Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2,5-di-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([O:9]CC)=O)(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:36]3[CH2:37][CH2:38][N:39]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])[CH2:40][CH2:41]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:25][CH2:26]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 30.8 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (361 mg) described in Preparation Example 28 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (243 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.
Reaction SMILES: [H-].[Na+].[ClH:3].[CH3:4][N:5]([CH3:29])[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[C:15]1[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=1.I[CH3:31]>CN(C)C=O.[Cl-].[NH4+].C(OCC)(=O)C>[ClH:3].[CH3:4][N:5]([CH3:29])[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:10]2[C:15]1[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH3:31])[CH:20]=1
Reactant: CN(C)c1ncnc2c1nc(-c1cccc(F)c1)n2-c1ccc(=O)[nH]c1
Reactant: CI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1ncnc2c1nc(-c1cccc(F)c1)n2-c1ccc(=O)n(C)c1
Temperature: 3 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
60 to 70% sodium hydride (28 mg, 0.700 mmol) was added to a suspension of 5-[6-(dimethylamino)-8-(3-fluorophenyl)-9H-9-purinyl]-1,2-dihydro-2-pyridinonehydrochloride (130 mg, 0.336 mmol) in Example 4 in N,N-dimethylformamide (3 ml), and the mixture was stirred in a nitrogen atmosphere at 0 to 6° C. After 1 hour, iodomethane (23 μl, 0.369 mmol) was added thereto and stirred. After 30 minutes, 60 to 70% sodium hydride (17 mg, 0.425 mmol) was added thereto, and 30 minutes thereafter, additional iodomethane (23 μl, 0.369 mmol) was added thereto and stirred. After 30 minutes, the reaction solution was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution (×1) and then extracted with 1N hydrochloric acid (×1). The 1N hydrochloric acid layer was adjusted to pH 9-10 with IN aqueous sodium hydroxide solution and extracted with ethyl acetate (×1). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol-4N hydrochloric acid/ethyl acetate (1.5 ml) and concentrated. The residue was crystallized from methanol/diethyl ether, and then the solid was collected by filtration and washed with diethyl ether, to give the title compound (90 mg, 67%) as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][C:22]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:23][C:18]=3[O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>C(O)C>[ClH:33].[C:27]1([S:24]([C:22]2[CH:21]=[CH:20][C:19]3[N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH2:15][CH2:16][O:17][C:18]=3[CH:23]=2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCNCC1
Reaction time: 0.5 h

Procedure:
4-(7-Benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.111 g, 0.242 mmol) was dissolved in 5 mL ethyl alcohol and brought to reflux. To the solution was added ethanolic hydrogen chloride (2 mL of a 2N solution, 4.0 mmol) and reflux continued for 0.5 hours. The solution is concentrated to 1 mL and ethyl ether (10 mL) is added until a white precipitate is observed. Filtration gave 0.085 g (quantitative) of 7-benzenesulfonyl-4-piperidin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride as a white powder. MS: 359 (M+H)+, mp: 251.9-253.2° C.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH:16][CH:17]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19][CH:18]1[CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Cl)(Cl)Cl.CCOC(C)=O>CC(C)=O>[CH3:25][C:21]1([CH3:24])[O:20][CH:19]([CH:18]([CH2:17][OH:16])[CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:23][O:22]1
Reactant: CC1(C)OCC(O)C(CNC(=O)OCc2ccccc2)CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)OCC(C(CO)CNC(=O)OCc2ccccc2)O1
Temperature: 25 °C
Yield: 47 %

Procedure:
Camphorsulfonic acid (0.069 g, 0.296 mmol) was added to a solution of benzyl ((5R/S,6R/S)-6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)methylcarbamate (1.83 g, 5.92 mmol) in acetone (50 mL) and the solution was stirred at RT. After 40 mins chloroform was added and the solution was washed with aq NaHCO3 and then processed normally. Chromatography (EtOAc/Hex 1:1, and then 3:1) gave firstly benzyl (RS)-2-((RS)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropylcarbamate (0.86 g, 2.78 mmol, 47.0% yield) and then benzyl ((4RS,5RS)-4-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methylcarbamate (0.942 g, 3.05 mmol, 51.5% yield) as syrups; compound 10.3 13C NMR (CDCl3) δ 157.6, 136.8, 128.9, 128.6, 128.5, 109.3, 76.4, 68.0, 67.3, 61.3, 44.3, 39.9, 26.9, 25.7; compound 10.4 13C NMR (CDCl3) δ 157.1, 136.8, 128.9, 128.6, 128.5, 99.0, 72.5, 69.1, 67.3, 64.2, 62.3, 40.3, 36.7, 29.1, 20.2.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH:28][CH:29]([CH2:31][CH3:32])[CH3:30])([CH2:26][CH3:27])[CH3:25]>CN(C)C=O>[CH:24]([N:28]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH:29]([CH2:31][CH3:32])[CH3:30])([CH2:26][CH3:27])[CH3:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CCC(C)NC(C)CC
Solvent: CN(C)C=O
Product: CCC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1)C(C)CC
Yield: 58.2 %

Procedure:
1.65 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 75° for 24 hours in 3 ml (17.5 mmol) of di-sec.-butylamine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate there were obtained 1.23 g (58%) of 3-(5-di-sec.-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of m.p. 155°-157°, which was converted into the hydrochloride of m.p. 133°-140°.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([NH:11][CH:12]1[C:41](=[O:42])[N:14]2[C:15]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:17](=[CH2:19])[S:18][C@H:13]12)=[O:10].CC(O)=O>CCO.O1CCCC1>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([NH:11][CH:12]1[C:41](=[O:42])[N:14]2[CH:15]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:26])[C:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:17]([CH3:19])[S:18][C@H:13]12)=[O:10]
Reactant: C=C1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1COC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)OCC1=C(C)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.12 h
Yield: 41.4 %

Procedure:
A solution of 4.4 g of NaBH4 in 250 ml of EtOH was added to a solution of 45 g of diphenylmethyl 7-(2-thienylacetamido)-2-methylene-3-acetoxymethylceph-3-em-4-carboxylate in 150 ml of tetrahydrofuran at 0° C., and the mixture was stirred for 7 minutes, followed by adding 15 ml of AcOH. After distilling off the solvent under reduced pressure, AcOEt and H2O were added to the residue to separate out the AcOEt layer. The AcOEt layer was washed with 5% aqueous NaHCO3 and saturated aqueous sodium chloride solution, and dried over Na2SO4 to distill off the AcOEt under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (10:1) were collected, followed by distilling off the solvent under reduced pressure, yielding 18.7 g (41%) of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-2-em-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>ClCCl>[CH:9]1([CH2:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.83 g, 35.1 mmol) in dichloromethane (50 ml) were added cyclohexylacetyl chloride (11.26 g, 70.1 mmol) and pyridine (5.67 ml, 70.1 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 41 ml) was added and the mixture was stirred at room temperature for 4 h. The solution was acidified with 1 N hydrochloric acid and the organic phase was removed by evaporation. The solid material was collected by filtration, dried and dissolved in methanol (100 ml). A solution of KOH (5.5 g) in methanol (50 ml) was added. After stirring for 1 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The title product was isolated by filtration and dried in vacuo (6.31 g, 77%, pink crystals).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][Mg]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:34][C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:23])[CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][C:17]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=2[O:34][C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH3:15])([CH3:13])[CH3:14]
Reactant: I[Mg]CCCC1CCCCC1
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(C(O)CCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using 3-cyclohexylpropylmagnesium iodide and N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>O1CCCC1>[N+:39]([C:36]1[CH:35]=[CH:34][C:33]([O:32][C:30]([CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]23)=[O:31])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.500 g (2.06 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one (step 6.1 of example 6) in dry tetrahydrofuran (20 mL) under argon at −40° C. was added 2.27 mL (2.27 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −50° C. for 10 min and 1.04 g (5.16 mmol) of 4-nitrophenyl chloroformate diluted in 3 ml of dry tetrahydrofuran was added. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was used as such for the next step.
Reaction SMILES: N1C=CN=C1.[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[I:23]I.C(OCC)(=O)C.ClCCl>ClCCl>[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][I:23])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Reactant: II
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CI)c1
Reaction time: 16 h
Yield: 119.7 %

Procedure:
Stir polystyrene-bound triphenylphosphine (4.27 g, 12.8 mmol) and imidazole (0.86 g, 12.7 mmol) in dichloromethane (45 mL). Add a solution of (3-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.70 g, 6.1 mmol) in dichloromethane (45 mL). Add iodine (3.22 g, 12.7 mmol) in 3 portions. Stir 16 hrs. Filter through a pad of diatomaceous earth. Wash with aqueous sodium thiosulfate. Dry the organic portion over sodium sulfate. Filter and concentrate. Chromatograph the residue on silica eluting with 25% ethyl acetate/dichloromethane to provide the title compound (2.53 g, 7.3 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]([C:14](=O)[CH2:15]Br)[CH:4]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[C:24]([NH2:26])=[S:25])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:24]2[S:25][CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=3)[N:26]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH3:19]
Reactant: CCOC(=O)c1cc(OC)cc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(OC)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-methoxy-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-methoxy-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH2:11]([C:9]1[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1cc(CC(C)C)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Cc1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 64 h
Yield: 71.6 %

Procedure:
5-Isobutyl-1H-pyrazol-3-carboxylic acid ethyl ester (16.2 g, 83 mmol) and 1M NaOH solution (173 ml, 173 mmol) were dissolved in 1,4-dioxan (260 ml) and the reaction was stirred at room temperature under nitrogen for 64 hours. The reaction mixture was adjusted to pH 7 using concentrated hydrochloric acid, and concentrated under reduced pressure. Water (500 ml) was added, the slurry was adjusted to pH 1 with concentrated hydrochloric acid and the aqueous phase was extracted with ethyl acetate (5×300 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 5-isobutyl-1H-pyrazol-3-carboxylic acid (10 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=12.72-12.90 (1H, brs), 6.39 (1H, s), 2.39-2.43 (2H, d), 1.77-1.86 (1H, m), 0.78-0.83 (6H, d) ppm. LRMS (electrospray): m/z [M+Na]+ 191, [2M+Na]+ 359, [M−H]+ 167, [2M−H]+ 335.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[C:18]([C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:20][CH3:21])#[N:19]
Reactant: COc1c(C#N)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C#N)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To 150 mg of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 121 mg (100% yield) of 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12].N[C@@](C)([C@H](O)C)CO>>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: C[C@@H](O)[C@](C)(N)CO
Solvent: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO

Procedure:
Prepared from (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (7A) as described for 7E (93%) (C, H, N) mp 163°-165° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 1-((4-bromo-2-nitrophenoxy)methyl)benzene 13.B (1.40 g, 4.55 mmol) and pyridin-4-ylboronic acid (665 mg, 5.45 mmol, available from Aldrich) in DMF (10 mL) was added cesium carbonate (2.93 g, 9.0 mmol). The mixture was stirred overnight at 80° C. and then partitioned between AcOEt and water. The organic phase was concentrated to afford 4-(4-(benzyloxy)-3-nitrophenyl)pyridine 13.0 (1.52 g, 109% yield) which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:12]1[N:13]=[N:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[C:10]([CH3:16])[CH:11]=1
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Cl)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
6-(3,4-dichlorophenyl)-5-methylpyridazin-3(2H)-one (500 mg) is added stepwise to phosphoryl trichloride (1.8 ml). The reaction mixture is heated to 100° C. for 1 hour, then cooled to room temperature and poured onto ice water. The formed precipitate is separated, washed with water and dried to give 3-chloro-6-(3,4-dichlorophenyl)-5-methylpyridazine (509 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Yield: 18.8 %

Procedure:
A solution of 2-amino-N,3-dimethylbenzamide (562 mg) and 2,4,5-trichloropyrimidine (1.3 g) in N-methylpyrrolidinone (20 mL) were heated with potassium carbonate (2 g) at 80° C. for 16 hours. The mixture was diluted with ethyl acetate, washed three times with brine, dried with sodium sulfate, filtered, and concentrated. Column chromatography (20-30% ethyl acetate in methylene chloride) followed by trituration with ethyl ether provided 200 mg of 2-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide: 1H NMR (300 MHz, CDCl3) δ 9.3 (s, 1H), 8.15 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.2 (t, 1H), 6.05 (m, 1H), 3.0, (d, 3H), 2.2 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].N>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][CH2:16][NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCN1CC2CC1CN2Cc1ccccc1
Agent: [Ni]
Agent: N
Product: NCCN1CC2CC1CN2Cc1ccccc1
Yield: 85.8 %

Procedure:
A solution of 5.74 g (25.3 mmoles) of 140 and 50 mL of NH3 were hydrogenated with 2 g of Raney nickel in a steel autoclave at 100 bar H2 and 100° C. for 2 hours. The catalyst was filtered off with suction and the solution was evaporated and distilled using a bulb tube (boiling point: 135°-145° C. at 0.01 mbar): 5.02 g of 141 as a colorless oil (87% of the theoretical yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[N+:11]([C:14]1[CH:18]=[CH:17][NH:16][N:15]=1)([O-:13])=[O:12].C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:17]=[CH:18][C:14]([N+:11]([O-:13])=[O:12])=[N:15]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COc1cc(I)ccc1Br
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc([N+](=O)[O-])n2)ccc1Br
Temperature: 95 °C
Yield: 60.5 %

Procedure:
A mixture of 1-bromo-4-iodo-2-methoxybenzene (3.99 g, 12.75 mmol), 3-nitro-1H-pyrazole (1.730 g, 15.30 mmol), Salicylaldoxime (0.350 g, 2.55 mmol), Cu2O (0.146 g, 1.020 mmol) and Cs2CO3 (6.23 g, 19.13 mmol) in DMF (13 mL) was degassed with N2 and heated at 95° C. overnight. After cooling to RT, the mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in 5% MeOH/DCM, and the precipitate filtered, rinsed with 5% MeOH/DCM, and dried to give 2.3 g of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a white solid. The filtrate from the above work up was purified by silica gel chromatography (EtOAc/Heptane=10:90 to 50:50) to give an additional 760 mg of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a light yellow solid.