Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C@@:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:22])[CH:3]=1.C([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:6]([SH:36]([C:28]1[CH:29]=[C:30]([CH3:35])[C:31]([CH2:33][OH:34])=[CH:32][CH:27]=1)[C:3]1[C:4](=[O:22])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:14])([CH3:8])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)C[C@@](CCc2ccccc2)(c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([SH](C2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)C(C)(C)C)ccc1CO

Procedure:
The title compound was prepared as described in General Method 9 using 0.12 g (0.40 mmol) of (S)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one (prepared in Example VV), 0.16 g (0.44 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.22 g (1.6 mmol) of K2CO3, and DMF (2 mL). Upon standard work-up, the residue was chromatographed on silica gel, eluting with 4:1 CHCl3 :EtOAc, to give the title compound, m.p. 186°-187° C. 1H NMR (DMSO-d6) δ (s, 9 H), 1.75 (s, 3 H), 2.25 (m, 3 H), 2.55 (m, 1 H), 3.51 (q, partially obscured by H2O, 2 H), 4.32 (br s, 2 H), 4.90 (br s, 1 H), 6.17 (s, 1 H), 7.09 (m, 2 H), 7.15 (m, 1 H), 7.23 (m, 3 H), 7.37 (m, 1 H), 7.44 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 72%).
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].CC([O-])(C)C.[K+].[Si:19]([O:26][CH2:27][C@@H:28]1[CH:33]=[C:32]([CH2:34][O:35][CH3:36])[C@H:31](OS(C)(=O)=O)[CH2:30][N:29]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ON>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[C@H:31]1[CH2:30][N:29]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@H:28]([CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:33]=[C:32]1[CH2:34][O:35][CH3:36])[CH:2]=[CH2:3]
Reactant: C=CCONC(=O)OC(C)(C)C
Reactant: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: NO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl allyloxycarbamate (7.39 g, 42.66 mmol) in DMF (150 mL) at rt, potassium 2-methylpropan-2-olate (42.66 mL, 42.66 mmol) was added and gave a purple solution. After 30 min at rt, the mixture was cooled to 0° C. and (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(methoxymethyl)-5-(methylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 16.55 g, 35.55 mmol) in 50.0 mL DMF was added. The mixture was then warmed up to rt for 1 h. It was then diluted with ethyl acetate (200 mL) and washed aqueous sat. NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated to give a residue which contains some starting material. The crude was purified on a silica gel column yielding a colorless oil. (19.3 g). 1HNMR shows still a mixture (with hydroxyamine starting material). It was used directly in TBS deprotection.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O.O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Cc1cc(O)c(Cl)c(=O)n1-c1c(F)cccc1F
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.27 g, 1.00 mmol) in DMA (5 mL) was added K2CO3 followed by the addition of 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol). The reaction mixture stirred at room temperature for 2 hours and then was diluted in water. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over Na2SO4 and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane 3:4 v/v) to afford the desired product. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, 1H), 5.36 (s, 2H), 2.11 (s, 3H); ES-HRMS m/z 398.0551 (M+H calculated for C19H13NO2F4Cl requires 398.0571).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:13]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])=[O:15])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A mixture of 7-nitroindole-2-carboxylic acid (4.38 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.89 g) in dichloromethane (50 mL) was treated with piperazine-1-carboxylic acid tert-butyl ester (1.63 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into in dichloromethane (20 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-5% methanol/dichloromethane) to give 4-(7-Nitro-1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.17 g). This material (1.69 g) was dissolved in CH3OH (50 mL). At room temperature, ammonium formate (2.85 g) was added, followed by 10% palladium on carbon (0.47 g). The reaction mixture was heated to reflux for forty min, cooled and filtered through celite pad. The filtrate was concentrated and the residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give 4-(7-Amino-1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.34 g). This material (1.3 g) was treated with 20% trifluoroacetic acid/dichloromethane (50 mL) and stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure to afford (7-Amino-1H-indol-2-yl)-piperazin-1-yl-methanone trifluoroacetate salt. This intermediate was dissolved in dichloromethane (100 mL), washed with saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound (0.824 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.09 (d, J=7.83 Hz, 1H), 6.95 (t, J=7.63 Hz, 1H), 6.72 (s, 1H), 6.60 (d, J=7.63 Hz, 1H), 4.20 (br s, 4H), 3.88 (br s, 4H), 2.94 (t, J=5.09 Hz, 3H). MS (electrospray): exact mass calculated for C13H16N4O, 244.13; m/z found, 245.1 [M+H]+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[CH2:17].[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]O>CN(C1C=CN=CC=1)C>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH3:27])=[O:23])=[CH:20][CH:19]=1)=[CH2:17]
Reactant: COCCOCCOCCO
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=Cc1ccc(C(=O)OCCOCCOCCOC)cc1
Yield: 78 %

Procedure:
As described in Example 6a) the compound was obtained by reacting together DCC (3.1 g, 14.9 mmol), 4-vinylbenzoic acid (2.0 g, 13.5 mmol), DMAP (1.3 g, 10.8 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol (3.3 g, 20.3 mmol) for 2 days. Flash-chromatography over SiO2 (heptane/ether gradient) and drying under high vacuum gave 3.1 g of a slightly yellow oil (yield: 78%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19](F)[N:18]=[C:17]([C:22]#[N:23])[N:16]=2)=[CH:10][CH:9]=1>C(O)(C)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:20]=[C:19]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:18]=[C:17]([C:22]#[N:23])[N:16]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1nc(F)cc(Nc2ccc(Cl)cc2)n1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: N#Cc1nc(Nc2ccc(Cl)cc2)cc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (0.16 g) was added to a solution of the product from step (ii) (0.16 g) in iso-propylalcohol (4 ml) and stirred for 2 h at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution, the organics separated, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (1:1). Yield 0.09 g
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:19][C@H:17]([C@@H:16]1[C@:20]2([CH3:28])[C@H:13]([C@H:12]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:9]([CH2:8][C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:26][CH2:25]2)=[CH:10][CH2:11]3)[CH2:14][CH2:15]1)[CH3:18])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
iii)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (56.9 g) in a mixture of dry pyridine (144 ml) and acetic anhydride (72.4 ml) was stirred at room temperature for 18 h. Water (482 ml) was added and stirring was continued for another 1 h. The product was extracted into ethyl acetate; the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (compound 4; 66.1 g) which was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[CH3:36][OH:37].O>C(Cl)Cl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([O:37][CH3:36])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Reactant: CO
Solvent: ClCCl
Solvent: O
Product: COc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 12 h
Yield: 73.5 %

Procedure:
To a solution of 0.45 g (0.87 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 15 ml methanol 0.123 g (2.17 mmol) sodiummethanolate (95%) were added at RT and the reaction solution stirred for 12 hrs. The reaction mixture was distibuted between 100 ml H2O and 100 ml CH2Cl2. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/methanol 40:1) to give 0.30 g (73%) 2-methoxy-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 97.5-98.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccc3ccn(-c4cc(N)ncn4)c3c2)c1
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
6-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (400 mg, 1.21 mmol) was dissolved in methanol/dioxane (1:1, 6 mL) and Raney nickel was added. The mixture solution was stirred under hydrogen gas (1 atm) for 1.5 hours. The mixture solution was filtered through a diatomite pad, and the filtrate was concentrated under reduced pressure. After adding methylene chloride to the residue, thus prepared solid was filtered. 6-(6-(3-Aminophenyl)-1H-indol-1-yl)pyrimidin-4-amine (158 mg) was yielded as white solid. Concentration of the filtrate followed by column chromatography (silica gel, EA:Hx=1:1→MC:MeOH=20:1) further gave the target compound.
Reaction SMILES: [NH2:1][C:2](=[N:32][OH:33])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[NH2:1][C:2](=[N:32][O:33][C:34](=[O:36])[CH3:35])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To an acetic acid (15 mL) suspension of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added 0.48 mL of acetic anhydride at room temperature, which was then stirred at the same temperature for one hour. The solvent was distilled off under reduced pressure, and the resultant residue was subsequently added to a mixture of water and chloroform, which was then adjusted to pH 7.5 using a saturated sodium bicarbonate aqueous solution. The precipitate was collected by filtration and washed with water and chloroform to provide 1.07 g of 4-{3-[4-(3-{4-[amino(acetyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-acetyloxime as white solid form.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]S(C)(=O)=O)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[I-:28].[Na+]>C(C(C)=O)C>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][I:28])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)O[C@@H]1O[C@H](CS(C)(=O)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 104.3 %

Procedure:
A 1 L round bottom flask containing 500 mL of methyl ethyl ketone was charged with 1,2,3,4-tetra-O-acetyl-6-deoxy-6-methanesulfonyl-β-D-glucopyranose (4.45 g, 10.44 mmol) and sodium iodide (15.73 g, 104.9 mmol). The reaction was heated at reflux for 24 hours. The solvent was removed in vacuo and the resulting residue was taken up in 250 mL dichloromethane. The organic layer was washed with sodium thiosulfate (2×100 mL), water (2×100 mL) and once with 100 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield crude 1,2,3,4-tetra-O-acetyl-6-deoxy-6-iodo-β-D-glucopyranose as a white solid (4.99 g) which was used directly in Preparation 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C[NH2:12]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([NH2:12])=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromobenzoyl chloride (21.75 g) in THF (20 ml) was added a 40% solution (50 ml) of methylamine in methanol at 0° C. and the mixture was stirred at 0° C. for 1 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, the mixture was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (18.6 g) as colorless powder crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1

Procedure:
A mixture of 6.75 gm of 5-methyl-6-(3-nitro-4-benzylamino-phenyl)-4,5-dihydro-2H-pyridazine-3-one and 0.7 gm of 10% palladium charcoal in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid was treated for 3.5 hours at room temperature with hydrogen at 5 bar. The catalyst was filtered off, the filtrate was evaporated, and the residue was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C(C(C)=O)C>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(Cc2ccc(F)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.16 g, 0.57 mmol) in ethylmethylketone (5.00 mL) was added Cs2CO3 (0.40 g, 1.20 mmol). The reaction mixture was stirred at ambient temperature for 15 min followed by the addition of 4-fluorobenzyl bromide (0.20 g, 1.0 mmol). The reaction mixture was refluxed for 4 h. After the completion of the reaction, the mixture was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from EtOAc/Hexane to yield the title compound (0.111 g) as a white solid in 50% yield: MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)c(OC)c1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (Intermediate AAAA) (56.22 mg, 0.118 mmol), (4-chloro-2-methoxyphenyl)boronic acid (Combi-Blocks, San Diego, Calif., 26.4 mg, 0.141 mmol), Pd(AmPhos)2Cl2 (4.17 mg, 5.89 μmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (442 μl), and water (147 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed fairly clean protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of MeOH. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 6% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (26.3 mg, 0.061 mmol, 51.5% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97 (br. s., 1H), 9.92 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32-7.22 (m, 2H), 6.91 (d, J=4.6 Hz, 1H), 3.70 (s, 3H); m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: [FH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:1])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: F
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: FC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of hydrogen fluoride (65-70%) in pyridine (4 ml) was added 4-(4-chloro-phenyl)-piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0° C. for 15 min and then warmed to rt and stirred 1 h. The mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with methylene chloride (100 ml; ADD SOLVENT AND EXTRACT SLOWLY AND WITH CAUTION). Excess hydrogen fluoride was neutralized with solid sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with a methylene chloride to methylene chloride/methanol/ammonium hydroxide (8.5/1/0.5) gradient to give 4-(4-Chloro-phenyl)-4-fluoro-piperidine (260 mg, 52%).