-(2,4-dichlorophenyl)-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline, trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 112 as the free base. 1H NMR (CDCl3) δ: 7.46 (d, 1H, J=2.2 Hz), 7.29-7.20 (m, 2H), 7.05 (d, 1H, J=1.1 Hz), 6.93 (d, 1H, J=0.8 Hz), 3.58 (dd, 1H, J=10.9, 7.7 Hz ), 3.50-3.30 (m, 4H), 3.15-2.95 (m, 5H), 2.90-2.77 (m, 2H). LRMS (ES)+: 345.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](OC)([OH:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1>O1CCOCC1.[Pd]>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:14])=[O:2])=[CH:7][CH:8]=1)=[O:13]
Reactant: COC(O)(C=Cc1ccc(C=O)cc1)OC
Agent: [Pd]
Solvent: C1COCCO1
Product: O=Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 16.7 g of 4-formylcinnamic acid dimethyl acetal in 200 ml of dioxane was hydrogenated in the presence of 1 g of 5% palladium-on-carbon at room temperature and atmospheric pressure. After about 61/2 hrs., the theoretical volume of hydrogen was consumed and the uptake ceased. The reaction mixture was filtered through Celite and the filter cake was washed with 300 ml of dioxane. The filtrate was concentrated to a final volume of 200 ml, 200 ml of 1N hydrochloric acid was aded, the solution was stirred at room temperature for 4 hrs. and then evaporated to dryness. The residue was dissolved in 700 ml of methylene chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a final volume of 100 ml and the solution was allowed to stand at 0° for 16 hrs. The precipitate was collected, washed with 1:1 methylene chloride-petroleum ether and dried at 55° for 4 hrs. under vacuum to give 10.9 g (81%) of 4-formyldihydrocinnamic acid as colorless crystals, m.p. 134°-138°.
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[NH2:1][C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: N#Cc1csc([N+](=O)[O-])c1-c1cnccn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: N#Cc1csc(N)c1-c1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
To 5-nitro-4-(pyrazin-2-yl)thiophene-3-carbonitrile (166 mg, 0.72 mmol) in conc HCl (3 mL) at rt was added tin(II) chloride (327 mg, 1.7 mmol). This was stirred at rt for 2 h, whereupon the reaction mixture was basified with aqueous NaOH and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated to give a brown oil (31 mg, 21%). HPLC method [4], retention time=1.458 min; MS (ESI) 203.1 (MH+).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccncc2)s1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Sc2ccncc2)s1
Yield: 69 %

Procedure:
A mixture of 2-acetylamino-5-(4-pyridylthio)thiazole (4.7 g), acetic acid (35 ml) and 6N-aqueous hydrochloric acid (10 ml) was refluxed for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted pH 8.5 using aqueous sodium bicarbonate under ice cooling. The precipitates were collected by flirtation, washed with water and dried in vacuo to give 2-amino-5-(4-pyridylthio)thiazole (2.7 g, yield: 69.5%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[C:23]([O:41][CH3:42])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[C:23]([O:41][CH3:42])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(Cc3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of ethyl [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (539 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetic acid (423 mg, yield 83%). The crystals were recrystallized from ethanol-hexane. melting point: 99–100° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc(N)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 3-chloro-2-nitro-phenylamine (172.6 mg, 1 mmol) and 1-methyl-piperazine (1.5 mL) was heated at 200° C. in a Biotage Initiator Sixty microwave reactor for 15 min, cooled to the room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (139 mg, 59%). 1H NMR (MeOH-d4) δ 2.32 (s, 3H), 2.55 (m, 4H), 2.99 (m, 4H), 6.45 (d, J=9 Hz, 1H), 6.57 (d, J=9 Hz, 1H), 7.15 (dd, J=9 Hz and 9 Hz, 1H). ESI-MS m/z 237.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:3]([CH2:22][CH2:23][CH:24]2[O:28][CH2:27][CH2:26][O:25]2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrCCC1OCCO1
Reactant: Clc1ccc(Cc2c(Br)[nH]c3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Clc1ccc(Cc2c(Br)n(CCC3OCCO3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of 0.32 g of the product from Step 2 of Example 1 in 5 mL of DMF was added sequentially 0.055 g NaH (60% in mineral oil), 0.27 mL of 2-(2-bromoethyl)-1,3-dioxolane and 0.01 g of n-Bu4NI. The mixture was stirred for 3 hours at room temperature and then quenched with 5 mL of saturated aqueous solution of NH4Cl and 5 mL of water, and extracted with 50 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluted with 9:1 hexane/EtOAc to give 0.3 g of the title compound as an oil.