Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(C(=O)OCC)CCCC1=O
Yield: 83.9 %

Procedure:
Under vigorously agitation, 52.0 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 126.73 g (purity of 98%,) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 66.0 ml (purity of 98%,) of 1-bromo-n-butane. Upon the completion of the addition, the reaction mixture was heated for reflux for 5 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 53.39 g of colorless liquid as a distillate cut of 140-141° C./16 mmHg was collected. Yield: 83.9%. MS: m/e 212(M+′), 197(M+″—CH3), 184(M+′—CH2CH2), 167(M+′—OCH2CH3), 156(M+′—C4H9,base), 139(M+′—CO2CH2CH3), 127, 111, 55.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([OH:21])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.Cl>O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:19](=[O:21])[N:33]([CH3:34])[CH3:32])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(C(=O)N(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
THF (5 ml) charged in to a R B flask followed by the addition of piperidine-1,4,4-tricarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.5 g) and 1-hydroxybenzotriazole (0.38 g). Allowed to stir the reaction mixture at 25-300 C for 30 mins. Dimethylamine (0.75 mL) followed by EDC HCl (0.38 g) was added in to the above reaction mixture at 25-300 C. Allowed the reaction mixture to stir at 25-300 C for 1-2 hrs. Reaction is followed by TLC. The reaction mixture concentrated under vacuum using rota vapour and the product slurry obtained is suspended in D M Water (5 mL). The product extracted in to ethyl acetate (2×5 mL). The combined product layer dried with sodium sulphate and concentrated under vacuum to yield crude product which in turn purified by a column chromatography to yield pure 4-dimethylcarbamoyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1>CS(C)=O>[OH:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), (S)-pyrrolidin-3-ol hydrochloride (163 mg, 1.32 mmol, 3.00 equiv), DIEA (227 mg, 1.76 mmol, 4.00 equiv), toluene (4 mL), in DMSO (2 ml). The resulting solution was stirred at 100° C. for 7 hrs. Then the reaction was quenched by the addition of water. The resulting solution was extracted with 5×15 mL of dichloromethane and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (70:1). This resulted in 176 mg (crude) of (S)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].O[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[C:9]=1[O:19][CH3:20].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:14]=[CH:15][C:8]=1[O:4][CH3:1])[CH:12]=[O:13]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
Anhydrous sodium carbonate (957 g., 9.03 moles), toluene (5 liters), 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (1424 g., 7.22 moles) and dimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4 hours. Toluene was removed in vacuo and the residual solid dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was separated, washed with 2 liters of 1 N NaOH and 6 liters of brine, decolorized with charcoal, dried over magnesium sulfate and filtered. Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527 g. product was obtained by filtration. The crude material was recrystallized from ethanol to yield 1187 g. (78%) of the title compound as a pale yellow solid, 60°-62° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([CH3:42])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:35]([CH3:42])[CH:34]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2)c(OC)c1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (INTERMEDIATE QQQQ, 55.8 mg, 0.117 mmol), (4-chloro-2-methylphenyl)boronic acid (Indofine Chemical, Hillsborough, N.J., 21.93 mg, 0.129 mmol), Pd(AmPhos)2Cl2 (4.14 mg, 5.85 mmol), potassium phosphate (74.5 mg, 0.351 mmol), 1,4-dioxane (439 μl), and water (146 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. LCMS showed two peaks with mass of protected desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 1 h, triflic acid (0.05 mL) was added drop wise. Following an additional 1 h of stirring, the mixture was diluted with 2-PrOH, then concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 0-60% EtOAc/Heptane, then with 100% EtOAc). The resulting material was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-6% MeOH/DCM) to give 4-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (24.08 mg, 0.058 mmol, 49.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.10 (d, J=4.4 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.88 (dd, J=2.0, 8.8 Hz, 1H), 7.61-7.53 (m, 3H), 7.43 (dd, J=1.9, 8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 1.97 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C>C(O[Pd]OC(=O)C)(=O)C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2ccc(I)cc2s1
Reactant: C=CC(=O)OC
Agent: CC(=O)O[Pd]OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2nc(C)sc2c1
Temperature: 100 °C

Procedure:
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), methyl acrylate (103 mg, 1.2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 mL) is heated in a microwave apparatus at 100° C. for 10 min. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give (E)-3-(2-methyl-benzothiazol-6-yl)-acrylic acid methyl ester. MS 234.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([O:15][CH3:16])[C:2]([OH:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)c(OC)cc1N
Yield: 91.9 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (3.88 g, 17.1 mmol) and Pd/C in EtOAc (100 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford methyl 2-amino-5-hydroxy-4-methoxybenzoate as a solid (3.1 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.08 (s, 1H), 6.31 (s, 1H), 6.24 (s, 1H), 3.74 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48][CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([N:46]4[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48][CH2:47]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S1(=O)CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was coupled with thiomorpholine 1,1-dioxide (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H48Cl2N5O5S [(M+H)+] 768.2748, observed 768.2748.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:17]=1.Cl.[NH+]1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:17]=1
Reactant: COc1ccc2c(c1)OCc1cc(Cl)ccc1-2
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1ccc2c(c1)OCc1cc(Cl)ccc1-2
Temperature: 25 °C
Yield: 83.3 %

Procedure:
8-chloro-3-methoxy-6H-benzo[c]chromene (670 mg, 2.7 mmol) and piridinium hydrochloride (3.16 g, 27.3 mmol) were heated to 185° C. for 2.5 hours. After cooling to room temperature, the reaction was diluted with water extracted into ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield 8-chloro-6H-benzo[c]chromen-3-ol (523 mg, 82%)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>ClCCl>[CH2:40]([Sn:35]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, a solution of 4-iodo-1-trityl-1H-imidazole (1.00 g, 2.29 mmol) in dichloromethane (10 mL) was treated with isopropylmagnesium bromide (2.75 mL of 1 M, 2.75 mmol, in tetrahydrofuran) and stirred at ambient temperature for 1 hour. After this time, the reaction was treated with tributyltin chloride (0.81 mL, 2.98 mmol) and the resulting mixture stirred overnight at ambient temperature. The reaction mixture was then diluted with dichloromethane (50 mL) and successively washed with saturated ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.37 g of crude 4-tributylstannyl-1-trityl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3,4-dichloro-phenyl)boronic acid (1.0569 g, 0.005539 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3636 g, 0.005019 mol) in the presence of tetrakis(triphenylphosphine(palladium(0) (0.1054 g, 0.0000912 mol) and 2.0 M aqueous sodium carbonate (5.5 mL, 0.011 mol) in toluene (11 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with hexanes-acetone (7:1) 1.432 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid: mp 120-121° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:32])[N:21]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:17]([C:33]([O:35]CC)=O)[N:16]=1)=O)(C)(C)C.[NH2:38]C1C(C(OCC)=O)=NC(NC[C@H]2CCCN2C(OC(C)(C)C)=O)=NC=1NC1C=CC=CC=1OC>ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[C:20](=[O:32])[NH:19][C:18]2[C:22]1=[N:23][C:15]([NH:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:16][C:17]=2[C:33]([NH2:38])=[O:35]
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Yield: 100 %

Procedure:
(R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 5-amino-2-((1-(tert-butoxy-carbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.360 g, 0.740 mmol) and carbonyldiimidiazole (1.19 g, 7.40 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title product (0.381 g, 100%). MS (ESI) m/z 513.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=CC=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@H]2[C@H](O)C[N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])C2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[C@H:12]([OH:20])[CH2:13][N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:19]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting benzyl (trans)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.38, 5.17, 4.48. 4.38, 4.28, 4.12, 3.91, 3.42, 2.86-2.78, 2.58, 1.32-1.24; HRMS (FAB) calcd for C20H25BrN4O3+H 449.1189, found 449.1175.
Reaction SMILES: CC(OC[C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[NH4+]>Cl.C(N(CC)CC)C.C(O)(=O)C>[CH2:23]([O:30][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: FB(F)F
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)O)=C(OCc3ccccc3)CS[C@H]12

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 128 ml of the etherate of boron trifluoride, 126 ml of benzyl alcohol and 90 ml of triethylamine were reacted to obtain 27.1 g of raw product. 25 g of the said product and 250 ml of acetic acid were added to 25 ml of the etherate of boron trifluoride followed by the addition of 25 ml of triethylamine which caused precipitation. The mixture was vacuum filtered and the product was rinsed with acetic acid, acetone and then ether to obtain 4.6 of product. 4.8 g of the said product were dissolved at 45° C. in 20 ml of 2N hydrochloric acid and 8 ml of concentrated hydrochloric acid and the solution was treated with activated carbon. 6 ml of ammonium hydroxide were added to the mixture which was then vacuum filtered. The product was rinsed with water, acetone and then ether to obtain 2 g of 3-benzyloxy-7-amino-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
5-(2,4-Difluoro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 216, triethylamine (28.0 uL, 0.20 mmol) and methanesulfonyl chloride (5.0 uL, 0.06 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([OH:29])[CH2:10][O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14](=[O:22])[C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C(Cl)(Cl)Cl>[C:23]1([C:13]2[C:14](=[O:22])[O:15][C:16]3[C:21]([C:12]=2[O:11][CH2:10][CH:9]([O:29][C:42](=[O:43])[C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=2)[CH2:8][N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=c1oc2ccccc2c(OCC(O)CN2CCOCC2)c1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)OC(COc2c(-c3ccccc3)c(=O)oc3ccccc23)CN2CCOCC2)cc(OC)c1OC
Reaction time: 2 h
Yield: 73.4 %

Procedure:
14.2 g. (0.034 mol) of 4-(3'-morpholino-2'-hydroxypropoxy)-3-phenyl-coumarin hydrochloride (Example 32) are placed in 130 ml. of chloroform containing 3.4 g. (0.034 mol) of triethylamine. A solution of 7.83 g. (0.034 mol) of 3,4,5-trimethoxy-benzoyl chloride in 20 ml. of chloroform are then added in 21/2 hours. The mixture is then brought over 2 hours to 40°-50° C. Cooling takes place, the insoluble substance is filtered off, the filtrate is washed with a sodium bicarbonate solution and dried over sodium sulphate. The solvent is evaporated under vacuum and there are obtained 14.3 g. of an oil which cannot be crystallised. Yield 73.4% (theoretical yield 19.5 g.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].Cl[CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]2[CH:22]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][N:13]2[CH:22]=1
Reactant: NCC1OCCO1
Reactant: FC(F)(F)c1ccn2cc(CCl)nc2c1
Solvent: ClCCl
Product: FC(F)(F)c1ccn2cc(CNCC3OCCO3)nc2c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a DCM 5 mL solution of 1-(1,3-dioxolan-2-yl)methanamine (814 mg, 7.89 mmol) was added 2-(chloromethyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (Intermediate 19) (620 mg, 2.63 mmol). After heating to reflux for 1.5 hr, the reaction mixture (suspension) was cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound as solid (450 mg). LC/MS: m/z 302(M+H).