Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.ClC1N=C(N2CCOCC2)C2C=C(CN3CCN(C4CC4)CC3)SC=2N=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([CH:21]4[CH2:23][CH2:22]4)[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Agent: Clc1nc(N2CCOCC2)c2cc(CN3CCN(C4CC4)CC3)sc2n1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CC4)CC3)cc2n1
Yield: 79.1 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (254 mg) and 1-cyclopropylpiperazine di-HCl (352 mg) was reacted under the reductive amination conditions described for 2-chloro-6-(4-cyclopropyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine, to give the title compound (279 mg) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[CH2:16][C@H:15]2[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[OH:19][CH2:18][CH2:17][C@@H:15]1[CH2:16][C@@H:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:13][CH2:12]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)OC(=O)N1CCC([C@H]2C[C@H]2CCO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Isopropyl chloroformate (0.12 μL, 1.0 mmol) was added dropwise to a solution of 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (170 mg, 1.0 mmol) and cesium carbonate (650 mg, 2.0 mmol) in acetonitrile (5 mL). After total addition, the mixture was stirred for 2 hours at RT. The solution was concentrated under reduced pressure and the residue taken-up in 10 mL DCM. The solution was washed with water, the organics were collected, dried over sodium sulfate, filtered and the filtrate concentrated to dryness under reduced pressure. The residue by flash chromatography (20 g of silica gel, ISCO, eluted with a gradient 0-100% ethyl acetate in Hexane) to afford the title compound (189 mg, 74%). LC/MS 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)=[CH:10][N:9]2[CH2:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(Cl)c1
Product: CCn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1cccc(Cl)c1

Procedure:
A 2.6 gram portion of 1-(3-chlorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, prepared in Example 3, was alkylated with ethyl iodide to produce 0.25 grams of the desired product, an oily liquid.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][C:17]1([CH3:19])[C:3]2[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][C:4]=2[O:7][CH:16]1[OH:20]
Reactant: CC(C)C=O
Reactant: O=C1C=CC(=O)C=C1
Solvent: CCN(CC)CC
Product: CC1(C)c2cc(O)ccc2OC1O
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution of 108 g. (1 mole) of p-benzoquinone in 1 liter of isobutyraldehyde is added dropwise with stirring to a refluxing solution of 500 ml. of isobutyraldehyde containing 5 ml. of triethylamine. The total addition and heating time is five hours. The excess isobutyraldehyde is stripped in vacuo leaving a crude oil that crystallized on standing. Trituration with cold chloroform gives 125 g. (70%) of product: m.p. 78°-81°C., nmr indicated the material to be 90-95% desired compound. A sample recrystallized from chloroform had a m.p. of 97°-99°C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1

Procedure:
A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([C:7](Cl)=[O:8])[C@@H:4]([CH3:10])[O:3]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([NH:19][C:7]([C@@H:5]1[C@@H:4]([CH3:10])[O:3][C:2]([CH3:11])([CH3:1])[O:6]1)=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H]1OC(C)(C)O[C@@H]1C(=O)Cl
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: C[C@H]1OC(C)(C)O[C@@H]1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A flask was charged with 70 mL dry tetrahydrofuran, 3.17 g (17.7 mmol) (4S,5R)-2,2,5-trimethyl[1,3]dioxolane-4-carbonyl chloride, and the solution was cooled in a 0° C. bath. To this solution, 3.48 mL (31.9 mmol) benzyl amine was slowly added, and a precipitate formed immediately. The reaction mixture was stirred for 1 hour at 0° C. and 1 hour at room temperature. The reaction mixture was filtered through Celite to remove salts, and the tetrahydrofuran was removed under reduced pressure giving 4.41 g (100%) of the title compound as a yellow oil. No further purification was necessary. MS (APCI) (m+1)/z 250.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)(=[O:19])=[O:18]
Reactant: CN1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
4-Hydroxy-N-methylpiperidine (200 μL, 1.70 mmol) was dissolved in methylene chloride (10 mL) and then cooled to 0° C. Triethylamine (296 μL, 2.13 mmol) was added, followed by the addition of methanesulfonyl chloride (145 μL, 1.87 mmol). After 1.5 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated under vacuum to give the desired product (280 mg, 88%). LCMS calculated for C7H16NO3S (M+H)+: m/z=194.1. Found: 194.1.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12
Reactant: ClCCCCI
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccc2c(OCCCCCl)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
817 mg (4.041 mmol) of 5-hydroxypsoralen and 1.413 g (6.47 mmol) of 4-chlorobutyl iodide were refluxed in 80 ml of acetone in the presence of an excess of (3.0 g) anhydrous potassium carbonate for 30 hours. The progress of the reaction was monitored by thin layer chromatography. After 30 hours the reaction mixture was concentrated under reduced pressure and distilled off the solvent almost completely. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×100 ml of dichloromethane. The dichloromethane layer was extracted with 1×25 ml of 1% sodium hydroxide to separate trace amounts of un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid and further washed with water to neutral pH. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was then suspended in petroleum ether and filtered to wash out the excess 4-chlorobutyl iodide. The resulting 5-(4-chlorobutoxy)psoralen was used for the synthesis of various derivatives without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)(=O)C>[Cl:16][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(COc1ccccc1)OC
Reactant: O=S(Cl)Cl
Solvent: CC(=O)Cl
Product: COC(Cl)COc1ccccc1

Procedure:
To 36 g of phenoxyacetaldehyde dimethyl acetal was added, dropwise, 40 ml of acetyl chloride and 0.5 ml of thionyl chloride. After 15 h at room temperature the solution was evaporated and the residue distilled under vacuum, 110°-120° C./1 mm, to yield the title compound as a colourless oil.
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CCCCCC>[C:15]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:23]=[CH:22][CH:21]=[C:17]([N:18]([CH3:20])[CH3:19])[CH:16]=1
Reactant: CN(C)c1cccc(Cl)c1
Reactant: Br[Mg]c1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 94 %

Procedure:
Using a THF solution of phenylmagnesium bromide (1.19 mL, 1.01 M, 1.2 mmol) and 3-chloro-N,N-dimethylaniline (155.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=50 and 100% in hexane), the above compound was obtained as a colorless liquid (0.185 g, yield=94%, purity=>98% (GC analysis)).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:1]([C:2]2[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(N2CCC(Cc3ccccc3)CC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 4-benzylpiperidine according to Method G+H.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([CH2:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]2=[O:12])[CH2:7][CH:6]1[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.O>[CH:2]([CH2:3][O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([CH2:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]2=[O:12])[CH2:7][CH:6]1[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:1]
Reactant: Cc1cn(C2CC(OC(=O)c3ccccc3)C(OCC(O)CO)O2)c(=O)n(CC(=O)c2ccccc2)c1=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(C2CC(OC(=O)c3ccccc3)C(OCC=O)O2)c(=O)n(CC(=O)c2ccccc2)c1=O
Yield: 93.3 %

Procedure:
A solution of compound 168 (4.5 g, 2.85 mmol) and NaIO4 (0.78 g, 3.66 mmol) in 1:1 THF/H2O (120 mL) was stirred at RT for 2 hrs. The solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 20:1→10:1) to give 1.31 g of the title compound as a white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@@H:25]5[NH:29][C@@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:37]=O>>[CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@@H:25]5[N:29]([CH3:37])[C@@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5C)cn3)nc2n1C1CCCC1
Yield: 80 %

Procedure:
Following general reductive alkylation method 1, 7-Cyclopentyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide was combined with formaldehyde (37% solution in water) which after purification gave 7-cyclopentyl-2-[5-((1S,6R)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (41 mg) in 80% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.81 (s, 1H), 8.31 (d, J=9.09 Hz, 1H), 8.12 (d, J=2.53 Hz, 1H), 7.58 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (m, 1H), 4.16 (d, J=14.65 Hz, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.20 (t, J=6.57 Hz, 1H), 3.06 (br. s., 6H), 2.99 (m, 1H), 2.46 (m, 2H), 2.34 (s, 3H), 2.06 (m, 6H), 1.81 (m, 2H), 1.67 (m, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH3:18][NH2:19]>CO.CCO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[N:19][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=Cc1ccc2c(c1)ncn2C1CCCCO1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CN=Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 64 (1.0 g, 4.34 mmol) in MeOH (10 mL) at 0° C. was added a solution of MeNH2 in EtOH (33%, 2 mL). After stirring at RT for 2 h, the mixture was concentrated under reduced pressure to afford 1.0 g (94%) of N-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methylene)-methanamine (66) as yellow oil: MS (ESI) m/z=244.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=O)[CH:28]=[CH:29][CH:30]=1.[O-]CC.[Na+]>C(O)C>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:32]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:22][C:20](=[O:21])[C:3]2=[C:4]([C:16]([F:19])([F:18])[F:17])[NH:5]1
Reactant: NC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(F)(F)F)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.3 %

Procedure:
To a stirred solution of 186 mg (0.50 mmol) of 5-amino-3-trifluoromethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 555 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.26 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 23 h at reflux, and the heating mantle was then removed. The reaction was treated with 10 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:3 ether-hexanes. The off-white solid was briefly air-dried to give 230 mg (91%) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass spec.: 503(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-:22].C(OC([N:30]1[CH:34]2[CH2:35][NH2+:36][CH2:37][CH:33]2[CH2:32][CH2:31]1)=O)(C)(C)C.Cl>>[Cl-:22].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:36]2[CH2:37][CH:33]3[CH:34]([NH2+:30][CH2:31][CH2:32]3)[CH2:35]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C[NH2+]CC21
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Agent: Cl
Agent: [Cl-]
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CC4CC[NH2+]C4C3)cccc2c1

Procedure:
0.088 g of 5-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydropyrrolo[3,4-b]pyrrol-1-ium chloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with 1-(tert-butoxycarbonyl)-octahydropyrrolo[2,3-c]pyrrol-5-ium chloride and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isoproanol.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH:24][C:25](=[O:39])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH:27]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3]1.[CH2:40]=O.[BH4-].[Na+]>CO>[CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH:24][C:25](=[O:39])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([CH3:40])[CH2:37][CH2:38]5)[CH:27]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3]1
Reactant: C=O
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C)CC5)c4)ccc3F)c2)CCN1C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of N-[(3′-{[(3S)-3,4-dimethyl-1-piperazinyl]methyl}-6-fluoro-3-biphenylyl)methyl]-3-(4-piperidinylmethyl)benzamide (165 mg, 0.313 mmol) in 3 mL of MeOH, was added dropwise formaldehyde (37%, 101 mg, 1.25 mmol). After stirring for 30 minutes, sodium borohydride (24 mg, 0.63 mmol) was added. After stirring of the resulting mixture at rt for 12 hours, the solvent was removed under vacuum and the residue was purified by loading onto a 2 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The DCM factions were combined and evaporated to give the title compound as a white solid (60 mg, 35%). LC/MS: m/z, 543 (M+H), 1.18 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]([C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:15]1)C(=O)OC(C)(C)C)[CH3:2].FC(F)(F)C(O)=O>>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:15]1)[CH3:29]
Reactant: CCN(CC)CCN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (7.9 g) was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 306.41 (C16H26N4O2); MS (ESI): 307 (M+H+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@@H:26]([O:34]C(=O)C)[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C@H:26]([OH:34])[C:27](=[O:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)-3,12-di(acetoxy)spirostan-11-one (purchased from Steraloids, Inc., or see preparation G13) was saponified with potassium carbonate in water, methanol and THF to provide the title compound.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][OH:44]>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:41][CH2:42][CH2:43][OH:44])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (600 mg, 1.08 mmol) was dissolved in THF (15 mL) to which was added DIEA (697 mg, 5.40 mmol), followed by 2-aminoethanol (132 mg, 2.17 mmol). This mixture was stirred at R.T. for 2 h., then the reaction solvent removed under reduced pressure and the resulting white solid suspended in Et2O. The solid was collected by filtration, then recrystallised from EtOAc/MeOH to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (394 mg, 85%) as a white solid, m.p. (EtOAc/MeOH) 205-208° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.10 (s, 1H), 8.43 (br s, 1H), 8.28 (s, 1H), 7.72 (dd, J=10.2, 1.8 Hz, 1H), 7.56 (br d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.58 (s, 1H), 4.76 (br t, J=5.2 Hz, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.36 (s, 3H), 3.32-3.26 (m, 2H). Anal. Calcd for C15H15FIN3O3: C, 41.8; H, 3.5; N, 9.8. Found: C, 4.19; H, 3.2; N, 9.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:21]=43)[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1.[AlH4-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[C:21]4[CH:24]=[CH:25][C:26]([CH2:28][NH2:29])=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C#N)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CN)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reaction time: 2 h

Procedure:
To 2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrile in tetrahydrofuran was added Lithium tetrahydroaluminate (1M in THF), dropwise at 0° C. The reaction was stirred for 2 hours and quenched with saturated Na2SO4 until H2 evolution ceased. MgSO4 was added and the whole was diluted with copious amounts of methylene chloride, filtered over celite, and concentrated in vacuo. The crude was purified by flash chromatography (1-15% MeOH in DCM spiked with Et3N) to afford to give 355. MS(ESI+) 409.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68 (td, J=8.7, 6.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.32-7.25 (m, 1H), 6.95 (s, 1H), 6.91 (dd, J=8.2, 1.2 Hz, 1H), 4.48-4.38 (m, 4H), 3.66 (s, 2H), 2.35 (s, 3H).