Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:6]=[O:7].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-(methyloxy)-4-{[3-(trifluoromethyl)phenyl]oxy}benzaldehyde (720 mg, 2.430 mmol) in ethanol (20 mL) was added slowly NaBH4 (110 mg, 2.92 mmol) at 0° C. The mixture was then allowed to warm to room temperature and stirring continued for 2 h. The reaction was quenched with NH4Cl sat. solution and extracted with EA. The organic layer was separated and concentrated to afford the title compound (715 mg, 2.397 mmol, 99% yield). LCMS: rt=3.12 min, [M+H+−H2O]=281
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([S:17]([NH:1][C:2]2[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1cnc(N)c(I)c1
Solvent: c1ccncc1
Solvent: O
Product: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
2-Amino-5-methylthio-3-iodo-pyridine (2.95 g) and benzenesulfonyl chloride (2.35 g) were dissolved in pyridine (11.1 ml) and the solution was stirred at 60° C. for 15 hours. The reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (chloroform:methanol=50:1) to obtain 2.55 g of the desired product as a pale yellow crystal.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C@@H:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1.[OH-].[Na+]>CS(C)=O>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C@@H:35]1[CH2:39][CH2:38][C@H:37]([NH:40][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:36]1
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN[C@H]1CC[C@@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Temperature: 80 °C
Yield: 45.9 %

Procedure:
A mixture of [(2R)-8-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzene-sulfonate (0.5 g, 1.42 mmole) and cis-3-(5-fluoro-1H-indol-3-yl)-cyclopentyl-amine (0.24 g, 1.1 mmol) in anhydrous DMSO (10 mL) was heated at 80° C. for 30 h. The cooled reaction mixture was poured into 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 0.5 g of crude product. Flash chromatography on silica gel (10% MeOH/ethyl acetate) afforded 0.2 g (48%) of the title compound as a thick oil, which was converted to its hydrochloride salt (0.195 g): MS (ESI) m/z 397 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:18]12CC(C=C1)C=[CH:19]2>O1CCOCC1>[I:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:19]=[CH:18][N:3]=[N:2]3)[O:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
(5R)-5-(Azidomethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (10.0 g, 29.1 mmol) was dissolved in 1,4-dioxane (100 ml). Bicyclo[2.2.1]hepta-2,5-diene (9.4 ml, 87.2 mmol) was added and the mixture heated to 100° C. for 24 h. The solution was cooled and purified by silica flash chromatography with 1-10% methanol in dichloromethane as eluent giving 7.2 g of the desired product.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c2ccsc2c1=O
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carbonitrile (3.00 g, 17.0 mmol) and 25 mL of phosphorous oxychloride is heated at reflux for 10 minutes. The reaction mixture is cooled to room temperature and the dark solids are removed by filtration. The filtrate is poured into hexane and allowed to stand at room temperature. The solvent is decanted off and the residual oil is dissolved in ethyl acetate and the solution is washed with water. The organic layer is dried over magnesium sulfate, filtered and passed through silica gel. The filtrate is concentrated in vacuo to give 770 mg of the desired product as a dark orange solid. A portion of this material is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 7-chlorothieno[3,2-b]pyridine-6-carbonitrile as tan crystals, mp 110–111° C.; 1H NMR (DMSO-d6) δ 7.81 (d, J=5 Hz, 1H), 8.59 (d, J=5 Hz, 1H), 9.12 (s, 1H); MS 194.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-methylthiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate u) (example 9, step a) (0.32 g) in DCM (3 mL) was treated with trifluoroacetic acid (1.0 g). After 2 h, the reaction mixture was evaporated in vacuo and azeotroped twice with toluene to yield the subtitled compound which was used directly. Yield 0.32 g.
Reaction SMILES: [NH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)N.[CH2:17](O)[CH3:18]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]3[NH:1][C:5]4[CH2:4][CH2:3][NH:1][CH2:17][C:18]=4[C:4]=3[CH:5]=2)[CH2:9][CH2:10]1
Reactant: CCO
Reactant: CN1CCN(Cc2ccc(NN)cc2)CC1
Product: CN1CCN(Cc2ccc3[nH]c4c(c3c2)CNCC4)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-hydrazinobenzyl)-4-methylpiperazine (3.4 g, 13.25 mmol) in ethanol (50 mL) were added piperidone. HCl (2.51 g, 18.55 mmol). The reaction temperature was raised to 90° C. and continued stirring for 2 hrs. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was cooled to rt and HCl gas was bubbled through the reaction mixture at 0° C. After the reaction mixture was saturated with HCl, the temperature was raised to 90° C. again and continued stirring for 2 hrs. The ethanolic HCl was removed under reduced pressure and the pH of the reaction mixture was adjusted to 12.0 with 10% NaOH solution. The mixture was partitioned between 20% MeOH:DCM and water (35 mL) and the organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue. Washing with ether gave 8-[(4-methylpiperazin-1-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g). 1H NMR (CD3OD, 200 MHz) δ: 7.31 (1H, s), 7.27 (1H, d, J=8.6 Hz), 7.06 (1H, d, J=8.6 Hz), 4.01 (2H, s), 3.60 (2H, s), 3.21 (8H, bm), 2.86 (4H, m), 2.28 (3H, s); m/e=285 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][C:10]2[S:14][C:13](B(O)O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:7][NH:8][CH2:9][C:10]2[S:14][C:13]([C:19]3[CH:20]=[C:21]4[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=3)[NH:24][CH:23]=[C:22]4[CH:31]3[CH2:32][CH2:33][N:34]([S:37]([CH2:40][CH3:41])(=[O:38])=[O:39])[CH2:35][CH2:36]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CNCC2CCCCC2)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCC5CCCCC5)s4)cc23)CC1
Yield: 6 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give 4.7 mg of the title compound (6%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:29][CH:28]=1.O>CN(C=O)C>[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:31][CH:32]=1)=[N+:18]=[N-:19]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(-c3ccc(OCCOCCOCCOCCN=[N+]=[N-])cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulphonate (175 mg, 0.58 mmol) and Cs2CO3 (190 mg, 0.58 mmol) are added to a mixture of 3-(4-hydroxyphenyl)-7-methoxyisoquinolin-1(2H)-one (compound 45) (130 mg, 0.48 mmol) in DMF (6 mL). The reaction mixture is heated at 80° C. for 24 hours. Then the solvent is evaporated off, the reaction crude is added to water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of EtOH (1 to 3%) in CH2Cl2 as eluents. Intermediate 3-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-7-methoxyisoquinolin-1(2H)-one (52 mg, 23%) is obtained, which is used directly in the following stage.
Reaction SMILES: [NH2:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)([C:5]1[CH:6]=[N:7][C:8]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:10]=1)[CH2:3][OH:4].Cl[CH2:23][C:24](Cl)=[O:25].C([O-])(C)(C)C.[K+]>C(O)(C)(C)C>[Br:21][C:17]1[CH:16]=[C:15]([C:2]2([C:5]3[CH:6]=[N:7][C:8]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:10]=3)[NH:1][C:24](=[O:25])[CH2:23][O:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: NC(CO)(c1ccc(OC(F)F)nc1)c1cccc(Br)c1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)N1

Procedure:
In close analogy to the reaction sequence described for the preparation of intermediate X-1, the acylation of the (RS)-2-amino-2-(3-bromo-phenyl)-2-(6-difluoromethoxy-pyridin-3-yl)-ethanol with chloroacetylchloride followed by cyclisation with tert-butanol and potassium tert-butanolate yielded the (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-one as a light yellow solid (1.6 g, 91% of theory). MS (ISP): m/z=400.9 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:17][C:10]=23)O1.Br[C:43]1[CH:44]=[CH:45][C:46]([C:49]([NH:51][CH3:52])=[O:50])=[N:47][CH:48]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:52][NH:51][C:49]([C:46]1[N:47]=[CH:48][C:43]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:17][C:10]=23)=[CH:44][CH:45]=1)=[O:50]
Reactant: CNC(=O)c1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 80 °C

Procedure:
A mixture of Example 369D (1.700 g, 2.93 mmol), 5-bromo-N-methylpicolinamide (0.757 g, 3.52 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.096 g, 0.117 mmol), and saturated sodium bicarbonate solution (10 mL, 2.93 mmol) in N,N-dimethylformamide (40 mL) was degassed and heated at 80° C. for 2 hours. The reaction mixture was filtered, treated with water and brine and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered, concentrated, and purified on an 80 g silica column using the ISCO Companion flash system eluting with heptanes/ethyl acetate (3:7 to 2:8) to give the title compound. MS (ESI+) m/z 588.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][Br:29]>CN(C)C=O>[Br:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:27][CH2:28][Br:29])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C(=O)c1ccc(OCCCBr)cc1)c1ccc(OCCCBr)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1,2-bis(4-hydroxyphenyl)ethane-1,2-dione (2.6 g, 10.74 mmol) was dissolved in DMF and K2CO3 (5.9 g, 42.7 mmol) was added, 100 mmol of 1,3-dibromopropane and a catalytic amount of KI were then added. The mixture was heated to 80° C. and stirred for 3 days. TLC check showed 1,2-bis(4-hydroxyphenyl)ethane-1,2-dione disappeared. Dimethylformamide (DMF) was removed, and water was added, extracted by EtOAc, washed with brine, dried over MgSO4. The solvent was removed and the residue was purified by column chromatography to give 1,2-bis(4-(3-bromopropoxy)phenyl)ethane-1,2-dione 6 as a pale yellow solid, as confirmed by the following nuclear magnetic resonance (NMR) data obtained therefrom: 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J=8.8 MHz, 4H), 6.99 (d, J=8.8 MHz, 4H), 4.20 (t, J=6.2 MHz, 4H), 3.61 (t, J=6.2 MHz, 4H), 2.34 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:42][C:5]1[C:4](=[O:27])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropyridazine-3-carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 mL, 8.86 mmol) and Et3N (1.23 mL, 8.86 mmol) in toluene (23 mL) was heated to 100° C. for 90 min. To the mixture was added 8 M NaOH aqueous solution (7.4 mL) at 0° C. The mixture was stirred at room temperature for 2 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and on silica gel (hexane/EtOAc=80/20 to 0/100) and triturated with EtOAc/hexane to yield the title compound (1.12 g, 53% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.73 (3H, s), 6.24 (2H, s), 7.92 (1H, d, J=10.5 Hz), 7.99 (1H, d, J=6.8 Hz), 8.37 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:19])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: CC(C)N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC(C)C)C1(C)C

Procedure:
The product from Example 173 and isopropylamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.02-1.05 (m, 6H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.44 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.95-2.08 (m, 1H), 2.60-2.67 (m, 3H), 2.72-2.82 (m, 1H), 3.80-3.92 (m, 1H), 7.39 (d J=7.4 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N2O3S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.80; H, 9.54; N, 9.50.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O1CCCC1.C([O-])=O.[NH4+]>[Fe].O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 75 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
tert-Butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate (1.25 g, 3.90 mmoles), 1 equivalent), tetrahydrofuran (10 ml), water (10 ml), iron dust (1.09 g, 19.5 mmoles, 5 equivalents), and ammonium formate (1.23 g, 19.5 mmoles, 5 equivalents) were combined and heated, with stirring to 75° C. for 12 hours (overnight). The hot mixture was filtered through a plug of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.11 g of tert-butyl 4-(4-amino-3-methylphenyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3), δ 6.47 (d, 1H), 6.16 (d, 1H), 6.14 (d, 1H), 5.85 (bs, 2H), 3.35 (m, 4H), 3.19 (m, 4H), 2.35 (s, 3H), 1.42 (s, 9H). MS (EI) for C16H25N3O2, 292 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FA) (1.03 g, 3.42 mmol) in 1,2-dichloroethane (15 ml) was treated with ethyl 7-oxoheptanoate (1.776 g, 10.25 mmol) followed by sodium triacetoxyborohydride (3.62 g, 17.09 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with saturated NaHCO3 (70 ml) and was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-60% EtOAc/iso-hexane to give an oil. The product was loaded onto an Isolute™ SCX-2 cartridge, washed with MeOH and eluted with 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford the title compound;
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.[CH3:18][O:19][CH2:20]CO>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:18][O:19][CH3:20])[CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Product: COCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Temperature: 45 °C

Procedure:
0.2 mol (13.2 g) of potassium hydroxide pellets (85%) is added to 100 ml of ethylene glycol monomethyl ether which has been heated beforehand to 45° C. 0.1 mol (21.2 g) of 4,5-methylenedioxy-1,2-dinitrobenzene, prepared according to Example 1, is added to this solution in the course of 5 minutes. The heating is maintained for 1 hour.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C[O-].[Na+].CO.[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(OC)(OC)OC>[CH:17]1([CH:23]=[CH:1][C:2]([C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=2[OH:11])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(C=CC1CCCCC1)c1cc(F)ccc1O
Reaction time: 0.75 h

Procedure:
A mixture of 5-fluoro-2-hydroxyacetophenone on Wang resin (4.0 g, 4.6 mmol) was swelled in trimethyl orthoformate (40 mL) for 10 min. 25% NaOMe in MeOH (2.0 g, 9.2 mmol) was added and the mixture was stirred for 45 min. Cyclohexanecarboxaldehyde (1.5 g, 13.8 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 4.3 g of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-2-propen-1-one on Wang resin.