Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([OH:3])=[O:2].Cl.[CH2:25](O)[CH3:26]>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])([OH:3])=[O:2]
Reactant: CCO
Reactant: Cc1ccc(C(=O)c2c(C)c(C(=O)O)c(CC(=O)O)n2C)cc1
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 37 g. (0.118 mole) of 3-carboxy-1,4-dimethyl-5-(ρ-toluoyl)-pyrrole-2-acetic acid in 370 ml. of ethanol containing 1.8 g. of dry hydrogen chloride is heated under reflux for 45 min. The solution is cooled, and the solid which recipitated, ethyl 3-carboxy-1,4-dimethyl-5-(ρ-toluoyl)-pyrrole-2-acetetate, is collected, M.P. 200°-202° C.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[ClH:2].[ClH:1].[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([CH2:3][S:16][C:15](=[NH:14])[NH2:17])[CH:5]=1
Reactant: NC(N)=S
Reactant: ClCc1cnc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1cnc2ccccc2c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A solution of 3-chloromethylquinoline hydrochloride (46.4 g) in ethanol (160 cc), at 70° C., is added dropwise, in the course of 10 minutes, to a suspension of thiourea (19.7 g) in boiling ethanol (110 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 10° C. The resulting crystals are filtered off, washed twice with ethanol (100 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Quinol-3-ylmethyl)-isothiourea dihydrochloride (59.3 g), melting at 226°-228° C., is thus obtained.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2([C:29]#N)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C[OH:32].Cl>CN(C=O)C.O>[O:32]=[C:29]1[C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[C:2](=[S:3])[N:1]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=1
Reactant: CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: Cc1ccc(NC2(C#N)CCCC2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A mixture of 1a (0.296 g, 1.3 mmol) and 8a (0.2 g, 1 mmol) in dry DMF (0.2 ml) was stirred for 48 h. To this mixture were added methanol (10 ml) and HCl aq. 2N (3 ml). The second mixture was refluxed for 6 h. After being cooled to room temperature, the reaction mixture was poured into cold water (20 ml) and extracted with ethyl acetate (30 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(4-Oxo-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.4]non-3-yl)-2-trifluoromethylbenzonitrile, 8b, [RD35] (0.3 g, 0.7 mmol, 70%) as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[N:13][C:12]([Br:23])=[CH:11][N:10]=1.CCCCCCC>CS(C)=O.ClCCl>[Br:23][C:12]1[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:10][CH:11]=1
Reactant: COCCO
Reactant: Clc1ccc(-c2nc(Br)cnc2Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COCCOc1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a solution of 0.077 g (0.001 mol) 2-methoxyethanol in 2 ml dimethylsulfoxide was added at room temperature 0.088 g (0.002 mol) sodium hydride (55% in oil) and the mixture was stirred at room temperature for 1 h. To the resulting solution was added 0.352 g 2,5-dibromo-3-(2,4-dichloro-phenyl)-pyrazine and the mixture was stirred at room temperature for 3 h. The resulting reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase washed twice with water, dried with sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using dichloromethane:heptane=3:1 to dichloromethane as eluent to yield 0.090 g (24% yield) of the title compound as the faster eluting compound as white crystals melting at 92-93° C. and 0.171 g (45% yield) of its isomer 2-bromo-3-(2,4-dichloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine as the slower eluting compound as yellowish oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CO[CH2:15][CH2:16][C:17]12[CH2:24][CH2:23][C:20]([CH3:25])([CH2:21][CH2:22]1)[O:19][C:18]2=O.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH3:25][C:20]1[CH2:23][CH2:24][C:17]2([C:18](=[O:19])[N:8]([C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[CH2:15][CH2:16]2)[CH2:22][CH:21]=1
Reactant: COCCC12CCC(C)(CC1)OC2=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1=CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(Trifluoromethoxy)-aniline (0.065 mL, [CAS Reg. No. 461-82-5]) was added to a solution of 4-(2-methoxy-ethyl)-1-methyl-2-oxa-bicyclo[2.2.2]octan-3-one (64 mg, obtained in example 59, step 1) in toluene (5 mL). The mixture was stirred for 10 minutes at r.t. Then, dimethylaluminiumchloride (1M in hexane, 0.65 mL) was added dropwise over a period of 5 minutes. The reaction mixture was stirred at reflux for 3 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give 8-methyl-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]dec-7-en-1-one as a light yellow solid as the main product (81 mg, 77%). MS (m/e)=326.4 [MH+]. From this reaction, a small amount of (5α,8α)-8-hydroxy-8-methyl-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (see example 57) was also isolated (6 mg, 5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=[CH:26][C:25]=2[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:22])=[CH:17][CH:16]=1)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=[CH:26][C:25]=2[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:22])=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Ethyl [(tert-butoxycarbonyl)amino][4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]acetate (1.08 g, 1.813 mmol) and 1N lithium hydroxide (3.99 mL, 3.99 mmol) were stirred in THF (16 mL) at room temperature for 2 days. The reaction was diluted with water, 2 mL of 2N HCl was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as a pale yellow powder. 1H NMR (DMSO-d6, 600 MHz) δ 12.90 (br s, 1H), 9.90 (s, 1H), 8.72 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.81 (d, J=1.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.51 (m, 2H), 7.44 (d, J=3.6 Hz, 1H), 7.12 (dd, J=5.1 and 3.6 Hz, 1H), 5.23 (d, J=8.4 Hz, 1H), 1.45 (s, 9H), 1.39 (s, 9H). MS: cal'd 568 (MH+), exp 412, 456, 468 (MH+).
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH:5]([Cl:7])[Cl:6])[Cl:3].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:8]([Si:2]([CH2:4][Si:5]([Cl:7])([Cl:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([Cl:3])[Cl:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCCCC
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)CCCCCC
Yield: 72.6 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 8 g(0.04 mole) of bisdichlorosilylmethane, 12.7 g (0.15 mole) of 1-hexene and 120 μl of 1% chloroplatinic acid solution in isopropanol were placed and reacted for 2 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation of the reaction products gave 11.1 g (118°-120° C./0.05 mmHg) of bis(hexyldichlorosilyl)methane in 72.6% yield.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[NH2:13][OH:14].O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>CO.O>[Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1/[C:4](=[N:13]/[OH:14])/[NH2:5]
Reactant: NO
Reactant: Cc1nc(Cl)c(C#N)c(C)c1Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Solvent: O
Product: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Temperature: 75 °C

Procedure:
A suspension of 2,5-Dichloro-4,6-dimethyl-nicotinonitrile (45.0 kg) and 50% hydroxylamine (59.2 kg) in the presence of catalytic amount of 1,10-phenanthroline monohydrate (0.680 kg) in methanol/water (214 kg/362 kg) is heated to 70-80° C. The mixture is agitated at 70-80° C. Water (353 kg) is added slowly into the resulting solution while the temperature is maintained at >79° C. The solution is cooled to 75° C. with stirring resulting in crystallization of (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide. The suspension is further cooled to 20° C., the solid is filtered off and the wet cake is washed with water (160 kg). (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide is dried under vacuum at max. 60° C. until residual water level is max 0.15% (KF).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])=[O:6].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[NH2:12][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[CH2:28][CH2:29]1)=[O:11]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: NC(=O)c1ccccc1NC(=O)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccccc1NC(=O)CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 81 %

Procedure:
A mixture of 7.2 parts of 2-[(4-chloro-1-oxobutyl)amino]benzamide, 7.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.1 parts of N,N-diethylethanamine and 120 parts of acetonitrile is stirred and refluxed for 24 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 10 parts (81%) of N-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide as a residue.
Reaction SMILES: Cl[C:2](OC)=[S:3].N[C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1.C([N:24]([CH2:27]C)CC)C>CC(C)=O>[CH3:2][SH:3]=[C:27]([C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)[NH2:24]
Reactant: CCN(CC)CC
Reactant: COC(=S)Cl
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Solvent: CC(C)=O
Product: C[SH]=C(N)c1cccc(N2C(=O)CC(C)(C)C2=O)c1

Procedure:
Four and one-half g. of methyl chlorothioformate was added dropwise at ambient temperature to a well-stirred mixture of 8.7 g of N-m-aminophenyl-2,2-dimethylsuccinimide, prepared in Example II above, 4.5 g. of triethylamine and 100 ml. of acetone. When the reaction was complete (approximately 30 minutes), the mixture was poured into approximately 500 ml. of water and the product, which crystallized from solution, was collected by filtration and dried. Yield was 9.3 g. of a product having a m.p. of 128°-129° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34]Br)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](OCC)(=[O:40])C.O(CC(NC1CN(C(OC)(C(C)=C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)C1=O)=O)C1C=CC=CC=1>CO.Cl([O-])(=O)(=O)=O.[Ag+]>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:36])[CH2:34][O:40][CH3:38])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: [Ag+]
Agent: C=C(C)C(OC)(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: COCC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 281 mg (0.5 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-bromo-2-butenoate in 10 ml of methanol at 0° was added 207 mg (1 mmol) of silver perchlorate. The reaction mixture was stirred for 1 hour. A large amount of ethyl acetate was added. The resulting solution was washed thoroughly with brine, dried, and evaporated in vacuo to dryness to provide a mixture of the title product and benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-2-methoxy-3-methyl-3-butenoate. The products were separated by preparative thin layer chromatography (silica gel plates developed with 1:1/hexane:ethylacetate). A purified sample of 46 mg of the title product was isolated: nmr (CDCl3) δ 2.20 (s, 3, CH3), 3.25 (s, 3, OCH3), 4.37 (s, 2, CH2OCH3), 3.73 (t, 1) and 3.50 (q, 1) [C4 --H], 4.97 (m, 1, C3 --H), 4.47 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1COCC1.C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (620 mg, 3.16 mmol) in THF (10 mL) was added 2-chloroacetyl chloride (0.277 mL, 3.48 mmol). The resulting mixture was then stirred at 60° C. for 10 minutes. The mixture was then diluted with ethyl acetate and washed with water (3×), 1:1 water:saturated sodium carbonate, and brine. The organic phase was dried, filtered, and concentrated, giving the desired product (860 mg, 100%). 1H NMR (DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 7.96 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 4.63 (s, 2H), 3.99-3.92 (m, 2H), 3.39-3.33 (m, 2H); ESI-MS (m/z, %): 295 (M+Na, 68), 273 (MH+, 100), 197 (43).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C=C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:18][CH:13]=[CH2:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CCC(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C=CCO
Product: C=CCOC(=O)CCc1cccc(N)c1
Reaction time: 24 h

Procedure:
3-(3-Aminophenyl)propionic acid (1 g, 6.06 mM) was dissolved in allyl alcohol (25 ml), and toluene-4-sulfonic acid (1.21 g, 6.36 mM) added. The mixture was heated to reflux, the distillate being passed through 3 Å molecular sieves, for 24 hours. After neutralisation of the mixture with triethylamine, the solvent was removed, the residue dissolved in ethyl acetate, and washed with water, aqueous NaHCO3, brine, and dried (MgSO4), to give title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][Br:29])=[CH:19][CH:20]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(-c2nnc(-c3cccc([N+](=O)[O-])c3)s2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nnc(-c3ccc(CBr)cc3)s2)c1

Procedure:
To a solution of 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole (0.66 g, 2.22 mmol) in CCl4 (75 ml) is added NBS (0.43 g, 2.44 mmol) and refluxed for 12 hours. The mixture is then concentrated and the residue is taken up in chloroform (50 ml) and washed with saturated NaHCO3 (50 ml) and brine (50 ml). The organic layer is dried over MgSO4 and concentrated to yield 2-(3′-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-thiadiazole as a tan solid. (0.69 g, 83%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5](O[C@@H]1[C@@H](COC(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)O[C@@H](N2C=CC(=O)NC2=O)[C@@H]1OCOCC(C(F)(F)F)C(F)(F)F)([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[C:66]([NH:69][C:70]1[C:71]2[N:72]=[CH:73][N:74]([C:119]=2[N:120]=[CH:121][N:122]=1)[C@@H:75]1[O:118][C@H:92]([CH2:93][O:94][C:95]([C:112]2[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=2)([C:104]2[CH:109]=[CH:108][C:107]([O:110][CH3:111])=[CH:106][CH:105]=2)[C:96]2[CH:101]=[CH:100][C:99]([O:102][CH3:103])=[CH:98][CH:97]=2)[C@@H:90]([OH:91])[C@H:76]1[O:77][CH2:78][O:79][CH2:80][CH:81]([C:86]([F:89])([F:88])[F:87])[C:82]([F:85])([F:84])[F:83])(=[O:68])[CH3:67]>>[C:1]([CH2:3][CH2:4][PH:5]([O:91][C@@H:90]1[C@@H:92]([CH2:93][O:94][C:95]([C:112]2[CH:113]=[CH:114][CH:115]=[CH:116][CH:117]=2)([C:104]2[CH:109]=[CH:108][C:107]([O:110][CH3:111])=[CH:106][CH:105]=2)[C:96]2[CH:97]=[CH:98][C:99]([O:102][CH3:103])=[CH:100][CH:101]=2)[O:118][C@@H:75]([N:74]2[C:119]3[N:120]=[CH:121][N:122]=[C:70]([NH:69][C:66](=[O:68])[CH3:67])[C:71]=3[N:72]=[CH:73]2)[C@@H:76]1[O:77][CH2:78][O:79][CH2:80][CH:81]([C:82]([F:83])([F:84])[F:85])[C:86]([F:89])([F:88])[F:87])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:9])[CH3:10])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 70 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2a instead of the compound 2u. Yield was 70% (white foam).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[N+:19]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C(OCC)(=O)C>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[NH2:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2N)cc1
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To 4′-methoxy-2′-nitro-biphenyl-4-carboxylic acid methyl ester (4.00 g) suspended in ethanol (150 mL) and ethyl acetate (150 mL) is added 5% palladium on carbon (0.300 g). The reaction mixture is placed under an atmosphere of hydrogen (50 psi) and shaken on a Parr apparatus. After 18 h, the reaction mixture is degassed with nitrogen and filtered though a plug of silica gel, eluting with 700 mL ethyl acetate and 600 mL methylene chloride. The filtrate is evaporated to give 2′-amino-4′-methoxy-biphenyl-4-carboxylic acid methyl ester (3.52 g, >99%) as a white solid.
Reaction SMILES: CO.[H-].[Na+].[C:5]([O:12][CH3:13])(=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=1[CH2:25]Br>CCOCC>[CH3:10][O:9][C:7]([C:6]1([C:5]([O:12][CH3:13])=[O:11])[CH2:25][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:15]1)=[O:8]
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature, to 5.0 mL methanol in 15.0 mL ether was added 60% sodium hydride (0.84 g, 0.021 mol) in small portions. After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtration and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: C1CNC1
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 84 h
Yield: 94.6 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), azetidine (71.6 μl, 1.07 mmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (112 μl, 640 μmol) in tetrahydrofuran (4 ml) was stirred for 3.5 days (weekend) at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (74 mg, 94.5%) as a white solid. mp: 226-227° C., MS: m/z=366.1 (M−H+)