Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36]#[N:37])[CH2:34][CH3:35])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36](=[O:39])[NH2:37])[CH2:34][CH3:35])=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(C#N)CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.6 %

Procedure:
The nitrile prepared in example 108(0.40 g, 0.80 mmol) and potassium carbonate (0.24 g, 1.70 mmol) were slurried in DMSO (5 mL) and cooled to 0° C. in an ice bath. Aqueous hydrogen peroxide (30%, 1.0 mL) was added slowly, and the reaction stirred at room temperature for 48 hours. The reaction was quenched by pouring into water, and extracting the aqueous layer with ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to a light tan oil. The material was purified by flash chromatography over silica gel eluting with EtOAc/hexanes/10% NH4OH in MeOH (5:4:1) to provide 0.28 g (67%) of a colorless oil. MS (FD+) 518.07 (MH+). NMR.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis-3-benzyloxymethylcyclobutanol (Albany Molecular Research Institute, 1.0 g, 5.2 mmol) in 50 mL of CH2Cl2 was added imidazole (2.7 g, 39 mmol) followed by tert-butyldimethylsilyl chloride (3.9 g, 26 mmol). This mixture stirred at ambient temperature for 2 hours and was quenched with 10 mL of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([NH:21][C:22]([CH:24]4CC4)=[O:23])[S:20][C:16]=3[C:15]=2[C:29]#[N:30])[CH:8]=1)=[O:5].N1C=CC=CC=1.C(Cl)(=O)C>O1CCCC1>[C:22]([NH:21][C:19]1[S:20][C:16]2[C:15]([C:29]#[N:30])=[C:14]([O:13][C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])[C:2]=4[Cl:1])[CH:12]=[CH:11][CH:10]=3)[CH:28]=[CH:27][C:17]=2[N:18]=1)(=[O:23])[CH3:24]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (8.0 g, 21.1 mmol) produced in Example 3 (iv) in tetrahydrofuran (100 mL) were added pyridine (20 mL, 250 mmol) and acetyl chloride (1.8 mL, 25.3 mmol), and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was diluted with ethyl acetate (500 mL). The obtained solution was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.43 g, 72%) as a white powder.
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[S:15][C:16]([C:24]#[N:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]2[S:15][C:16]([C:24](=[S:1])[NH2:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1
Reactant: S
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reaction time: 60 h
Yield: 40 %

Procedure:
Hydrogen sulphide was bubbled through a solution of the compound of Example 77 (539 mg, 1.64 mmol) in pyridine (1 0 mL) and triethylamine (0.5 mL) for 30 minutes. The reaction was left to stand for 60 h at r.t. and then nitrogen bubbled through the mixture to ensure the solution was purged of H2S. The solution was diluted with DCM and washed with water (×2), 2M HCl(aq) (×2) and brine. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from DCM-hexane to give the title compound as a solid (327 mg, 40%). δH (DMSO-d6) 9.70 (1H, s), 7.70–7.47 (9H, m), 7.45 (2H, m), 7.38 (1H, d J 9.6 Hz), 6.52 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.33 minutes, 385 (M+Na)+, 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(CN)CC1>CN(C=O)C>[CH:35]1([CH2:34][NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and cyclopropanemethylamine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (45 mg, 65%) which was obtained as a white solid. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:33]=[C:34]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)[C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1
Temperature: 100 °C

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.100 g, 0.23 mmol) in DME (5 mL) was added [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.074 g, 0.23 mmol), followed by potassium carbonate (0.079 g, 0.58 mmol) and water (3 mL). The solution was purged with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.02 mmol) was added. The reaction was stirred at 100° C. until no starting material was seen by analytical LCMS and thin layer chromatography (tlc), and then cooled to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography to give (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:42])[NH:11][CH:12]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]([OH:34])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]=[C:28]([CH2:31][NH2:32])[C:27]=3[CH:33]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>C1COCC1>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:42])[NH:11][CH:12]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:13]([OH:34])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH:29]=[C:28]([CH2:31][NH:32][C:43](=[O:50])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:27]=3[CH:33]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occ(CN)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occ(CNC(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
{3-[(3-Aminomethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester from the previous step (20 mg, 33 umol) was dissolved in 0.5 mL THF. 5.8 uL (50 umol) benzoyl chloride and 7 uL (50 umol) triethylamine were added and the reaction was stirred at room temperature for 1 h. The reaction mixture was purified by prep TLC on the silica gel plate with ethyl acetate/hexanes=2/1 to afford 12 mg (17 umol, 52%) of product. MS 706 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:27])=[O:26])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:10][C:9]=2[OH:8])=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of 2-[3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetamide (0.38 g) in methanol (5 mL) was added 10% palladium-carbon powder (0.075 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1–20/1) to give 2-[4-(4-ethylbenzyl)-3-hydroxyphenyl]acetamide (0.16 g).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([Cl:31])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1>O.O1CCCC1>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1
Reactant: CNNC
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNN(C)C(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.3 %

Procedure:
To a mixture of 0.13 g of N,N′-dimethylhydrazine dihydrochloride, 1 ml of water, 0.14 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.23 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 30 ml of water, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(N,N′-dimethylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:11](=O)C(C)C)[CH2:4][C:5]1[CH:10]=CC=C[CH:6]=1.[CH3:16][CH:17]([CH3:21])CC=O.C1([NH2:25])CC1.C[Si](C#N)(C)C>C(OCC)(=O)C.CO>[ClH:1].[CH:21]1([NH:2][CH:3]([CH2:4][CH:5]([CH3:6])[CH3:10])[C:11]#[N:25])[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)C(N)Cc1ccccc1
Reactant: NC1CC1
Reactant: CC(C)CC=O
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC(C#N)NC1CC1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
Following a procedure outlined in Synth. Commun. 15 (2), 1985, 157-163, 3-methylbutyraldehyde (2.0 g) and cyclopropylamine (0.81 mL) were combined and heated to 95° C. in a pressure tube for 2 minutes. The clear, yellowish solution was cooled to RT and trimethylsilyl cyanide (2.76 mL) was added carefully over 5 minutes. The mixture was re-heated to 100° C. for 2 minutes and then allowed to cool to RT. Methanol (12 mL) was added and the mixture was heated to reflux for 12 hours. The mixture was cooled, dissolved in ethyl acetate, washed with brine, dried over Na2SO4 and evaporated. The residue was treated with HCl in dioxane (approx. 0.7 M, 30 mL) and then with ether (60 mL) with stirring. After one hour, the precipitated white solid was filtered off and dried in vacuo (1.65 g). MS (ESI): 153.4 (MH+, free base).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([O-:29])=[O:28])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])=[O:22])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(NC(=O)Nc1cccc(C(=O)[O-])c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(NC(=O)Nc1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl-(-)-[S-(R*,R*)]-3-[[[[2-[[[(4-chlorophenyl)amino]carbonyl]amino]-1,2-diphenylethyl]amino]carbonyl]amino]benzoate (0.15 g, 0.27 mmol) in MeOH (8 mL) is added lithium hydroxide monohydrate (0.01 g, 0.27 mmol) followed by water to the cloud point. The resulting mixture is stirred overnight at room temperature. The mixture is warmed to 50° C. for 3 hours. The solvent is removed in vacuo and the residue partitioned between water and diethyl ether. The layers are separated and the aqueous layer is acidified to pH=2 with 2 M HCl. The resulting solid is filtered and dried in vacuo at 114° C. for 5 hours, mp 172.5°-173° C. IR (KBr): 3383, 1662, 1550, 1493, 1234, 698 cm-1. NMR (DMSO-d6): δ5.02 (m, 2H), 6.95-7.53 (m, 19H), 8.06 (s, 1H), 8.80 (s, 1H), 8.88 (s, 1H), 12.83 (br s, 1H). Analysis calculated for C29H25ClN4O4.0.5H2O: C, 64.74; H, 4.87; N, 10.41. Found: C, 64.57; H, 4.83; N, 10.10. [α]D25 =-22.3° (c=1, DMF).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([Cl:33])(C)=O>CO>[ClH:33].[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)Cl
Agent: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Solvent: CO
Product: Cl

Procedure:
Using a procedure similar to Example 33, 8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine (0.55 g, 1.36 mmol), MeOH (6 mL) and AcCl (0.098 mL, 1.36 mmol) furnish the title compound (0.11 g, 0.25 mmol, 42%). 1H NMR (CDCl3), δ 0.96 (t, J=7.2 Hz, 6H), 1.74-1.89 (m, 2H), 1.89-2.02 (m, 2H), 2.22 (s, 3H), 2.68 (s, 3H), 2.78 (s, 3H), 3.08 (s, 3H), 3.88-3.98 (m, 1H), 7.23 (s, 1H), 7.40 (d, J=6.9 Hz, 1H), 7.71 (d, J=4.8 Hz, 1H), 8.06 (s, 1H), 8.82 (s, 1H). LC/MS (m/z): calcd. for C24H29ClN4S (M+H)+: 441.3; found: 405.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 74.5 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (150 g), 4-chloropyridine hydrochloride (190 g) and triethylamine (320 g) in ethanol (800 ml) was reacted in a sealed tube at 150° C. for 15 hours. The reaction mixture was concentrated to obtain a residue, which was made alkaline by an addition of a 6N aqueous solution of sodium hydroxide, and then extracted with dichloromethane. After drying and concentrating, the resultant residue was triturated from hexane, collected by filtration and then dried to obtain 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4.5]decane (172 g) as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.5 ml),4-fluoro aniline (14.2 ml) and sodium carbonate (5.3 g) was heated at 180° for 3 h. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water (50 ml), brine (2×50 ml) dried and evaporated under vacuum to give the crude compound (22.6 g), which was purified by flash chromatography with CH-EA 4/1 to give the title compound as an orange solid (12.35 g).M.p. 115°-6° T.l.c. CH-EA (10:1), Rf 0.52.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:6]([CH:8]([C:11](=O)[CH3:12])[C:9]#[N:10])[CH:7]=1.Cl.Cl.[NH2:26][NH2:27].C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:6]([C:8]2[C:11]([CH3:12])=[N:26][NH:27][C:9]=2[NH2:10])[CH:7]=1
Reactant: NN
Reactant: COCCOc1cc(F)cc(C(C#N)C(C)=O)c1OCCOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cc(F)cc(-c2c(C)n[nH]c2N)c1OCCOC
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 2-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.26 mg, 0.80 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (105 mg, 0.9 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled to room temperature then poured into a saturated sodium bicarbonate solution (10 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 5% methanol-dichloromethane) to provide 4-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (0.15 g, 0.45 mmol, 56%) yield 1H NMR (400 MHz, d6-DMSO): 7.06-7.02 (m, 1H), 6.72-6.69 (m, 1H), 4.18-4.16 (m, 2H), 3.83-3.81 (m, 2H), 3.71-3.69 (m. 2H), 3.36-3.64 (m, 2H), 3.32 (s, 3H), 3.10 (s, 3H), 2.16 (s, 3H); MS (EI) for C16H22FN3O4: 340 (MH+).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.F[C:15](F)(F)[C:16](OC(=O)C(F)(F)F)=[O:17]>C1C=CC=CC=1>[C:16]([O:12][C:10]1[C:3]2[C:4](=[CH:5][CH:6]=[C:1]([CH3:13])[CH:2]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:17])[CH3:15]
Reactant: Cc1ccc(CCCC(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc2ccc(C)cc12

Procedure:
To a 2 liter round-bottomed flask equipped with condenser and a nitrogen inlet were added 98.3 grams (0.552 mol) 4-(p-tolyl)butyric acid and 900 mL dry benzene. After the acid had dissolved, 132.6 mL (0.939 mol) trifluoroacetic anhydride was added dropwise over 35 minutes. The reaction was then refluxed for 20 hours (starting material confirmed to be consumed by thin layer chromatography (tlc), Rf 0.1 to 0.6 (DNP +ve) in 2/1 ethyl acetate (EtOAc)/hexane) cooled, and evaporated to remove most of the trifluoroacetic acid. The reside was taken up in ethyl acetate, washed with dilute aqueous ammonium hydroxide, water and brine, dried over sodium sulfate, and evaporated. The resulting solid was suitable for use in the next step.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C.CCOCC>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:5][C:4]3[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=3)[CH:1]=[O:10])=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
A solution of isophthalaldehyde (4.0 g) and 7-chloroquinaldine (5.39 g) in acetic anhydride was heated at 125° in an oil bath for 48 hours. The reaction was cooled to room temperature, diluted with ether (30 mL) and the resulting suspension was stirred vigorously. The solid title compound was collected by filtration and was used as such in the next step.