Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.N1C2C(=C(C3C=C(C=C(NC4C=NC=CC=4)C=3)C#N)C=CC=2)C=C1>>[Br:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: Nc1cccnc1
Agent: N#Cc1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: N#Cc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-benzonitrile was prepared from 3,5-dibromobenzonitrile and pyridin-3-ylamine as described for Example 36, except that the reaction was run at 130° C. This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzonitrile by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 2H), 8.28 (d, J=4.3 Hz, 1H), 7.55-7.49 (m, 3H), 7.44 (d, J=8.2 Hz, 1H), 7.30-7.23 (m, 4H), 7.12 (dd, J=7.3, 0.9 Hz, 1H), 6.63 (t, J=2.5 Hz, 1H), 6.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH:15]=3)[N:10]([CH3:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2n[nH]c3cc4ccccc4cc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nc(-c2ccc(Cl)cc2)c2cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 14 g of 3-(p-chlorophenyl)-1H-benz[f] indazole dissolved in 150 ml. dry dimethylacetamide under nitrogen is added 3 g. of a 57% suspension of sodium hydride in mineral oil. The reaction mixture is stirred at room temperature for 1 hour and then 5 ml. of methyl iodide is added. Stirring is continued for 2 hours then the mixture is poured on ice-water, and the precipitate recovered by filtration. The precipitate is recrystallized from ether to yeild the title compound, m.p. 157°-159°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[S:11])[CH:6]=[CH:7][CH:8]=1.BrBr>C(O)(=O)C>[OH:1][CH2:2][C:3]1[C:4]2[S:11][C:10]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2cccc(CO)c2)c(C)c1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C)c(Nc2nc3cccc(CO)c3s2)c(C)c1
Reaction time: 0.08 h

Procedure:
To 0.25 g (0.83 mmol) of 1-(3-hydroxymethylphenyl)-3-mesitylthiourea in 5 mL of glacial acetic acid was added 47 μL (0.91 mmol) of bromine. The reaction was stirred for 5 min and concentrated in vacuo to give the title compound and its regioisomer as their O-acetates. The mixture was stirred in methanol over potassium carbonate for 1 h. The mixture was concentrated in vacuo, slurried in dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 33-66% ethyl acetate/hexanes gradient mixture to give 0.070 g (28%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([OH:32])[CH2:23][CH2:24]2)=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])[C:3]([OH:8])([CH2:6][CH3:7])[CH2:4][CH3:5]>C1C=CC=CC=1.C(O)C>[CH3:5][CH2:4][C:3]([OH:8])([C:2]([F:33])([F:1])[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@@:30]2([CH3:31])[CH2:29][CH2:28][CH2:27]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:32])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:16]2[CH2:15][CH2:14]1)[CH3:12])[CH2:6][CH3:7]
Reactant: CCC(O)(CC)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: CCO
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCC(F)(F)C(O)(CC)CC)CC[C@@H]12
Yield: 28 %

Procedure:
9.3 mg of 24,24-difluoro-3β,25-dihydroxy-26,27-dimethylcholesta-5,7-diene was dissolved in a mixture of 90 ml of benzene and 40 ml of ethanol, and in anargon stream at 0° C., the solution was irradiated with ultra-violetlight for 7 minutes using a medium-pressure mercury lamp through a Vycor filter. Subsequently, the reaction mixture was heated under reflux for 1 hour in at atmosphere of argon. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by thin-layer silica gel chromatography (developing solvent: benzene/ethyl acetate=10:1;developed four times) to give 2.6 mg of the captioned vitamin D3 derivative [the compound of formula (I) in which X is H].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([O:23]CC)=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1>C(O)C>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2cccc(CO)c2)nc2c1cnn2C(C)C
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3cccc(CO)c3)nc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 6-(3-(hydroxymethyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.81 g, 2.38 mmol) in EtOH (15 mL) aqueous NaOH (0.47 g, 11.94 mmol) was added and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution till pH 4. Extraction was carried out using 5% MeOH/DCM, the combined organic layers were washed with water & dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford the desired acid which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:9]([O-:12])(=[O:11])=[O:10])[N:4]=1.[Na+:13]
Reactant: Cc1nc(CCl)cs1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(CS(=O)(=O)[O-])cs1
Yield: 101.2 %

Procedure:
4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 200® C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer is concentrated to afford 0.368 g of the desired product as a yellow solid. LC/MS ESI+ 194 (M+1, free acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Mg]Cl)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][SiH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:27]([Si@H:24]1[CH2:23][CH2:22][C@H:21]([CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][CH:17]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCC[SiH]1CCC(CCc2ccc(Br)cc2)CC1
Reactant: Fc1ccc(C#C[Mg]Cl)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCc2ccc(C#Cc3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml (30.0 mmol) of a tetrahydrofuran solution of 1.5M p-fluorophenylethynyl magnesium chloride was dripped into a mixture of 3.50 g (10.8 mmol) of 4-(2-(p-bromophenyl) ethyl)-1-n-propyl-1-silacyclohexane, 80 mg of tetrakis (triphenylphosphine) palladium (0) and 20 ml of tetrahydrofuran. The reaction mixture was stirred for 8 hours at room temperature. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 2.87 g (yield 73%) of the target product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[Cl-].[NH4+]>[Fe].CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([Br:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(O)c(Br)c1

Procedure:
The target compound was obtained by reducing 2-bromo-4-nitrophenol with iron in a mixed solution of methanol and ammonium chloride aqueous solution. 2-bromo-4-nitrophenol was manufactured by the method described in the literature (J. Org. Chem., Vol. 62, 1997, p. 4504).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[CH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1O)=O)[CH2:8]2.C12(CC(NC3C=CC(O)=CC=3O)=O)CC3CC(CC(C3)C1)C2.C12CC3CC(CC(C3)C1=CC(O)=O)C2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1[S:84]SC1C=CC=CN=1.C(N(C(C)C)C(C)C)C.[OH-].OC1C=C(O)C=CC=1N>ClCCl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[CH:11][C:12]1[S:84][C:16]3[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=3[N:14]=1)[CH2:8]2
Reactant: O=C(C=C1C2CC3CC(C2)CC1C3)Nc1ccc(O)cc1O
Reactant: c1ccc(SSc2ccccn2)nc1
Agent: Nc1ccc(O)cc1O
Agent: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc(O)cc1O
Agent: O=C(O)C=C1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Oc1ccc2nc(C=C3C4CC5CC(C4)CC3C5)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Adamantan-2-ylidene)-N-(2,4-dihydroxyphenyl)acetamide (formula VII) 3.0 g (adamantan-2-ylidene)acetic acid (formula R3COOH), 5.91 g triphenylphosphane and 4.95 g dipyridyldisulfide, dissolved in 100 ml of dichloromethane, are stirred at room temperature overnight. To the mixture obtained, 5.13 ml of N-ethyl-diisopropylamine and 4.83 g 2,4-dihydroxyaniline hydroxide (formula V) are added and the mixture is stirred for about 24 hours, the solvent is evaporated off, the evaporation residue is dissolved in ethyl acetate and extracted with a saturated aqueous NaH2PO4 solution and brine. The organic layer is dried, the solvent is evaporated off and the residue is purified by chromatography. The title compound is obtained (m.p. 166-169°).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.40 g (93% yield) of tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12]([CH3:14])=[O:13]>CC(O)CC>[CH3:3][N:4]([CH3:6])/[CH:5]=[CH:14]/[C:12](=[O:13])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CCC(C)O
Product: COC(OC)C(=O)/C=C/N(C)C

Procedure:
A solution of N,N-dimethylformamide dimethyl acetal (147 g, 1.23 mol) and 1,1-dimethoxyacetone (146 g, 1.24 mol) in 2-butanol (1 L) was heated at reflux for 20 hours. After removal of solvent in vacuo, the residue was distilled under vacuum to provide the product as an oil. Yield: 145 g, 0.837 mol, 68%. Boiling point: 132-140° C./0.15 torr. NMR and MS data were obtained using the product of a reaction run under similar conditions. LCMS m/z 174.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.77 (br s, 3H), 3.02 (br s, 3H), 3.30 (s, 6H), 4.47 (s, 1H), 5.23 (br d, J=12.6 Hz, 1H), 7.63 (d, J=12.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.0 mg) with purity >90%: LCMS (pos) m/z 431.0; HRMS m/z 427.9238 (calc. of monoisotopic mass for C13H11Cl3N2O4S2 gives 427.9226).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30]>>[CH2:29]([N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CCNc1ccccc1
Product: CCN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and N-ethylaniline, the title compound was isolated as a yellow solid in 70% yield (96% purity by HPLC).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][C:23]=3[F:32])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:30])[N:34]([CH3:35])[CH3:33])=[CH:24][C:23]=3[F:32])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Oc2ccc(CC(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(CC(=O)N(C)C)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 4-[6-(4-carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (150 mg, 0.335 mmol) and HATU (178 mg, 0.469 mmol) in DMF (4 mL) was stirred for 30 minutes at room temperature. Then, dimethylamine (235 μL, 0.47 mmol) was added and the reaction was stirred for 24 hours at room temperature. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo and purified by HPLC to provide Compound C150 as a white solid (40 mg, 25%). 1H NMR (DMSO-d6, 400 MHz) δ 1.21 (d, 6H), 1.62-1.72 (m, 2H), 1.92-2.01 (m, 2H), 2.16 (s, 3H), 2.87 (s, 3H), 3.06 (s, 3H), 3.32-3.41 (m, 2H), 3.61-3.69 (m, 2H), 3.75 (s, 2H), 4.08 (h, 1H), 5.33 (h, 1H), 7.08 (d, 1H), 7.23-7.33 (m, 2H), 8.27 (s, 1H). Exact mass calculated for C24H31FN4O5 474.53, found 475.5 (MH+).
Reaction SMILES: ClC1C=C([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)C=CN=1.Br[C:17]1[CH:18]=[C:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([O:23][CH3:24])=[N:21][CH:22]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:17]2[CH:18]=[C:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([O:23][CH3:24])=[N:21][CH:22]=2)[CH2:9]1
Reactant: COc1ncc(Br)cc1C(=O)OC(C)(C)C
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Product: COc1ncc(N2C[C@@H](C)N[C@@H](C)C2)cc1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) using 1,1-dimethylethyl 5-bromo-2-(methyloxy)-3-pyridinecarboxylate (D23) and cis-2,2-dimethylpiperazine as the starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=5[F:17])[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)c(F)c1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)c(F)c1

Procedure:
The title compound, off-white solid (29 mg, 22%), MS (ISP) m/z=407.4 [(M+H)+], mp 133° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(2,4-difluoro-phenyl)-1H-benzo[d]imidazole (intermediate K) (100 mg, 324 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (79.2 mg, 356 μmol).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:35][CH2:36]3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(F)cc2)CC=CCN1OCc1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CS(C)=O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(N3CCC(c4ccccc4)CC3)cc2)CC=CCN1OCc1ccccc1
Temperature: 70 °C
Yield: 61 %

Procedure:
To a solution of 100 mg of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-fluoro-benzenesulfonamide from Step A in 2 mL of methylsulfoxide was added 100 mg of 4-phenyl piperidine. The solution was heated to 70° C. for 5 days. The reaction was cooled, and the mixture extracted with ethyl acetate. The organic layers were washed twice with NaCl(aq.) solution, followed by drying over Na2SO4(s). Filtration, solvent removal, was followed by dilution with ethyl ether. Filtration of the resulting solids, washing with ethyl ether and methanol, and drying gave 83 mg of an off-white solid. MS: 1063 (2M+H), 532 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][S:8][C@H:3]12.[OH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](O)=[O:28]>>[CH2:14]([O:13][C:11]([CH:10]=[CH:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:27](=[O:28])[CH:26]([OH:25])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23](=[O:24])[N:4]2[C:5]=1[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: CCOC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)C(O)c1ccccc1
Product: CCOC(=O)C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccccc3)[C@H]2SC1

Procedure:
Following the general procedure of Example 9, a salt of tert-butyl 7-amino-3-(2'-ethoxycarbonylvinyl)-3-cephem-4-carboxylate was acylated with the acid chloride derivative of 2-hydroxy-2-phenylacetic acid (mandelic acid), and after ester group removal the title compound was obtained as product.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.39 (t, J=8.9 Hz, 2 H), 7.64 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 8.27-8.35 (m, 2 H), 8.55 (ddd, J=8.1, 2.0, 1.8 Hz, 1 H), 8.74 (dd, J=5.0, 1.8 Hz, 1 H), 9.29 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH3:10])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19]Cl>CN(C)C=O>[Cl:17][CH2:18][CH2:19][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([CH2:9][CH3:10])[NH:6][C:5]1=[O:7]
Reactant: ClCCCl
Reactant: CCC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(C)NC(=O)N(CCCl)C1=O
Reaction time: 25 h

Procedure:
284.3 g of 5-methyl-5-ethyl-hydantoin (2.0 mols), 138.2 g of anhydrous potassium carbonate (1.0 mol), 791.7 g of 1,2-dichloroethane (8.0 mols) and 230 ml of dimethylformamide are subjected to an azeotropic circulatory distillation, analogously to A, for 25 hours at 90° C to 107° C internal temperature (external temperature: 160° C). After completion of the reaction, the mixture is filtered whilst still hot and the filtrate is concentrated on a rotary evaporator at 90° C under a water pump vacuum. The reaction mixture is then dried to constant weight at 90° C and 10-1 mm Hg. 392.5 g of a brown, clear product (95.9% of theory) are obtained, and purified by vacuum distillation (boiling point0.2 : 147° C). Yield of pure material: 327.3 g (80% of theory). A sample recrystallised from diethyl ether melts at 58.0° C to 59.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[Br-].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COc1cc(/C=C/CCCBr)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzaldehyde (9.81 g) and 4-bromobutyltriphenylphosphonium bromide (23.93 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.