Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]2)[C:5]2[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=2[N:3]=1.Cl>C(O)C>[CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=2[N:3]=1
Reactant: CC(=O)N1CCC(n2c(C)nc3cc(C)ncc32)CC1
Agent: Cl
Solvent: CCO
Product: Cc1cc2nc(C)n(C3CCNCC3)c2cn1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 1-[4-(2,6-dimethyl-imidazo[4,5-c]-pyridin-3-yl)-piperidin-1-yl]-ethanone) 20 mg, 0.0735 mmol) in ethanol (0.5 mL) was treated with concentrated HCl (0.5 mL). The reaction mixture was heated at 100° C. for 18 h. The solvent was evaporated and the mixture was diluted with water (2 mL). The mixture was washed with diethyl ether and the aqueous phase was adjusted to pH=10 by addition of a solution of 25% aqueous NaOH. The aqueous mixture was extracted with CH2Cl2 (5×10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2,6-dimethyl-3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine (13 mg, 77%) as a light yellow solid which was used without further purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.Cl>N1C=CC=CC=1>[F:29][C:27]1[CH:26]=[C:25]([S:30]([NH:21][C:20]2[C:14]3[CH2:13][O:12][C:11]([NH:10][C@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)=[N:16][C:15]=3[CH:17]=[CH:18][CH:19]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([F:22])[CH:28]=1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
(R)—N2-Indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) (150 mg, 0.54 mmol) was dissolved in 5 mL pyridine and 3,5-difluoro-benzenesulfonyl chloride (112 mg, 0.53 mmol) was added. The reaction mixture was stirred at room temperature overnight. 1N HCl was added until pH5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was purified by a silica gel column chromatography with heptane/ethyl acetate 1:1 to give a white solid (24 mg, 9%), MS: m/e=456.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH3:11]>C(O)C>[CH3:11][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: CC(=O)CCl
Reactant: Nc1ccccn1
Solvent: CCO
Product: Cc1cn2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-aminopyridine (9.4 g), chloroacetone (9.5 ml), and ethanol (25 ml) was heated and stirred for 5 hours on an oil bath at 100° C. After that, the reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate-aqueous potassium carbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to a column chromatography using NH silica gel with 20 to 30% ethyl acetate/hexane to yield the title compound (5.5 g).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CN3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CN3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydro-1,2,4-triazin-6(1H)-one-3-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (5 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (165 mg) as colorless plates.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-])=O.[OH-].[Na+].[S:18]([O-:21])([O-:20])=[O:19].[Na+].[Na+].[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(=O)(=O)(O)O>O.[Fe].C(O)(=O)C>[NH2:13][C:4]1[CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[S:18]([OH:21])(=[O:20])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O
Temperature: 24 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
484 g of moist sodium salt of 4-chloro-3-nitrobenzene-1-sulphonic acid (with adhering sulphuric acid and sodium hydrogen sulphate), corresponding to 1 mol, were initially introduced in 650 ml of water and adjusted to a pH of 7 to 8 using 59 ml of 50% strength by weight sodium hydroxide solution. 147 g of anhydrous sodium sulphite (1.2 mol) were then added, and the reaction mixture was heated to boiling temperature and left at this temperature for 2 hours. 115 g of sodium chloride (1.97 mol) were then added, the mixture was cooled to 24° C. with stirring and the precipitate deposited was filtered off. The isolated solid was dissolved in 2,300 ml of water and this solution was added dropwise at 98° C. in the course of one hour to a mixture of 414 g of iron (7.4 mol), 150 ml of water and 2 ml of acetic acid. 20 minutes after completion of the addition, the reaction mixture was rendered alkaline with sodium carbonate and the iron oxide deposited was filtered off with suction. The iron oxide was then washed with 300 ml of warm water. The combined filtrates were warmed to 80° C., acidified with 182 ml of 78% strength by weight sulphuric acid (2.47 mol), which gave a pH of 0.5. The mixture was subsequently stirred at 80° C. for a further 30 minutes, then 1,600 ml of water were removed by distillation at 102° to 108° C. up to the start of crystallization. After cooling to 20° C. with stirring, the deposited precipitate was filtered off. 235 g of moist 2-aminobenzene-1,4-disulphonic acid were obtained in the form of pale-grey, coarse crystals. This corresponds to 192.2 g of 100% pure product and a yield of 76% of theory.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][N:23]=3)[CH:18]=[CH:17]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:25]NC(=O)CCC(N)=O>C1COCC1>[C:7]1([S:13]([N:16]2[C:24]3=[N:23][CH:22]=[CH:21][CH:20]=[C:19]3[C:18]([Br:25])=[CH:17]2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.6 %

Procedure:
Potassium carbonate (47.1 g) was added to a solution of N-phenylsulfonyl-7-azaindole (1c) (80.0 g) in THF (500 mL) at 0° C. N-Bromosuccinamide (60.6 g) was then added portionwise to the suspension. The reaction mixture was warmed to rt and stirred for 2 days. It was quenched with water and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, then dried over Na2SO4 and concentrated. The residue was subjected to silica gel column (eluted with 7:3 dichloromethane/hexane) to give 1-benzenesulfonyl-3-bromo-1H-pyrrolo[2,3-b]pyridine (1d) (50.78 g, 49%). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 HZ, 2H), 7.26 (m, 1H).
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)(C)C.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[N:22]1[CH:21]=[C:20]([O:19][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=[N:24][CH:23]=1
Reactant: Oc1cncnc1
Reactant: BrC1=NOCC1
Agent: CC(C)Oc1ccc(C=O)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-141a and I-141b were prepared in 3 steps from 4-iso-propoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=299.3 m/z. Activity: A
Reaction SMILES: [ClH:1].[Si:2]([O:19][CH2:20][C@@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Si](OC[C@H]1COCCN1C(OC(C)(C)C)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[ClH:1].[Si:2]([O:19][CH2:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1)([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCOC[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[Si](OC[C@H]1COCCN1)(c1ccccc1)c1ccccc1
Yield: 77 %

Procedure:
The title product (1.2 g, yield: 77%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 103. (R)-tert-Butyl 3-((tert-butyldiphenylsilyloxy)methyl)morpholine-4-carboxylate (INTERMEDIATE 106, 2.0 g, 4.39 mmol) was used as starting material. The title product was obtained as a hydrochloride salt after evaporation of the volatiles under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[CH3:26])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-methylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.58 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[S:1]([Cl:14])(=[O:3])=[O:2])#[N:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Product: N#Cc1ccccc1S(=O)(=O)Cl

Procedure:
heating saccharin and phosphorus pentachloride under conditions and for a time sufficient to provide 2-cyanobenzenesulfonyl chloride; and
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH:25]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26]([C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[CH:4]=2)([OH:29])[CH:25]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:24]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)CC1CC(OCc2ccccc2)CCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCC(OCc4ccccc4)CC3CN(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
The corresponding Grignard reagent was produced in 11 ml THF p.a. from 0.28 g magnesium and 2.72 g 2-bromo-6-methoxynaphthalene, a solution of 2.00 g 4-benzyloxy-2-dimethylaminomethylcyclohexanone in 8 ml THF p.a. added dropwise with ice cooling, and the mixture stirred for 1 hour. For working up, 4 ml 4 M ammonium chloride solution were added to the ice bath, the organic phase separated off, the aqueous phase extracted twice with diethyl ether, the combined organic phases dried by sodium sulphate, filtered and concentrated. The crude product obtained (3.20 g) was chromatographed with ethyl acetate/methanol/hexane (V/V/V=1:1:1) on silica gel. 1.52 g 4-benzyloxy-2-dimethylaminomethyl-1-(6-methoxynaphthalen-2-yl)cyclohexanol were obtained and converted into the corresponding hydrochloride (1.32 g) in the same way as in AAV 1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:11][N:12]=2)[C:5]([NH2:30])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].NC1C(C(NN)=O)=NC(Br)=C(C(F)(F)F)C=1.NC1C(C(NN)=O)=NC=C(C(F)(F)F)C=1>>[F:17][C:14]([F:15])([F:16])[C:13]([C:10]1[O:9][C:8]([C:6]2[C:5]([NH2:30])=[CH:4][C:3]([C:31]([F:32])([F:33])[F:34])=[CH:2][N:7]=2)=[N:12][N:11]=1)([O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:28])[CH3:29])[CH3:18]
Reactant: CC(C)[Si](OC(C)(c1nnc(-c2nc(Br)c(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C
Agent: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: NNC(=O)c1ncc(C(F)(F)F)cc1N
Product: CC(C)[Si](OC(C)(c1nnc(-c2ncc(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C

Procedure:
The title compound was prepared analogously to 6-bromo-2-(5-(1,1,1-trifluoro-2-(triisopropylsilyloxy)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (Example 10, step 3) by replacing 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Intermediate H) (step 1) with 3-amino-5-(trifluoromethyl)picolinohydrazide (Int. I); LCMS: Rt=1.66 min; [M+H]+ 499.3 Method 2minLC_v003.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][Cl:16].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:16][CH2:15][CH2:14][CH2:13][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH2:9][CH2:10][CH3:11])[CH:4]=1
Reactant: CCCc1cc(S)ccc1C
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCCc1cc(SCCCCl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
36.4 g of 4-methyl-3-n-propylthio-phenol, 35 g of 3-bromo-1-chloro-n-propane and 3 g of tetrabutylammonium bromide were added into 10% aqueous solution of sodium hydroxide, and this mixture was stirred drastically for 2 hours at room temperature, then for 6 hours at 50° C. After the reaction was finished, the mixture was poured into 200 ml of water, and extracted 2 times by 200 ml of toluene. After the toluene layer was washed with water, toluene was distilled off, and the residue thus obtained was purified by silica-gel column chromatography (developing solvent: toluene+n-hexane) to give 40 g of the intended 1-chloro-3-(4-methyl-3-n-propylthiophenoxy)-n-propane (yield: 77.3%) as a colorless oil, nD25 1.5505.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:21])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[ClH:21].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][C:27]=3[F:32])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCc1ccccc1

Procedure:
A mixture of 0.200 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile 0.108 g of 4-chloro-2-fluoroaniline, 0.071 g of pyridine hydrochloride, and 3 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 10 ml of water. To this mixture was added sodium carbonate until pH 9. The product was collected, washed with water, and dried to give 0.150 g of 7-Benzyloxy-4-(4-chloro-2-fluoro-phenylamino)-6-methoxy-quinoline-3-carbonitrile hydrochloride as a solid, mp 241-243° C.; mass spectrum (electrospray, m/e): M+H 433.9.
Reaction SMILES: [CH:1](/[C@H:7]1[O:11][C:10]([CH3:13])([CH3:12])[O:9][C@H:8]1[CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:2]\[CH:3]=[CH:4]\[C:5]#[CH:6].[CH3:20][Si](C=[N+]=[N-])(C)C.[N+](=C)=[N-].C(O)(=O)C>C1COCC1.CCOCC>[CH:1](/[C@H:7]1[O:11][C:10]([CH3:13])([CH3:12])[O:9][C@H:8]1[CH2:14][O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:2]\[CH:3]=[CH:4]\[C:5]#[CH:6]
Reactant: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)OC

Procedure:
A solution of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid in THF was cooled in an ice bath and treated with a solution of trimethylsilyldiazomethane in THF in portions. Excess diazomethane was decomposed with acetic acid and the mixture was diluted with ether and washed with water, saturated sodium bicarbonate, water (2×), and brine, dried, treated with silica gel and concentrated. Purification by chromatography on silica gel using a gradient of ether in hexane gave 0.9 g of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (W), as an oil: 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.51 (s, 3H), 3.06 (s, 1H), 3.49 (m, 2H), 3.74 (s, 3H), 4.16 (m, 2H), 4.42 (m, 1H), 4.65 (t, 1H), 5.60 (dd, 1H), 5.79 (dd, 1H), 6.33 (dd, 1H), 6.65 (dd, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC.C1COCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 18-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and THF (80 mL) were stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted with EtOAc (2×), washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane ˜20:1 and filtration provided the title compound 18-4 as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[C:13]([Cl:26])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:26][C:13]1[CH:12]=[N:11][C:10]2=[N:15][C:14]=1[NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([O:25][CH2:2][C:3]3[CH:4]=[C:5]([NH:9]2)[CH:6]=[CH:7][CH:8]=3)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCCc1cccc(c1)OCc1cccc(c1)N2
Yield: 64 %

Procedure:
To a solution of 3-{2-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (25.0 mg, 0.0576 mmol) in tetrahydrofuran (0.561 mL) was added a solution of sodium hydroxide in water (0.46 mL, 0.50 M). The resultant solution was stirred at rt for 16 hours until the reaction was complete. The reaction mixture was neutralized with aqueous HCl solution (3 M) to pH 7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (13 mg, 65%). LCMS for C19H18ClN4O (M+H)+: m/z=353.0. 1H NMR (400 MHz, CD3OD): δ 7.72 (s, 1H), 7.52 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J=7.6, 0.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.93 (dd, J=7.2, 0.8 Hz, 1H), 6.73 (dd, J=2.4, 0.8 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.25 (s, 2H), 3.70 (m, 2H), 2.72 (t, J=6.8 Hz, 1H).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:39]>>[ClH:39].[NH2:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 0.58 g.) was treated with conc. hydrochloric acid (0.16 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 0.5 g.).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:25]([O:27][CH3:28])=[O:26])[C:14]([O:29]C)=[N:13][C:12]=1[CH2:31][CH3:32])=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH2:31]([C:12]1[NH:13][C:14](=[O:29])[N:15]([C:25]([O:27][CH3:28])=[O:26])[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C:11]=1[C:9]([OH:10])=[O:8])[CH3:32]
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Agent: [Pd]
Solvent: CO
Product: CCC1=C(C(=O)O)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(=O)N1
Reaction time: 12 h
Yield: 104.6 %

Procedure:
To a solution of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine (0.45 g, 1.18 mmol) in 20 mL of MeOH was added 0.05 g of 10% Pd on carbon and the resulting suspension was hydrogenated under 100 psi for 12 h. The catalyst was then filtered through a pad of celite and was washed thoroughly with MeOH. All the MeOH washings were collected and the solvent was removed in vacuo to obtain 0.42 g (99% yield) of (−)-1,2,3,6-tetrahydro-4-ethyl-2-oxo-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylic acid as a white solid which was used in the next reaction without further purification.