Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]([Cu])#[N:16].O>CN1CCCC1=O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:15]#[N:16])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Yield: 88.1 %

Procedure:
A solution of 3-bromo-9H-carbazole (123.4 mg, 0.50 mmol) and CuCN (49.9 mg, 0.56 mmol) in N-methyl-pyrrolidone (2 mL) was heated at 200° C. for 5 h. The cooled reaction mixture was poured into water and the precipitate was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the product as a white solid (84.7 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccc1)(c1ccccc1)c1cncnc1
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of 5-bromopyrimidine (10 g, 0.063 mol) in a mixture of dry THF (150 mL) and hexane (50 mL) was cooled to −100° C. To this cooled solution was added n-BuLi (4 g, 21 mL, 0.062 mol) over a period of 30 min and stirred for another 30 min. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 1 h at RT. The reaction was quenched with cold water (200 mL), ethyl acetate was added and the organic layer was separated. The organic layer was dried, concentrated and the crude product was purified by column chromatography on silica gel (up-to 25% ethyl acetate in pet ether) to give the product (8 g). TLC: Pet. ether/EtOAc, 1:1, Rf=0.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:38]=1[NH2:39]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([NH:39][C:38]2[CH:40]=[C:41]([C:44]([F:46])([F:45])[F:47])[CH:42]=[CH:43][C:37]=2[C:36]([F:48])([F:49])[F:35])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 2,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:10][C:9]=1[NH:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]2[S:38][CH:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[N:41]=2)[CH:30]=1)[C:4]([OH:6])=O)C.[NH3:47]>>[C:42]([C:40]1[N:41]=[C:37]([CH2:36][O:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:9]2[CH:10]=[C:11]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:12]=[CH:13][C:8]=2[O:7][CH2:3][C:4]([NH2:47])=[O:6])=[O:46])[S:38][CH:39]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCC(Oc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1)C(=O)O
Reactant: N
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC(N)=O)c2)n1
Yield: 77 %

Procedure:
Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid (0.30 g, 0.44 mmol) was dissolved in ammonia-saturated methanol (10 ml) and the solution was subjected to 12 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was crystallized from acetonitrile to give 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetamide (0.22 g, 0.34 mmol, 77%) as colorless crystals. Its structure is shown in Table 30.
Reaction SMILES: O1CCN([C:7]2[N:12]=[C:11](C3CCOCC3)[N:10]=[C:9]([C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[N:23][CH:24]=3)[CH:8]=2)CC1.N1CCOCC1>CN1C(=O)CCC1>[N:12]1[CH:7]=[CH:8][C:9]([C:19]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21][CH:20]=2)=[N:10][CH:11]=1
Reactant: Nc1ncc(-c2cc(N3CCOCC3)nc(C3CCOCC3)n2)cn1
Solvent: CN1CCCC1=O
Solvent: C1COCCN1
Product: Nc1ncc(-c2ccncn2)cn1
Temperature: 150 °C

Procedure:
A mixture of 6-morpholino-2-(tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidin-2′-amine (10 mg, 0.0343 mmol), morpholine (24 mg, 8 equiv, 0.274 mmol) in NMP (0.55 mL) was heated at 150° C. for 10 min in a microwave. The mixture was purified on HPLC to give 6-morpholino-2-tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidin-2′-amine. LCMS (m/z): 343.1 (MH+). Rt: 1.62 min.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[N:19]=[C:18]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])[CH:17]=[CH:16][N:15]=1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of (R)-4-phenyloxazolidin-2-one (2.9484 g, 18.07 mmol) and 2,4-dichloropyrimidine (3.1872 g, 21.39 mmol, 1.184 equiv) in DMF (30 mL) was treated with NaH (95%, 0.4773 g, 18.89 mmol, 1.046 equiv), then the resulting mixture (yellow to red cloudy) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (200 mL), washed with sat. NH4Cl (75 mL) and 4% aqueous NaCl (2×100 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (2.7020 g, white sticky solid) in 46.9% yield. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=5.6 Hz, 1H), 8.18 (d, J=6.1 Hz, 1H), 7.38-7.30 (m, 5H), 5.81 (dd, J=8.6, 3.5 Hz, 1H), 4.88 (t, J=8.6 Hz, 1H), 4.37 (dd, J=8.6, 3.5 Hz, 1H); MS m/z 276.4 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]3=[N:16]2)[C:12]([OH:26])=[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:10]=1)C1C=CC=CC=1.C(O)=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[C:27]([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]3=[N:16]2)[C:12]=1[OH:26])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc2nn(-c3cc(OCc4ccccc4)cc(C(C)(C)C)c3O)nc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CCO
Solvent: O
Product: COc1ccc2nn(-c3cc(O)cc(C(C)(C)C)c3O)nc2c1
Temperature: 50 °C
Yield: 52.1 %

Procedure:
To a stirred solution of (XIII) (3.1 Kg) in ethanol (52 L), was charged a slurry of 10% Pd/C (300 g in 750 ml water) under nitrogen atmosphere. Formic acid (1.16 L) was added followed by addition of solution of ammonium formate (1.452 Kg) in DM water (755 ml). The reaction mixture was heated at 50° C. for 6 hr. The reaction mixture was cooled to room temperature and filtered. DM Water (31 L) was added to the filtrate, stirred and extracted with toluene (62 L). The organic layer was separated and washed with of (1:1) water: ethanol mixture (31 L). The organic layer was dried on sodium sulfate and evaporated up to 80%. The residual liquid was cooled to 0-5° C., filtered and dried at 50° C. for 1 hr to give the title product (XIV) (1.254 Kg). If required, the product was leached with methanol to obtain required purity.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](=O)[CH3:17])([CH3:10])([CH3:9])[CH3:8].[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23].Cl>O1CCCC1>[CH2:26]([O:25][C:22](=[O:24])/[CH:23]=[C:16](\[CH3:17])/[CH2:15][C:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21])([CH3:19])[CH3:20])[CH3:27]
Reactant: CC(=O)CC(C)(C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethyl phosphonoacetate (4.7 g; 20.9 mmol) was dissolved in tetrahydrofuran (36 ml). Potassium tert-butoxide (2.3 g; 20.9 mmol) was added and the reaction mixture was stirred for 40 min at room temperature. (1,1-Dimethyl-3-oxobutyl)carbamic acid tert-butyl ester (2.5 g; 11.6 mmol) was dissolved in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture which was heated to reflux for 12 h. Ethyl acetate (100 ml) and hydrochloric acid (1N; 100 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with an aqueous solution of sodium hydrogen carbonate (saturated; 100 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica (3×40 cm) using ethyl acetate/heptane (1:2) as eluent to afford 2.0 g of (E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Br:16][C:17]1[CH:18]=[C:19]([C:24]([NH:26][C:27]2[C:28]([NH:34][CH2:35][CH3:36])=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:25])[C:20](Cl)=[N:21][CH:22]=1.O>N1C=CC=CC=1>[Br:16][C:17]1[CH:22]=[N:21][C:20]2[N:34]([CH2:35][CH3:36])[C:28]3[N:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=3[NH:26][C:24](=[O:25])[C:19]=2[CH:18]=1
Reactant: CCNc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A 1 M solution of NaHMDS in THF (167.5 mL, 167.5 mmol) was slowly added to a solution of 5-bromo-2-chloro-N-{2-(ethylamino)-6-choro-3-pyridinyl}-3-pyridinecarboxamide (28.4 g, 72.8 mmol) in pyridine (146 mL) heated to 50° C. The reaction mixture was stirred at 50° C. for 1.5 h. The mixture was then poured into a mixture of water and ice (1 L) and, after 1 h, the resulting suspension was filtered. The solid was washed with water and dried under reduced pressure to give the title compound (23.4 g, 91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[SH:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1S
Yield: 85 %

Procedure:
2-{[(Phenylamino)carbonyl] amino}thiophenol was prepared from 2-aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85%). mp: 194.5° C.; 1H NMR (CD3OD/CDCl3): δ7.48-7.26 (m, 4H) 7.25-7.10 (m, 3H), 7.04-6.79 (m, 2H); EI-MS m/z 244 (M+H)+ ; Anal. (C13H12N2OS) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.[N:12]([O-])=[O:13].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:12]=[O:13])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCc2cc(Cl)ccc21

Procedure:
A mixture of 77 g. (0.5 mole) of 5-chloroindoline, 80 ml. of concentrated hydrochloride acid and 500 ml. of crushed ice was stirred while a solution of 35 g. of sodium nitrite in 100 ml. of water was added over five minutes. The temperature was kept between 10°C. to 15°C. by addition of ice. The mixture was stirred for 1 hour and then filtered. Recrystallization of the product from benzene-isooctane gave 57 g. (68%) of product which melted at 120°-122°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N:19]3[CH2:24][CH2:23][CH2:22][C:21]4([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=1.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33].CCN(CC)CC>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([C@H:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:13][C:12]3[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][CH2:22][C:21]5([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]5)[CH2:20]4)[CH:16]=[C:17]([CH3:18])[C:11]=3[N:10]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A solution of 4-Chloro-3-[6-(2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (16 mg, 0.039 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (20 mg, 0.117 mmol) and Et3N (16 mg, 0.156 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h. After it was cooled to room temperature, the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL). The yellow solid then was mixed with 3 mL MeOH and the mixture was heated at 100° C. for 1 h. After it was cooled to room temperature, the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL) to afford the title compound (10 mg, 47%). ESI-MS m/z 547 (MH+).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[OH:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1)[O:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCc1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a stirred mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (1.504 g, 3.85 mmol) and (5-hydroxy-1,3-phenylene)dimethanol (21) (0.54 g, 3.50 mmol) in anhydrous DMF (7.8 ml) was added potassium carbonate (0.726 g, 5.25 mmol). The reaction was stirred at room temperature for 18 hours at 75° C. The mixture was allowed to cool to room temperature, quenched with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% MeOH/CH2Cl2) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b)(340 mg, 26%). 1H NMR (400 Hz, CDCl3): δ 6.83 (s, 1H), 6.75 (s, 2H), 4.52 (s, 4H), 4.05 (t, J=4.8 Hz, 2H), 3.79 (t, J=4.8 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.70-3.56 (m, 8H), 3.26 (s, 2H), 2.55 (t, J=6.4 Hz, 2H); 13C NMR (400 Hz, CDCl3): δ 172.31, 159.1, 143.0, 117.7, 112.1, 70.8, 70.7, 70.5, 70.4, 69.8, 67.5, 66.6, 64.7, 51.8, 34.9; MS (m/z), found 395.2 (M+Na)+.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[Bi](Cl)(Cl)Cl>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 15 ml of sulfolane were added 2.72 g of 7-ACA, 2.3 g of methanol, 2.8 g of antimony pentachloride and 12 g of bismuth trichloride. The mixture was heated at 50° C. for 40 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. The resulting precipitate was filtered off To the filtrate was added 60 ml of water, and then the resulting mixture was stirred homogeneously. To the resulting solution was added 0.5 g of activated carbon, and then the mixture was stirred, followed by filtration. The filtrate was adjusted to pH 3.5 with sodium bicarbonate. To the resulting mixture was added 30 ml of methanol, thereby to form a white crystalline precipitate. The white crystalline precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.29 g. The yield of the desired product was 53 %. .
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]([NH:25][C:26]1[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]3)[CH2:18]2>CN(C)C=O>[O:7]([CH2:14][CH2:15][N:24]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][CH:19]([NH:25][C:26]1[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]3)[CH2:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCOc1ccccc1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(OCCN2C3CCC2CC(Nc2ccc4[nH]ncc4c2)C3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
Potassium carbonate (52 mg, 0.376 mmol) and then 2-phenoxyethyl bromide (38 mg, 0.189 mmol) were added to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (30 mg, 0.124 mmol) obtained in Example 525 in dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. After the solid was removed by filtration, the dimethylformamide was distilled off under reduced pressure as an azeotrope with toluene to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/triethylamine=20/1/1) to obtain N-(8-(2-phenoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (40 mg, 89%).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.Cl.[Cl:28][CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:28].[OH:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:29][C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: Cn1ccnc1CCl
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nccn1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 2-chloromethyl-1-methylimidazole hydrochloride (354 mg, 2.12 mmol), and potassium carbonate (585 mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) and 2M sodium hydroxide (1 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and 2M hydrochloric acid (3 ml) was added. The resulting solid was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline hydrochloride (150 mg, 29%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.CC(OC([NH:42][C@@H:43]([C:45](O)=[O:46])[CH3:44])=O)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:42][C@@H:43]([C:45]([NH:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)=[O:46])[CH3:44]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)[C@@H](C)N)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of N-((1S)-2-amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.28 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol), EDCI (0.56 mmol), and TEA (1.12 mmol) stirred in methylene chloride (2 mL) at RT for 18 h. The reaction was then treated with 4 M HCl in 1,4-dioxane (2 mL) and stirred at RT for 1 h and concentrated in vacuo, redissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (25%). ESMS [M+H]+: 613.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (100 mg, 0.424 mmole), 4-(trifluoromethoxy)phenylboronic acid (113 mg, 0.551 mmole), CsF (129 mg, 0.847 mmole), and bis(tri-t-butylphosphine)palladium(0) (22 mg, 0.043 mmole) were combined in a screw cap vial. To this was added 1,4-dioxane (2 mL). N2 was bubbled through the mixture for 10 seconds. The vial was capped then heated to 100° C. After 6 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 0-15% EtOAc/hexanes) gave ethyl 2-[4-(trifluoromethoxy)phenyl]-1,3-thiazole-4-carboxylate (71 mg, 53%) as a pale orange solid. 1H NMR (399 MHz, CDCl3): δ 8.18 (s, 1 H); 8.07-8.03 (m, 2 H); 7.30 (d, J=8.4 Hz, 2 H); 4.46 (q, J=7.1 Hz, 2 H); 1.44 (t, J=7.1 Hz, 3 H).