Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CS(C)=O.[OH-].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>O>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][N:24]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Reactant: CCC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(Br)c2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.8 %

Procedure:
To a stirred mixture of 45 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one and 90 parts of dimethyl sulfoxide were added 15 parts of potassium hydroxide (pulverized). Then there were added 6.2 parts of 2-bromobutane and the whole was stirred for 20 hours at room temperature. The reaction mixture was poured into water. The produce was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of methylbenzene and hexane (1:2 by volume). The precipitated product was filtered off and recrystallized from 80 parts of methanol. The product was filtered off and dried in vacuo at 60° C., yielding a first fraction of 14.7 parts (29.8%) of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.6° C. The less pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of ethyl acetate and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding a second fraction of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.7° C. (int. 35).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([NH:19][CH2:20][C:21]#[CH:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(NC(C)C)(C)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][NH:19][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C(NCC#Cc1ccc(Br)cn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 2,5-dibromopyridine (1.19 g), N-Cbz-propargylamine (1.04 g), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (20 mL) was stirred at ambient temperature for 3 hours under nitrogen. The mixture was diluted with ethyl acetate (50 mL). The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate and wash were combined, concentrated under reduced pressure and triturated in MTBE to give crystalline 7-1 (1.28 g). The mother liquor was further purified by silica gel column chromatography using a mixture of MTBE: hexanes (1:1) to give an additional 280 mg of 7-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1ccc(=O)[nH]n1
Reaction time: 4 h

Procedure:
A mixture of 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (20 g), acetic anhydride (60 ml) and pyridine (10 drops) was heated and stirred on a steam-bath for 13/4 hours. The mixture was evaporated under reduced pressure, and the residual oil was treated with water (100 ml) and methanol (10 ml) and was allowed to crystallise to give 6-(2-acetoxyphenyl)-3(2H)-pyridazinone (22.7 g) m.p. 181°-183.5°. A sample recrystallised from 50% aqueous ethanol had m.p. 182.5°-184.5°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH:14]3[NH2:21])[CH2:12]1)[CH2:18]2)=O>C1COCC1>[NH2:21][CH:14]1[CH:13]2[CH2:12][C:11]3([CH2:9][OH:8])[CH2:18][CH:17]([CH2:16][CH:15]1[CH2:20]3)[CH2:19]2
Reactant: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1C2CC3CC1CC(CO)(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Lithium aluminium hydride (5 g, 135 mmol) was added to a solution of 4-aminoadamantane-1-carboxylic acid methyl ester (5 g, 23.9 mmoles) in dry THF (100 ml) at 0-5° C. and the mixture heated under reflux for 3 h. It was then cooled to 0° C. and quenched with water (10 ml) followed by NaOH solution (20%, 12.5 ml). After stirring for 30 min, it was filtered through hyflo bed to remove inorganics. The clear filtrate was concentrated under reduced pressure and the residue triturated with hexane to give 4-amino-1-hydroxymethyladamantane (3.9 g, 90%). LC-MS (m/z): 182 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 3.0 (d, 2H), 2.85 (b. s., 1H), 1.2-2.1 (13H, m).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.CCOCC>[N:25]([CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 90.6 %

Procedure:
(S)-2-[[[(4-Methylphenyl)sulfonyl]oxy]methyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3.55 g, 10 mmol, see J. Das et al, J. Med Chem, 1992, Vol. 35,2610 for preparation) was dissolved in dimethyl sulfoxide (DMSO) (40 mL) and treated with sodium azide (980 mg, 15 mmol). The mixture was heated at 70° C. for 5 hours, then cooled and diluted with ether. After washing with water (3×50 mL), the ether layer was dried (MgSO4) and freed of solvent in vacuo to give title compound as a colorless oil (2.05 g, 91%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH:10]=O)[C:3]=1[OH:12].C[C:14]1[CH2:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1>>[OH:12][C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH2:8][OH:9])[C:4]=1[CH:10]=[C:18]1[C:17](=[O:19])[N:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: Cc1ncc(CO)c(C=O)c1O
Product: Cc1ncc(CO)c(C=C2C=NN(c3ccccc3)C2=O)c1O

Procedure:
Provided that, the substituent introduced to methylene at 4-position are not always present stably depending on the variation. For example, when to introduce pyridoxal residue to methylen at 4-position, 3-methyl-1-phenyl-2-pyrazolin-5-one is reacted with pyridoxal, then actually obtain not 4-(3-hydroxy-5-hydroxymethyl-2-methylpyridin-4-yl-methylene)-1-phenyl-2-pyrazolin-5-one, but 1-(5-hydroxy-3-methyl-1-phenyl-1H-4-yl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1
Reactant: CCc1cccc(CNCC(O)C(Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reaction time: 1.17 h

Procedure:
The slurry of [1-(3,5-difluorobenzyl)-3-(3-ethylbenzylamino)-2-hydroxypropyl]-carbamic acid tert-butyl ester (5.25 g, 0.012 m) in anhydrous dioxane (20 ml) was stirred (magnetic bar) at RT under nitrogen atmosphere in an 250 ml round-bottom flask, immersed in a cold water bath. The solution of hydrogen chloride in dioxane (4M, 32 ml) was added in one portion. The reaction mixture, initially homogenous, became a thick slurry within ca. 20 min. Mixture was stirred for 70 min, and was monitored by the TLC (silica gel plates, 5×10 cm, eluted with ethyl acetate-methanol 95:5 mixture). Ethyl ether (100 ml) was added, precipitated product was filtered off and rinsed with ether (2×50 ml). The filter cake was air-dried for 1 hour then placed in an vacuum oven at 35° C. and the oven evacuated (5 torr). Product was dried to constant mass for 7 hours. Yield was 5.24 g. LC-MS (m/e): 335 (M+1); purity: 100% (254 nm).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[N:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:39][C:35]4[CH:36]=[CH:37][N:38]=[C:33]([CH3:32])[CH:34]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1cc(C=O)ccn1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(C)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 6-methyl-4-pyridinecarboxaldehyde (10 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:11][CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:24]=[C:17]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:6]([OH:25])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2cccnc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
3-[4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid tert-butyl ester (680 mg, 2.03 mmol) was dissolved in DCM (15 ml) and TFA (5 ml). The resulting solution was stirred at room temperature for 4 h then the solvent was removed under vacuo giving 600 mg of 3-[4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid as trifluoro acetate salt.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[NH:14][CH:13]2[CH2:15][CH2:16][N:10]([CH2:11][CH2:12]2)[CH2:9]1>O1CCCC1>[N:10]12[CH2:16][CH2:15][CH:13]([CH2:12][CH2:11]1)[NH:14][CH2:8][CH2:9]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CN2CCC(CC2)N1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
Lithium aluminum hydride (2.0 g, 51.4 mmoles) was slurried in 250 ml of dry tetrahydrofuran and 3-oxo-1,4-diazabicyclo[3.2.2]nonane (3.6 g, 25.7 mmoles) was added carefully as a solid in one portion at room temperature. The resulting mixture was then heated to a gentle reflux for 20 hours. The reaction was cooled to room temperature and quenched by slow addition of 2.5 ml water. The salts were filtered and washed several times with diethyl ether totaling 1.0 l. These washings and the supernatant were combined, dried over magnesium sulfate and concentrated to give 2.09 g (64.5%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:17][N:5]([CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc(CN(C)S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-[(methanesulfonamido)methyl]benzoate (5 g, 20.6 mmol) in MeOH (100 mL) at rt was added K2CO3 (2.9 g, 21 mmol). Methyl iodide (7 mL 16 g, 112 mmol) was added and the mixture stirred overnight. The reaction was faltered and the solid washed with CHCl3 /MeOH. The combined filtrates were evaporated and the residue was purified by flash chromatography on eluting with 0-5% MeOH/CHCl3. The title compound was isolated as a white solid (4.9 g, 94%): 1H (CDCl3): δ8.08 (d, 2H); 7.48 (d,2H); 4.41 (s, 1H); 3.97 (s, 3H); 3.91 (s, 3H); 2.83 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
To a solution of the compound from step 36a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (270 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2 M solution), and the mixture was heated at reflux for 60 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 105 mg of the title compound. MS (CI/NH3) m/z 322 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.80 (m, 3H), 2.05 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.13 (m, 1H), 3.78 (s, 3H), 4.04 (m, 2H), 6.62 (s, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.66 (m, 1H), 8.38 (m, 2H).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:11]([O:24]C)=[N:12][C:13]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[N:14][C:15]=1[CH3:16].I[CH3:28]>>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[C:13]1[N:12]([CH3:28])[C:11](=[O:24])[C:10]([NH:9][C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:26])=[C:15]([CH3:16])[N:14]=1)[CH2:19][CH3:20]
Reactant: CI
Reactant: CCCN(CCC)c1nc(C)c(Nc2c(C)cc(C)cc2C)c(OC)n1
Product: CCCN(CCC)c1nc(C)c(Nc2c(C)cc(C)cc2C)c(=O)n1C
Temperature: 140 °C
Yield: 29 %

Procedure:
N5-Mesityl-4-methoxy-6-methyl-N2,N2-dipropylpyrimidin-2,5-diamine (9.0 mg, 0.025 mmol) was dissolved in iodomethane (2 mL). The solution was heated in a sealed tube for 6 h at 140° C. The solution was cooled and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 2.6 mg (29% yield) of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CCO>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(=O)c1ccc(N2CCOCC2)nc1
Yield: 101.9 %

Procedure:
A solution of 32 (1.25 g, 7.9 mmol) and morpholine (2.20 mL, 25.2 mmol) in EtOH (22 mL) was refluxed for 12 h and then evaporated to dryness. The residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO3 (50 mL×2) and brine (50 mL), dried over Na2SO4, filtered and evaporated to afford the title compound 33a (1.66 g, quantitative yield) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:27][C:28]1[N:32](CCC#N)[N:31]=[N:30][N:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH2:22][CH2:21]2)(=[O:13])=[O:12].Cl>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH2:22][CH2:21]2)[CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)(=[O:12])=[O:13]
Reactant: N#CCCn1nnnc1CN(CCOc1ccc2c(c1)CCC2)S(=O)(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(CCOc1ccc2c(c1)CCC2)Cc1nnn[nH]1
Reaction time: 8 h

Procedure:
1 M NaOH solution (0.63 mmol, 1.0 eq) is added to a stirred solution of 2,4-dichloro-N-[1-(2-cyano-ethyl)-1H-tetrazol-5-ylmethyl]-N-[2-(indan-5-yloxy)-ethyl]benzene sulfonamide (0.325 g, 1 eq.) in tetrahydrofuran (3 ml) at room temperature and the reaction mixture stirred overnight. The reaction mixture is acidified with 1 M HCl solution to pH 3, and then extracted with EtOAc (20 ml). The organic extract is washed with 1 M HCl solution (2×5 ml), and then with brine (1×10 ml), dried over MgSO4, and concentrated to give a crude solid (0.211 g), which is triturated with Et2O, filtered, washed with Et2O and dried under suction. The solid is purified by preparative HPLC to give pure 2,4-dichloro-N-[2-(indan-5-yloxy)-ethyl]-N-(1H-tetrazol-5-ylmethyl)benzene-sulfonamide.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].S(O)(O)(=O)=O.[CH3:18][NH:19][NH2:20]>>[CH3:18][N:19]1[C:4]([C:5]([F:8])([F:7])[F:6])=[CH:3][C:2]([NH2:1])=[N:20]1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: CNN
Agent: O=S(=O)(O)O
Product: Cn1nc(N)cc1C(F)(F)F
Yield: 23.1 %

Procedure:
Using the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (1.83 g, 10 mmol) and methylhydrazine sulfate (1.586 g, 11 mmol) were reacted and the crude product purified by silica gel chromatography (with 0-10% EtOAc/CH2Cl2 as eluants) to afford 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as solid (0.381 g, 23%). 1H NMR (300 MHz, CDCl3) δ 5.94 (s, 1H), 3.78 (s, 3H), 3.67 (br, 2H); LC-MS (ESI) m/z 166 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])(=[O:15])=[O:14])=[O:11])[N:3]=1.Cl>C(O)C.[OH-].[Na+].O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2C(=O)O)n1

Procedure:
A solution of 1.0 g of methyl 3-[[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-2-thiophenecarboxylate in 10 ml of ethanol and 1 ml of 50% sodium hydroxide in water was stirred overnight at room temperature. To this was added icewater and aqueous hydrochloric acid until acidic, and the precipitate was filtered and washed first with acetone and then with methylene chloride. The product, 0.8 g, melted at 127°.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[C:11]=1[CH3:12].[H][H]>C(O)C.[Pd]>[NH2:13][C:3]1[C:2]([F:1])=[C:11]([CH3:12])[C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2oc(=O)[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)c(N)cc2oc(=O)[nH]c12
Yield: 67.2 %

Procedure:
A mixture of 1.80 g (8.50 mmoles) of 5-fluoro-4-methyl-6-nitro-2-benzoxazolone (Example 1) and 180 mg of 5% Pd/c in ethanol was shaken in a Parr shaker under one atmosphere of hydrogen gas at room temperature for 8 hours. The reaction mixture was filtered through celite and the filtrate evaporated to solids. Crude product was recrystallized from methanol to yield 1.04 g of the title compound as pale brown solids: m.p. 209°-212° C. (dec).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])(=O)[CH3:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[OH:17][N:16]=[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)c(C)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=NO)c(C)c1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
Methyl 4-acetyl-3-methylbenzoate (1.49 g, 7.76 mmol), hydroxylamine hydrochloride (4.18 g, 60.1 mmol), and sodium acetate (4.93 g, 60.1 mmol) were suspended in methanol (40 mL) and the reaction mixture heated at 40° C. for 2 h. Upon cooling to room temperature the solvent was removed under reduced pressure. The residue obtained was partitioned between ethyl acetate (75 mL) and water (30 mL). The organic extract was washed with water (20 mL) and brine. The washed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (1.61 g, 100%). LC-MS: (FA) ES+ 208; 1H NMR (300 MHz, MeO D) δ 7.91-7.77 (m, 2H), 7.31 (d, J=8.0 Hz, 0.7H), 7.16 (d, J=7.9 Hz, 0.3H), 3.89 (s, 3H), 2.37 (s, 2H), 2.28 (s, 1H), 2.17 (s, 2H), 2.10 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.[Zn]>[CH3:2][CH2:3][CH2:4][CH2:5][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)Cl
Reactant: BrCCCCBr
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCC(=O)CCCCC(=O)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To the stirring slurry of Zn* in THF was added 1,4-dibromobutane (1.186 g, 5.495 mmol) via disposable syringe. The reaction mixture became slightly warm and stirring was continued for 8 hours. The stirring was then stopped and the excess zinc was allowed to settle for 8 hours. The light brown solution of the bis-organozinc halide reagent was carefully transferred to a solution of CUCN (0.10 g, 1.1 mmol) and dry THF under argon. The resulting solution was stirred for 10 min. and valeroyl chloride (1.40 g, 11.6 mmol) was added by disposable syringe. The reaction was stirred overnight, slowly warming to room temperature. The reaction mixture was then quenched by addition to 30 ml 3M HCl. The organic layer was taken up in 20 ml ether and the aqueous layer was extracted two times, using 20 ml ether each time. The combined organics were washed consecutively with 20 ml each of saturated sodium bicarbonate, water, and brine. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated. 5,10-tetradecandione (1.11 g, 4.90 mmol) was isolated from silica gel using ethyl acetate/hexanes (1:4) as the eluent system.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[O:18]1[CH2:17][CH2:16][N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:20][CH2:19]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCOCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1

Procedure:
7.2 g (16.4 mmol) of trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 mL of MeOH and hydrogenated on 1.4 g of Pd/C (10%) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and concentrated HCl.