Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[C:3]=1[N:24]=O.C1(CN2C(N)=C(N)C(=O)N(CC3CCCCC3)C2=O)CCCCC1.[CH:50]([C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[CH:55]=[CH:56][C:57]([OH:59])=[O:58])=O>>[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:50]([C:52]4[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=4)/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58])[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: O=Cc1cccc(C=CC(=O)O)c1
Agent: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Yield: 49 %

Procedure:
In the manner of step (d) of Example 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c) example 1, 2.79 g, 8.00 mmol) was reduced to 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil, which was condensed with 3-formylcinnamic acid (T. Higa, A. J. Krubsack, J. Org. Chem. 1975, 40: 3037-3045, 1.424 g, 8.00 mmol) to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as an off-white solid (1.947 g, 49%), m.p. >350° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[N:25]=1.[CH3:32][NH2:33].O.C(OCC)(=O)C>O1CCOCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:33][CH3:32])[N:25]=1
Reactant: CN
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(Cl)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 0.100 g (0.180 mmol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-6-chloropicoline amide in 5 ml of 1,4-dioxane were added 0.00600 g (0.0360 mmol) of copper sulfate and 0.140 g (1.80 mmol) of a 40% aqueous methylamine solution, followed by stirring at an oil bath temperature 80° C. for 3 hours under an enclosed condition. The reaction liquid was returned to room temperature and opened, and water and ethyl acetate were added thereto. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=2:1) to prepare 0.0700 g (yield 69%) of a target compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: OB(O)c1ccccc1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1O
Yield: 39 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenyl boronic acid in 39% yield using method F; δH [2H6]-DMSO 13.48,(1H, b), 13.38,(1H, b), 8.33,(2H, m), 8.23, (2H, t), 8.17,(2H, d), 8.13,(1H, d), 7.70,(2H, d), 7.37,(1H, t), 7.09,(1H, d), 7.02,(1H, d), 6.94,(1H, t), 3.84,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.03 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[CH:24]=1.O>ClCCCl.C1COCC1>[CH3:14][C:15]1[N:20]=[C:19]([NH:21][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[CH:24]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(-c2cncs2)c1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(-c2cncs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.071 g, 0.703 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.062 mL, 0.703 mmol), stirred at RT for 1 h, then heated at 75° C. for 2 h. The mixture was cooled to RT, treated with a solution of 6-methyl-5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.1 g, 0.352 mmol) and TEA (0.146 mL, 1.055 mmol) in THF (3 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford N-((6-methyl-5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (122 mg, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 10.45 (br s, 1H), 9.13 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=5.8 Hz, 1H), 7.92 (s, 1H), 7.66-7.65 (m, 2H), 6.75 (dd, J=5.8, 2.4 Hz, 1H), 2.27 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 412.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 1 g (5.48 mmol) 4-chloro-3-nitrobenzonitrile, Compound 126, and 1.14 g (11.51 mmol) of cyclohexylamine were heated overnight in 5 mL anhydrous DMF. After cooling to room temperature, the solution was added dropwise into 100 mL H2O stirring vigorously. The solids were collected by filtration and dried under vacuum yielding 1.34 g (100%) bright yellow solids which were used as such without analysis in the next step.
Reaction SMILES: [CH3:1]CN(CC)CC.[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15](=[S:19])[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=1.CI>CS(C)=O>[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15]([S:19][CH3:1])=[N:14][CH:13]=[N:12][C:11]=2[CH:10]=1
Reactant: CCN(CC)CC
Reactant: Nc1cc2nc[nH]c(=S)c2cn1
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2cc(N)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
NEt3 (6 mL, 43 mmol) is added to a solution of 7-amino-4-thiono-3H-pyrido[4,3-d]pyrimidine (0.77 g, 4.3 mmol) in DMSO (7 mL) stirred under N2 at 25° C. After the two phases have been stirred for 20 min, MeI (0.26 mL, 4.2 mmol) is added. After 2 h, the reaction mixture is poured onto stirring ice-water. Solid forms instantly. After further cooling at 0° C., the solid is collected by suction filtration and dried in a vacuum oven to give 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.564 g, 68%). 1H NMR (DMSO) δ 8.98 (1H, s), 8.71 (1H, s), 6.94 (2H, brs), 6.49 (1H, s) 2.63 (3H, s).
Reaction SMILES: COCN[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].[C:13]1([O:21][CH3:22])[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:15][CH3:16]>>[CH3:16][O:15][C:14]1[C:13]([O:21][CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: COCNC(=O)c1ccncc1
Reactant: COc1ccccc1OC
Product: COc1cccc(C(=O)c2ccncc2)c1OC

Procedure:
In Scheme H, step c, 4-[(methoxymethylamino)carbonyl]pyridine (19) is reacted with lithiated veratrole to give 4-(2,3-dimethoxybenzoyl)pyridine (12).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)[C:13]#N)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:28]1([Mg]Cl)[CH2:30][CH2:29]1.S(=O)(=O)(O)[OH:34]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:13]([CH:28]4[CH2:30][CH2:29]4)=[O:34])[CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cl[Mg]C1CC1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(C(=O)C3CC3)cc(-c3ccc4c(c3)OCO4)c2)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 3-benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-benzonitrile (250 mg) in anhydrous THF (3 mL) were added a solution of cyclopropylmagnesium chloride (4.1 mL of 0.5 M solution in THF) and catalytic amount of cuprous bromide (2 mg). The resulting reaction mixture was refluxed for 1.5 h. After it was cooled down, 10% sulfuric acid (1.5 mL) was added and stirring was continued for 30 min at room temperature. Then the reaction mixture was diluted with diethyl ether, washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 253 mg of the title compound (91% yield). HRMS calcd for C25H22O5 [M+H]+ 403.1540, observed 403.1537.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:23]>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:23])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4-phenylbenzoic acid (5.46 g, 27.6 mmol) in methylene chloride (66 mL) was added 2 drops of DMF and oxalyl chloride (2.80 mL, 30.3 mmol). The reaction mixture was stirred overnight and added to a stirred solution of ice and ammonium hydroxide. The resulting precipitate was filtered, washed with methylene chloride, and triturated with water. The product was collected by filtration and dried in vacuo to yield 4-phenylbenzamide (3.88 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3([CH3:27])[CH2:26][CH2:25]3)[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].Br[CH2:38][C:39]([NH2:41])=[O:40].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:41][C:39]([CH2:38][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24]1([CH3:27])[CH2:25][CH2:26]1)=[O:40].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Reactant: NC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C2N(CC(N)=O)C(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (800 mg, 1.36 mmol) and 2-bromo-acetamide (938 mg, 6.8 mmol) in DMF (1 mL) was added Cs2CO3 (4.4 g, 13.4 mmol). The mixture was stirred at 50° C. for 1.5 h, then purified by column chromatography to give title compound (60 mg, 6.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C.O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: O
Solvent: CCO
Product: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
At 20° C., 12.43 g (0.048 mol) of 4,4′-dimethylbenzilic acid in 50 ml ethanol is added dropwise to freshly prepared sodium ethoxide solution containing 1.1 g (0.045 mol) of sodium and 100 ml of ethanol and the mixture is stirred for 30 minutes. The solution is evaporated to dryness, the residue dissolved in 50 ml of DMF, 9.08 g (0.064 mol) of methyl iodide is added dropwise at 20° C., and stirring is continued for a further 24 hours. 300 ml of water are added dropwise to the resulting suspension while cooling with ice, the mixture is extracted with diethylether; the organic phase is washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 8.6 g (99% of theory); melting point: 83° C.-84° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[CH:24][C:25]=1[CH3:26].[NH4+].[Cl-]>ClCCl.CN(C=O)C.CCN(C(C)C)C(C)C>[N:7]1[CH:8]=[C:9]([C:16]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (10 mL) was added dropwise to a stirred solution of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3 g, 18.5 mmol) in dry dichloromethane (100 mL) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4-methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 mL) was dissolved in dichloromethane (100 mL) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4Cl was added to the reaction solution and the phases were separated. The organic layer was dried over Na2SO4 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:28]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][C:19]([C:21]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH:29]4[CH2:30][CH2:31][CH2:32][N:27]([CH3:26])[CH2:28]4)[CH2:39][CH2:38]3)=[O:23])=[N:18][N:17]=2)(=[O:11])=[O:12])=[C:5]([CH3:25])[CH:4]=1
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCCN(C)C4)CC3)o2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-[(1-methylpiperidin-3-yl)methyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH:14][S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.C(OC(=O)C)C>C(COC)OC.[Li+].[OH-]>[C:1]1([CH:7]([NH:14][S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1

Procedure:
0.2 g of Ethyl 3-phenyl-3-{[3′-(1,3-thiazol-2-ylamino)[1,1′-biphenyl]-3-yl]sulfonylamino}-propanoate 15.1.1 were saponified in 15 ml dimethoxyethane 12 ml water and 0.2 g LiOH. After aqueos work-up and flash chromatography (dichloromethane/methanol 10+1) 65 mg were obtained.
Reaction SMILES: O[C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[C:8](C)=[CH2:9])=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].Cl.[OH-:20].[Na+]>C(Cl)Cl.O>[S:15]([OH:18])([OH:20])(=[O:17])=[O:16].[C:7]([NH:6][C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1)(=[O:11])[CH:8]=[CH2:9]
Reactant: C=C(C)C(=O)Nc1ccc(O)cc1
Reactant: [OH-]
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1
Product: O=S(=O)(O)O
Reaction time: 8 h

Procedure:
An acrylanilide sulfate co-polymer was synthesized by first suspending 17.7 g (0.1 mol) of p-hydroxymethacrylanilide in 100 ml of methylene chloride in a suitable glass reaction vessel and then adding 12 g of chlorosulfonic acid to the suspension. Hydrogen chloride gas was observed evolving during the addition; and the reaction mass was mechanically stirred overnight at room temperature. The resultant product was dissolved in a solution of 60 g water and about 10 g of 50% sodium hydroxide, giving a pH of about 11; and methylene chloride was then separated by vacuum. A yield of about 75% of sulfated monomer, observed to be a viscous liquid, was then determined using nuclear magnetic resonance techniques.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[C:4]=1[CH3:14])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:14][C:4]1[C:5]([CH2:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:13])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Product: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)propionic acid (1.37 g, 6.50 mmol) reacted with 1-methylpiperazine (719.6 mg, 7.15 mmol) to give 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.30 g, 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)([OH:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:3]=1
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Reactant: Cc1ccnc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccnc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)c1

Procedure:
75 Milligrams of 4-methyl-2-pyridinecarbaldehyde, 58.3 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide and 12 mg of acetic acid were dissolved in 10 ml of dichloroethane. To the solution 68 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254Art 5744 (Merck), chloroform/methanol=9/1] to give 49.5 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].BrC[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:26]([O:28][CH3:29])=[O:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-amino-1H-pyrazole-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)carboxyamide (1.0 g, 1.92 mmol) in 10 mL of DMF was added sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) The resulting mixture was stirred at 85° C. for 16 h. The reaction was not complete so additional portions of sodium bicarbonate (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) were added and the reaction was stirred at 95° C. for 6 h longer. The reaction was cooled to ambient temperature and was diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and was stirred at reflux for 20 min and then was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 450 mg (44%) of the title compound as a white powder. LRMS (ES+): 536.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=O)[CH2:22][C:23](=O)[CH3:24])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.[CH:50]1([NH:54][NH2:55])[CH2:53][CH2:52][CH2:51]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:21]1[N:54]([CH:50]2[CH2:53][CH2:52][CH2:51]2)[N:55]=[C:23]([CH3:24])[CH:22]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as colorless oil. MS (ESI): m/z=456.2 [M+H]+.