Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23])[C:6]=2[N:14]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 138 mg, 0.610 mmol) in a 1:1 mixture of THF-DMF (4.5 mL) was added NaH (73.0 mg, 2.50 mmol). The mixture was stirred at RT. After 10-15 min, dimethylsulfamoyl chloride (212 mL, 1.10 mmol) was added and the reaction was stirred for another 2 h. The reaction was quenched with water (50 mL) and poured into a separatory funnel containing EtOAc (100 mL). The mixture was shaken and the layers were separated. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to give 2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (17, 24.9 mg, 12%). HCOOH standard conditions. DAD Retention time=3.68 min. M+H=334. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.06 (s, 1H), 8.00-7.97 (m, 1H), 7.84-7.81 (m, 1H), 7.72 (br s, 2H), 7.40-7.32 (m, 3H), 3.02 (s, 6H).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(CNc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To an acetic acid (1.5 mL) and dimethyl sulfoxide (26 mL) solution of (4((E)-2-nitro-vinyl)-benzyl)-phenyl-amine (1.53 g, 6.02 mmol) described in Manufacturing Example 73-1-4 was added sodium borohydride (364 mg, 9.63 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.5 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC

Procedure:
According to Scheme I, an optionally substituted dimethoxybenzaldehyde of formula 2, nitromethane and a catalytic amount of ammonium acetate (about 10 mol% per dimethoxybenzaldehyde) are heated to about 70°-100° C. for about 2-6 hours. The resulting product is precipitated from a mixture of water and isopropanol (about 7:1) to yield a nitrostyrene derivative of formula 3 (step 1). For example, 3,4-dimethoxybenzaldehyde is treated with NH4OAc and nitromethane to yield 3,4-dimethoxy-β-nitrostyrene (3). Alternatively, one can purchase 3,4-dimethoxy-β-nitrostyrene commercially.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[NH:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]2[NH:35][N:34]=[CH:38][CH:37]=2)[CH:3]=1
Reactant: OB(O)c1ccn[nH]1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
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: [Na+]
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccn[nH]1)c(OCc1ccccc1)c2=O
Yield: 62.5 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.27 mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060 g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62% yield) of the title material as a white solid after chromatography on silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.65 (2H, d, J=6.5 Hz, NCH2), 5.25 (2H, s, OCH2), 6.54 (1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m, aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN5O4 [M+H+]: 504.2047. found: 504.2068.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])=[O:6])([O-:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCSC(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)SCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Yield: 85.7 %

Procedure:
A solution of 7.0 g of 2-acetylthioethyl acetoacetate, 5.14 g of 3-nitrobenzaldehyde and 0.99 g of piperidinium acetate in 100 ml of benzene was heated at reflux under azeotropic dehydration conditions for 2 hours. The reaction mixture was poured into water and extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9.83 g of 2-acetylthioethyl 2-(3-nitrobenzilidene)acetoacetate.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.080 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-2-{(5-fluoro-pyridin-2-ylmethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.085 g, 0.146 mmol, 48.7%), as a white solid. LC-MS (ESI) calcd for C24H28FN5O7S2 581.14, found 582.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[NH:5][CH3:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[CH2:11]([N:5]([CH3:6])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cc(Cl)cc(Cl)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(Cc1ccccc1)c1cc(Cl)cc(Cl)c1

Procedure:
The mixture of 3,5-dichloro-N-methylaniline (345 mg) and excess amount of benzyl bromide and triethylamine in acetonitrile (7 ml) was refluxed for 4 hours. The reaction mixture was separated with ethyl acetate and water, and the organic layer was washed with water, dried and concentrated in vacuo to give N-benzyl-3,5-dichloro-N-methylaniline (532 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1.C(N(C(C)C)C(C)C)C>>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:30]([CH3:29])[CH2:31][CH2:32][O:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:28][CH:27]=3)=[O:8])[S:11][C:12]=2[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=1
Reactant: CNCCOC(=O)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)OCCN(C)Cc2ccc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)cc2)cc1OC
Yield: 57 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with 3,4-dimethoxybenzoic acid 2-methylamino-ethyl ester chlorohydrate (96 mg, 0.4 mmol) and N-ethyl diisopropylamine (0.14 ml, 0.80 mmol) using the general procedure C affords the product as light yellow solid in 57% yield. MS: m/e=621 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Br>CC(C)=O>[Br:1][C:2]1[C:3]([O:22][CH2:29][CH:31]2[CH2:32][O:33]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[N:8]=[CH:7]2
Reactant: CC(Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 73.6 %

Procedure:
A suspension of the product from Step C (4.47 g, 11.6 mmol), potassium carbonate (2.25 g, 16 mmol), and epibromohydrine (1.59 mL, 19 mmol) in acetone (230 mL) was heated at reflux for 20 h. Additional epibromohydrine (1.5 mL, 17.9 mmol) was added and the mixture heated at reflux for 18 h. The solid was removed by filtration and the filtrate was concentrated to an oil which was dissolved in EtOAc (150 mL). This solution was washed with saturated aqueous ammonium acetate (150 mL), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 2% to 10% EtOAc/hexane) to afford an oil (3.77 g, 74%): LC/MS (+APCI) m/z 441, 443 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4Cl)CC3)c(OC)nc2c1
Yield: 89 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.13 (s, 4H), 3.78 (s, 4H), 3.90 (s, 3H), 4.12 (s, 3H), 6.98-7.37 (m, 7H), 7.76 (d, J=9.9 Hz, 1H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:32]2[S:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)S1

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 0.7 g of 2,4-thiazolidinedione, 1 g of piperidine and 20 ml of ethanol. The resulting product was a pale brown powder having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[N:9]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[CH2:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:11][CH2:10]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=c1cc(Cl)nc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: O=C(OCc1ccccc1)N1CCN(c2cc(=O)[nH]cn2)CC1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (36984-063-A; 3.90 g, 29.9 mmol), benzyl 1-piperaz-inecarboxylate (Aldrich; 8.81 g, 40.0 mmol), and diisopropylethylamine (7.0 mL, 40.2 mmol) in 2-butanol (100 mL) was heated in a 250 mL round-bottomed flask equipped with a reflux condenser in an oil-bath at about 80° C. (oil-bath temperature) for 8 hours. The heating bath was removed and the reaction mixture was left standing at room temperature overnight. The white solid was filtered off, washed with 2-butanol, and air-dried to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (7.76 g, 83%) as a white powder, mp 247-249° C. 1H NMR (d6-DMSO) δ 1.39 (s, 9H), 3.45-3.50 (m, 8H), 5.08 (s, 2H), 5.26 (s, 1H), 7.28-7.38 (m, 5H), 7.90 (s, 1H), 11.66 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:32].[K+].[K+].OO.CO>CS(C)=O>[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:32])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 173.1 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile (compound of example 368) (0.246 g, 0.642 mmol), potassium carbonate (0.0429 g, 0.310 mmol), and 30% hydrogen peroxide Solution (aq) (0.220 mL, 1.94 mmol) in dimethylsulfoxide provide, after ion exchange chromatography (methanol→2 M ammonia/methanol), 0.223 g (87%) of the title compound as a while solid: high resolution mass spectrum (electrospray): m/z calc for C25H25N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.32-7.22 (m, 4H), 7.20-7.14 (m, 3H), 7.04 (d, 1H, J=8.8 Hz), 3.77 (s, 2H), 2.97 (ddd, 1H, J=3.4, 6.3, 13.2 Hz), 2.92-2.83 (m, 3H), 2.81-2.72 (m, 1H), 2.04-1.76 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1OC
Yield: 60 %

Procedure:
4-[2-(3,4-Dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl was prepared analogous to Example I from 4-[2-amino-ethyl]-4'-hydroxy-biphenyl and 3,4-dimethoxybenzoyl chloride. Yield: 60% of theory; m.p. 170° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[NH:17][C:18](=[NH:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(C)S[C@H]12)c1csc(=N)[nH]1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1 N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as sodium 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (4.8 g.), mp>250° C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3° to 5° C., and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (1.44 g.), mp 165° to 170° C. (dec.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[Br:1][C:17]1[C:12]([CH:9]([CH3:11])[CH3:10])=[N:13][C:14]([NH2:18])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccnc(N)n1
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
N-Bromosuccinimide (0.5 g, 2.8 mmol) was added to a solution of 4-isopropylpyrimidin-2-amine (0.39 g, 2.81 mmol) in chloroform. The resultant yellow solution was stirred at ambient temperature for 1 h and concentrated in vacuo. The residue was purified by column chromatography (3-10% 9:1 methanol:ammonium hydroxide in chloroform) to afford 5-bromo-4-isopropylpyrimidin-2-amine (0.69 g, 3.18 mmol, 113%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1 H, s), 6.75 (2 H, s), 3.10-3.23 (1 H, m), 1.14 (6 H, d, J=6.80 Hz). MS (LC/MS) R.T.=2.58; [M]+=216.09.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11](N)=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34]C2C=CC(C(O)=O)=C(C3C=CC=CC=3)C=2)[CH:28]=1.[N+](C1C=CC(C(O)=O)=C(C2C=CC=CC=2)C=1)([O-])=O>>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([O:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2cccnc2)cc1-c1ccccc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared by according to the procedure used in step C of the preparation of compound 8, except substituting 4-(3-pyridylmethyloxy)-2-phenylbenzoic acid, prepared as in Example 240E, for 4-nitro-2-phenylbenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14].CC(N(C)C)=O>O1CCOCC1>[C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([O:15][CH3:16])=[O:14]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: COC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 65 °C

Procedure:
To suspension of the 4-aminomethylbenzoic acid (10 g, 66.2 mmol) in 1,4-dioxane (100 mL) were added methyl chloroformate (5.4 mL, 69.5 mmol) and dimethyl acetamide (3.4 mL). The reaction mixture was then heated to 65° C. overnight. Reaction mixture was evaporated to dryness and the residue was triturated with water. The solids were filtered and dried to give pure product as white solid. 1H NMR (600 MHz, DMSO) δ 12.84 (bs, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.73 (t, J=6 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 4.20 (bd, J=6 Hz, 2H), 3.52 (s, 3H); MS: (MH+), (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99%), mp >250°.