Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:53])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=3)[N:28]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:27]=2[CH2:49][CH2:50][CH2:51]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:53])[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=3)[N:28]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:27]=2[CH2:49][CH2:50][CH2:51][NH:11][S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])=[CH:21][CH:22]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCc2c(CCCBr)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCc2c(CCCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
33.3 mg of α-toluenesulfonamide (0.0002M, 1.2 eq.) was dissolved in 0.5 mL of DMF and added to a slurry of 8.0 mg of 60% sodium hydride (0.0002M, 1.2 eq.) in 0.5 mL of DMF. The reaction was stirred for 30 min. at which point 100 mg of 4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0002M, 1.0 eq.) in 0.5 mL of DMF was added and the solution was stirred for an additional 1 hour. The reaction was quenched with water and diluted with 10 mL of ethyl acetate. The organic layer was washed with water(2×5 mL) and brine (2×5 mL), dried over magnesium sulfate and evaporated to a yellow oil. The residue was purified via column chromatography (ethyl acetate/hexanes 5:95) to give 20 mg (17%) of 4-{2-[1-Benzhydryl-5-chloro-2-(3-phenylmethanesulfonylamino-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a clear oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][CH:22]=2)=[N:11][CH:10]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ncc(O)cn2)cc1
Yield: 88.5 %

Procedure:
A mixture of 10.0 g of 4-(5-benzyloxypyrimidin-2-yl)benzaldehyde, 0.2 g of sodium carbonate and 250 ml of ethyl acetate was treated with 1.0 g of palladium on active charcoal (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. The inorganic material was filtered off over Sillit and the filtrate was concentrated. Recrystallization of the crude product from hexane gave 6.1 g of pure 4-(5-hydroxypyrimidin-2-yl)benzaldehyde.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:29][CH:30]([O:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:31])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+]=[N-]>[Pd].CO>[C:33]([O:32][CH:30]([CH3:31])[CH2:29][CH:5]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:1])(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of 1.617 g (2.89 mM) of 1-azido-2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropane m7b and 170 mg of 10% palladium on charcoal in 150 ml of methanol is hydrogenated under hydrogen atmosphere for 1 hour. The mixture is filtered and the solvent of the filtrate is evaporated to obtain crude titled compound m8.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>ClCCl>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:11]1
Reactant: NN
Reactant: O=Cc1cccnc1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cnc2[nH]ncc2c1
Temperature: 150 °C

Procedure:
2-Chloro-3-formylpyridine (15.02 g, 106 mmol, 1 equiv), hydrazine (10 mL, excess), and dioxane (90 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. After cooling to room temperature, the solvent was evaporated in vacuo to provide a crude residue which was diluted with dichloromethane (600 mL). The organic solution was washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to provide 1H-pyrazolo[3,4-b]pyridine as a yellow powder which was used without further purification: LCMS (ES) M+H 120.3, Rf 0.20 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[C:10]1([N:9]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
NaH (0.220 g, 5.54 mmol) was dissolved in anhydrous DMF (2 mL) under argon and cooled to 0° C. To it was added diphenylamine (0.0.750 g, 4.43 mmol) dissolved in anhydrous DMF (2 mL). The reaction was stirred for 15 min at 0° C. followed by the addition of methyl 4-(bromomethyl)benzoate (1.02 g, 4.43 mmol) in anhydrous DMF (2 mL). The reaction was stirred for 2 h at 60° C. and then quenched by the addition of H2O (20 mL). The organic products were extracted with EtOAc (3×30 mL), washed with H2O (2×30 mL), brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The title compound was purified using automated column chromatography method 1 (0.746 g, 53%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.2 Hz, 2H), 7.45 (d, J=7.7 Hz, 2H), 7.27 (m, 4H), 7.07 (d, J=7.9 Hz, 4H), 6.98 (t, J=7.3 Hz, 2H), 5.06 (s, 2H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.9, 147.8, 144.8, 130.0, 129.4, 128.9, 126.5, 121.7, 120.7, 56.3, 52.0. ESI-LRMS: [M+H]+=318 m/z.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([C:16]#N)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(O)=[O:21]>[Al].[Ni]>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[O:21])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: [Ni]
Agent: [Al]
Product: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2

Procedure:
3-Trifluoracetyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (20.3 g) and nickel-aluminium alloy (35.5 g) in 75% aq. formic acid (400 ml) were heated at 80° C. for 3 h. The reaction was allowed to cool, filtered and the filtrate extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, dried and evaporated to give 3-trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde (20.0 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[C:10]([CH3:11])[N:9]=2)(=[O:21])=[O:22])=[CH:16][C:15]=1[C:24]([F:27])([F:25])[F:26]
Reactant: CCOCc1ccc(N)nc1C
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: CCOCc1ccc(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.07 g) and 4-chloro-3-(trifluoromethyl)- benzenesulfonyl chloride (0.129 g) as a yellow gum (0.068 g). MS (ESI−): 407.2 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
As in Example 115, (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid (21.0 g) and 4-nitrophenol (11.2 g) in dichloromethane (300 mL) was treated with 1,3-dicyclohexylcarbodiimide (14 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature overnight. After the usual work up, the crude product was crystallized from ether-hexane to give 24.7 g of (E)-5,5-bis (4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 121°-123° C. Recrystallization of the material from 2-propanol afforded the purified ester, mp 125°-126° C. Anal. Calculated for C25H21NO6 : C, 69.60; H, 4.91; N, 3.23 Found: C, 69.19; H, 4.94; N, 3.25
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+]>CCO.C1COCC1>[S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH:15]([OH:20])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3O)cc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (5 g, 17.22 mmol) in EtOH/THF (30 mL/30 mL)) was added NaBH4 (1.3 g, 34.44 mmol) under ice-bath. The mixture was stirred for 1 h at this temperature and quenched with aqueous NH4Cl solution. Removed the solvent under reduced pressure and extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue 1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (4.94 g, yield 98.2%) was used directly to next step. MS-ESI (m/z): 293 (M+1)+ (Acq Method: 10-80AB_2 min; Rt: 1.01 min)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>O>[Cl:14][C:15]1[C:16]([C:17]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]3[N:9]=2)=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2cccnc2Cl)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 0.96 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.95 g of 2-chloronicotinic acid, 0.85 g of EDCI hydrochloride and 10 ml of pyridine was heated and stirred at 120° C. for 3 hours. Water was poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.02 g of 2-(2-chloropyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine. 2-(2-Chloropyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:36])[N:18]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C@@H:19]4[C@H:24]([C:25]=3[OH:26])[C@@H:23]3[CH2:27][C@H:20]4[CH2:21][CH2:22]3)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:14])(=[O:15])[N:11]=[C:10]([C:16]3[C:17](=[O:36])[N:18]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[C@@H:19]4[C@H:24]([C:25]=3[OH:26])[C@@H:23]3[CH2:27][C@H:20]4[CH2:21][CH2:22]3)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (1R,2S,7R,8S)-5-(7-azidomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.10 g, 0.19 mmol) in ethanol (6 mL) and ethyl acetate (3 mL) was added 10% palladium on carbon (10 mg). The mixture was degassed and stirred under an atmosphere of hydrogen gas (balloon) overnight. The resulting mixture was diluted with N,N-dimethylformamide (10 mL) and filtered through a pad of Celite. The organic was concentrated in vacuo to afford the crude product, (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (95 mg, 0.19 mmol, 100%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:29][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)CC(C)Br
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCOc1c(O)c2cccc(OCCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromobutanoate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(3-ethoxycarbonylpropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH:18]3[CH2:20][CH2:19]3)[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.Cl>[Cl:16][C:15]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=2)=[N:11][C:12]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Temperature: 50 °C
Yield: 90 %

Procedure:
4-(5-Chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid methyl ester (90 mg, 0.30 mmol) was dissolved in THF and 50 mg (1.2 mmol) of lithium hydroxide monohydrate dissolved in water was added. The reaction mixture was heated to 50° C. for 5 hours, cooled to room temperature, diluted with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-(5-chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid as a yellow solid, 78 mg, 0.27 mmol, 90% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>ClCCl.CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reaction time: 0.5 h

Procedure:
3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10° C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15° C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutralized by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dichloromethane (2×150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow solid. Flash column chromatography using as eluant 5% methanol in dichloromethane gave a pure sample of the title compound (660 mg) and a sample (1.95 g) containing ca. 10% of the 8-nitro isomer.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]([OH:6])=[O:28])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of sodium chlorite (1.17 g; 12.9 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.01 g; 8.44 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (2 mL) and 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethoxy]-benzaldehyde (690 mg; 2.34 mmol; 1 eq.) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (690 mg, 95%) as a white solid. UPLC/MS: (MS−) 309.1 ([M−H]−).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and aniline (Aldrich) according to the method described in Example 1c. Melting Point: 125-128° C. (diethylether)
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11]2(O)[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[C:12]2([CH2:25][CH2:26][CH3:27])O)=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.O>[C:3]([CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[CH:12]2[CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)([OH:31])=[O:2]
Reactant: CCCC1(O)c2c(ccc(C(C)=O)c2O)OC1(O)COc1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1COc1ccc(CC(=O)O)cc1
Reaction time: 3 h

Procedure:
The compound from Example 16 (650 mg, 1.63 moles) was taken up in 5 ml THF to which was added 1 N NaOH (4.2 ml). After three hours, the reaction volume wad diluted with H2O and the THF was removed in vacuo. The aqueous phase was wahsed with CHCl3, then acidified and extracted into CHCl3. The organic extract was dried and concentrated. The residue was triturated with ether to afford the title compound as a white solid which was recrystallized from toluene, m.p.: 104°-106°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][N:10]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[Br:35][C:6]1[CH:7]=[C:8]2[CH:13]3[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]3[N:10]3[CH2:11][CH:2]([CH3:1])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]([CH:5]=1)=[C:9]23
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 0.1 mmol) in DMF (10 mL) at 0° C. was added NBS (20 mg, 0.11 mmol) and stirred at 0° C. for 2 hours. The solution was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 88%) as a clear oil. MS [M+H]+454.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CO.O>[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18](=[O:2])[CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CCCC2N(CCC3(O)CCCCC3)C(=O)CS2=O)cc1

Procedure:
Sodium metaperiodate (0.75 g., 3.5 mmoles) is added to a cold (0°-5° C.) solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (1.33 g., 3.4 mmoles) in methanol (20 ml.) and water (5 ml.). The resulting mixture is stirred without further cooling for 16 hours. The precipitated solid is then removed by filtration. The filtrate is diluted with water and extracted with chloroform. The organic extract is washed with brine, dried over sodium sulfate, and evaporated in vacuo to leave an oily residue which is chromatographed on silica gel (25 g.). Elution with 4% acetic acid in chloroform affords the title compound as a viscous, yellowish oil.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[CH:16]1>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([C:25]2[S:40][C:28]3[N:29]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=3[C:26]=2[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:6])=[CH:16]1
Reactant: CON(C)C(=O)c1c(Cc2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1c(C(=O)c2c[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
DDQ (0.25 g) was added to a stirred solution of the product of example 4 (0.25 g) in THF (9 ml) and water (1 ml). The solution was stirred for a further 2 h and the concentrated in vacuo. The residue was purified by flash silica chromatography eluting with ethyl acetate:isohexane (7:3) to give the title compound as a pale pink solid (0.1 g).