Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH:10]([S:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:8])=[O:9])=[CH2:11]
Reactant: O=S(=O)(CCO)C1CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-cyclohexylsulfonylethanol (22 g) and triethylamine (30 ml) in methylene chloride (200 ml) was treated dropwise with a solution of methanesulfonyl chloride (15 ml) in methylene chloride (100 ml) at 10° C. After stirring for 2 h at room temperature the mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo leaving the product, cyclohexyl vinyl sulfone, as an oil (19 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]([CH3:21])[C:6](=[O:20])[S:7][C:8]1[C:13]2[C:14]([CH3:19])=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=[CH:10][CH:9]=1>CO>[OH:2][C:1]1[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:6]([N:5]([CH3:4])[CH3:21])=[O:20])[C:13]=1[C:14]([CH3:19])=[CH:15][C:16]([O:17][CH3:12])=[O:18]
Reactant: Cc1cc(=O)oc2cccc(SC(=O)N(C)C)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=C(C)c1c(O)cccc1SC(=O)N(C)C
Reaction time: 4 h
Yield: 76 %

Procedure:
4.4 ml of sodium methylate (8% of Na (w/v) in methanol) are added under an inert atmosphere to a solution of 2 g (7.6.10-3 mol) of S-(4-methyl-2-oxo-2H-1-benzopyran-5-yl) dimethylthiocarbamate in 20 ml of methanol. After 4 hours at room temperature, the reaction medium is hydrolyzed in an ice/hydrochloric acid mixture and the precipitate formed is filtered off to give 1.7 g (yield: 76%) of the expected product.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]([S:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=3)=[C:4]2[C:3]1=[O:26].[NH2:27][OH:28].Cl.C[O-].[Na+]>CO>[OH:28][NH:27][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([S:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]3[CH2:24][CH2:25][N:2]([CH3:1])[C:3](=[O:26])[C:4]=23)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Sc2c3n(c4ccccc24)CCN(C)C3=O)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCn2c(c(Sc3ccc(C(=O)NO)cc3)c3ccccc32)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
To a solution of methyl 4-((2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl)thio)benzoate (0.25 g, impure) and NH2OH.HCl (0.35 g) in 4 mL of dry MeOH was added 1.4 mL of 25% NaOMe solution in methanol. The reaction mixture was stirred for 20 min at r.t. and 0.3 mL of more 25% NaOMe solution in methanol was added. After stirring for 2 h, the reaction mixture was quenched with 10 mL of potassium phosphate buffer solution. The mixture was extracted with 2×30 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 0.097 g of the title product as beige solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13]([C:20]2[C:21]([CH3:35])=[N:22][N:23]3[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:27][C:26]([CH3:34])=[N:25][C:24]=23)=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=1)(C)(C)C.[ClH:37]>CO>[ClH:37].[CH2:30]([CH:29]([C:28]1[N:23]2[N:22]=[C:21]([CH3:35])[C:20]([C:13]3[S:12][C:11]([NH:10][CH2:9][CH2:8][NH2:7])=[N:15][C:14]=3[C:16]([F:17])([F:18])[F:19])=[C:24]2[N:25]=[C:26]([CH3:34])[CH:27]=1)[CH2:32][CH3:33])[CH3:31]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(NCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)c(C)nn12
Agent: Cl
Solvent: CO
Product: CCC(CC)c1cc(C)nc2c(-c3sc(NCCN)nc3C(F)(F)F)c(C)nn12
Yield: 78 %

Procedure:
Add (2-{5-[7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-4-trifluoromethyl-thiazol-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (101 mg, 0.192 mmol) to 1 M HCl in methanol (1 mL). Heat the reaction at 70° C. overnight. Cool the reaction and concentrate under vacuum from methanol/ethyl acetate. Triturate the resulting residue with ethyl acetate to obtain the title compound (64 mg, 78%). ES/MS m/z 427.0 (M+1)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.C(OC(=O)C)(=O)C>[OH-].[Na+]>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:16][C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1cccnc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C=Cc2cccnc2)cc1

Procedure:
p-Tolualdehyde (12.0 g), 3-picoline (8.6 g) and acetic anhydride (10.2 g) were heated at 160°C for 16 hrs. The reaction mixture was then poured hot into 10% NaOH (60 ml). The solid which crystallised was filtered off and subjected to column chromatography with neutral alumina using chloroform as solvent. Mpt. 166°C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:18]4([CH2:19][CH2:20][O:16][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC2(CCOC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), dihydro-3(2H)-furanone (0.215 g, 2.50 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 5 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol) to afford the title compound (0.0165 g, 11%) as a yellow solid:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:54]([O:61][CH2:62][CH2:63][CH2:64]O)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Si:54]([O:61][CH2:62][CH2:63][CH2:64][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([C:57]([CH3:58])([CH3:59])[CH3:60])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 53.4 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (136 mg, 0.519 mmol), 3-(tert-butyldimethylsilyloxy)propanol (0.111 mL, 0.519 mmol) and 40% DEAD-toluene solution (0.237 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-[3-(tert-butyldimethylsilyloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (58.6 mg, yield 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]CC)=[O:25])=[C:12]2[O:29][CH2:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[O:29][CH2:30][CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(C(=O)O)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 78.8 %

Procedure:
To a solution of ethyl 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate (6.57 g, 13 mmol) in ethanol (50 mL) was added an aqueous solution (20 mL) of sodium hydroxide (2.08 g, 52 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium, sulfate and concentrated under reduced pressure. The obtained, crystals were recrystallized from ethyl acetate-n-hexane to give 6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylic acid (4.89 g, 78.7%) as crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][CH:6]([F:34])[C:7]1[N:11]([C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:13]=2)[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=2[N:8]=1.C1COCC1>O>[C:1]([N:27]1[CH2:26][CH2:25][N:24]([C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:12]([N:11]3[C:10]4[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=4[N:8]=[C:7]3[CH:6]([F:34])[F:5])[N:13]=2)[CH2:29][CH2:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 770 %

Procedure:
Acetyl chloride (0.14 ml, 2.0 mmol) was added dropwise to a mixture of 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine (417 mg, 1.0 mmol) and THF (10 ml). The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to give the target compound 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (354 mg, 7.7 mmol) in a yield of 77% as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:21])[C:11](=[O:22])[C:10]2[C:5](=[CH:6][C:7]([N+]([O-])=O)=[CH:8][CH:9]=2)[N:4]=1)C.BrN1C(=O)CCC1=O.[CH3:34][N:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Pd].[C]>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:1][N:38]1[CH2:39][CH2:40][CH2:41][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH3:21]
Reactant: CN1CCCNCC1
Reactant: CCOc1ccccc1-n1c(CC)nc2cc([N+](=O)[O-])ccc2c1=O
Agent: [Pd]
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccccc1-n1c(CN2CCCN(C)CC2)nc2ccccc2c1=O

Procedure:
Briefly, 2-amino-4-nitrobenzoic acid was acylated with propionyl chloride in triethylamine (TEA) and tetrahydrofuran (THF). The acylated compound was refluxed with 2-ethoxyaniline in phosphorus oxychloride (POCl3) and toluene to produce 2-ethyl-7-nitro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one. The 2-ethyl-7-nitro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one was brominated with N-bromosuccinimide (NBS) in carbon tetrachloride, the product of which was subsequently reacted with N-methylhomopiperazine in THF. The product of this reaction was subjected to hydrogenation conditions using catalytic amounts of Pd/carbon (10% Pd) to afford Compound 10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: OCc1cccc(Br)c1
Agent: Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)c1
Reaction time: 48 h

Procedure:
The alcohol of Step 1 (41.23 mmol), dihydropyran (12.5 mL, 137 mmol) and triphenylphosphine hydrobromide (725 mg, 2.11 mmol) were mixed together in 200 mL of CH2Cl2 and stirred for 2 days. The solvent was then evaporated and the title product was purified by flash chromatography on silica using EtOAc:toluene.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].C[Si]([N:32]=[N+:33]=[N-:34])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:13]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:12][C:9]([C:10]2[NH:34][N:33]=[N:32][N:11]=2)=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c2nc(-c3cc(C#N)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCc1c2nc(-c3cc(-c4nnn[nH]4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Temperature: 80 °C
Yield: 65.1 %

Procedure:
5-[2-Isobutoxy-5-cyano-3-pyridinyl]-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-a]pyrimidin-7-one (Example 36) (200 mg, 0.55 mmol), trimethylsilylazide (0.069 mL, 0.54 mmol) and dibutyltin oxide (54 mg, 0.22 mmol) were heated at 80° C. in toluene (10 mL) for 14 h. The reaction mixture was transferred to a PTFE lined sealed vessel, a further 0.069 mL trimethylsilylazide added and the reaction heated at 80° C. for a further 5 h. After cooling and filtering the filtrate was diluted with pentane. Further solid precipitated and this was combined with the original precipitate and purified by flash column chromatography (eluting with dichloromethane/methanol/ammonia in a ratio of 5:1:0.1) to give 144 mg product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)=O)[O:7]2.FC1C=CC=C2C=1CCC(C(O)=O)O2.C(N1CCNCC1)C1C=CC=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:19]1)[O:7]2
Reactant: O=C(C1CCc2c(F)cccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1CCc2c(F)cccc2O1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Fc1cccc2c1CCC(CN1CCN(Cc3ccccc3)CC1)O2

Procedure:
By carrying out the preparation as in Example 1, but using, at the start, 1-[(5-fluorochroman-2-yl)carbonyl]-4-benzylpiperazine resulting from the condensation of 5-fluorochroman-2-carboxylic acid with N-benzylpiperazine, the title compound is obtained.
Reaction SMILES: [CH:1]1([CH:7]=[N:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:10].OOS([O-])=O.[K+]>CN(C=O)C>[Cl:10][O:9][N:8]=[CH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=CC1CCCCC1
Reactant: Cl
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: ClON=CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the oxime formed in Example 1 (1 g, 8.25 mmol) in HCl (0.5 M in dioxane; 18.16 ml, 9.08 mmol) and DMF (40 ml) was added oxone (2.79 g, 4.54 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction was partitioned between diethylether and water and the layers were separated. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate, then concentrates in vacuo using a room temperature water bath. The resulting low boiling liquid was carried on directly to the next step. 1H NMR (CDCl3) δ 1.0-2.2 (m, 10H), 2.35 (m, 1H), 7.8 (bd, 1H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:21][C:22]([F:27])([F:26])[C:23](O)=[O:24]>C(Cl)Cl>[ClH:1].[F:21][C:22]([F:27])([F:26])[C:23]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)C(F)(F)F
Yield: 60.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.70 ml (4.96 mmol) of anhydrous trifluoroacetic acid under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate ) to obtain the powder which was washed with hexane and dried to obtain 750 mg of the desired compound (free base) (68.4%, pale yellow prisms).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]2[CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24](OCC)=[O:25])[O:21][C:17]=2[CH:16]=1>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]2[CH:19]=[C:20]([CH2:22][CH2:23][CH2:24][OH:25])[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)/C=C/c1cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2o1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCCO)oc2c1

Procedure:
To a solution of (E)-ethyl 3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]acrylate (1.30 g) in tetrahydrofuran (50 ml), palladium-carbon (5%, 0.70 g) was added, followed by catalytic reduction at room temperature and under an atmospheric pressure of 1 atm. After the catalyst was filtered off, sodium borohydride (0.61 g) was added to the filtrate, followed by dropwise addition of methanol (10 ml) under refluxing conditions. After heating under refluxing conditions for 1 hour, the reaction mixture was poured over water and neutralized with 2N hydrochloric acid, followed by extraction with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (1:5, v/v), 3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]propanol was obtained as an oily substance (0.90 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH3:26]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH3:26]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CCCI
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 43.3 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodopropane (0.25 mL, 2.54 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (75 mg, 39%) as a beige foam. ES(+)-MS (M+H) 347.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(O)(=O)C.CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCN(Cc2ccncc2)CC1
Reaction time: 15 h

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamide trifluoroacetate (25 mg, 0.053 mmol) in methanol (0.5 mL) was added 4-pyridinecarboxaldehyde (17.1 mg, 0.16 mmol) followed by a solution of sodium cyanoborohydride (7 mg, 0.106 mmol) in 7.5% acetic acid/methanol (1 mL). After shaking for 15 h, the solution was loaded onto an SCX column, which was pretreated with a solution of 5% acetic acid in methanol. The column was washed once with methanol and eluted with 2 N ammonia in methanol. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in a small amount of methanol and a few drops of acetic anhydride were added. After shaking for 0.5 h, the SCX purification procedure was repeated to give 9.8 mg (41%, 91% pure by HPLC analysis) of the title compound. IS-MS, m/e 450.1 (m+1) HPLC, Analytical method, RT=18.56 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
70 (171 mg, 0.81 mmol), methyl 3-(bromomethyl)benzoate (0.01 mL, 0.97 mmol), and Cs2CO3 (791 mg, 2.43 mmol) were suspended in DMF (3 mL), and stirred overnight at ambient temperature. The reaction solution was purified directly via flash chromatography on silica gel to provide 458 (130 mg, 44% yield) as a white powder. LC-MS (M+H=360, obsd.=360). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (dd, J=6.3, 11.9, 2H), 8.06 (d, J=8.7, 1H), 7.86 (s, 1H), 7.80 (d, J=8.0, 1H), 7.56 (d, J=7.6, 1H), 7.44 (d, J=8.5, 2H), 7.31 (m, 1H), 6.91 (d, J=9.0, 1H), 6.22 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H).