Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:19][O:20]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[C:13]([CH:19]=[O:20])=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:8][CH2:9][CH2:10]1)[CH3:2]
Reactant: CCc1cc2c(c(CC)c1O)CCC1(CCC1)O2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1c(O)c(CC)c2c(c1C=O)OC1(CCC1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution of 5,7-diethylspiro[chroman-2,1′-cyclobutan]-6-ol (900 mg) in dichloromethane (5 mL) was added titanium tetrachloride (670 mg, 0.4 mL) and dichloromethyl methyl ether (505 mg, 0.39 mL). The solution was stirred at room temperature for 5 hours. The reaction was quenched using diluted hydrochloric acid. Work up and chromatography (silica gel, ethyl acetate in hexane 5%) gave 680 mg of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutane]-8-carbaldehyde.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[H-].[Na+].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1CCl.CN([CH:29]=[O:30])C>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:30][CH3:29])=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1ccccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1c(C(C)=O)ccc2cc(-c3ccccn3)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of 6-hydroxy-2-acetylnaphthalene (1.04 g) in DMF (20 ml) were added sodium hydride (60%, 0.65 g) and 2-picolyl chloride hydrochloride (1.28 g) under ice-cooling and the resultant-mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between toluene and water. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was subjected to column chromatography on silica gel eluting with ethyl acetate/hexane to obtain the title compound (1.17 g, yield =75.5%). The NMR spectrum is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:15])[CH3:14])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:14])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isopropyl-pyrrolidin-3-yl-amine (0.68 mmol, 1.7 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol, 2 eq) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.4 mmol, 1.0 eq) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.85 (6H, d), 1.50-1.90 (10H, m), 2.10-2.60 (8H, m), 3.50 (3H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.10-7.40 (8H, m), 7.50 (1H, d), 8.50 (1H, dd). ESI-MS m/z: 546 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)[C:8]([O:10]C(C)(C)C)=O)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:44][CH2:45]C(Cl)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[ClH:35].[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)[C:8](=[O:10])[CH2:45][Cl:44])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)OCCN(C(=O)OC(C)(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Reaction time: 0.25 h

Procedure:
22 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 2) and 20.7 g of potash are introduced into 650 ml of toluene, and the mixture is kept at 45° for 15 minutes. At that temperature and with stirring, a solution of 7.1 g of chloroacetyl chloride in 30 ml of toluene is added dropwise. The mixture is stirred for 30 minutes at 45° and then stirring is continued at room temperature. The reaction solution is diluted with 500 ml of ethyl acetate and washed twice with 250 ml of water each time. The oil obtained after concentration by evaporation is chromatographed over silica gel and recrystallised in the form of the hydrochloride from acetone/ether, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 146°-147°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[F:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
(3R,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (300 mg, 1.374 mmol) was taken up in DCM (8 mL) and a solution of sodium bicarbonate (346 mg, 4.12 mmol) in water (1 mL) was added. The reaction mixture was cooled to 0° C. and benzyl chloroformate (0.235 mL, 1.649 mmol) was added dropwise. The reaction was stirred at 0° C. for 30 min, then brought to room temperature and stirred overnight. The reaction mixture was diluted with DCM and water, and the organic layer was collected. The aqueous layer was re-extracted with DCM and the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-30% EtOAc/Hex. The fractions were combined and concentrated to give (3R,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-fluoropiperidine-1-carboxylate (450 mg) as a colorless glass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([Br:24])[CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 1.00 g (2.985 mmol) of the product of Example 3 in 100 mL of CHCl3 was added 0.531 g (2.985 mmol) of N-bromosuccinimide and 0.025 g of AIBN. The resulting mixture was heated to reflux for 18 h and then an additional 0.411 g of NBS and 0.013 g of AIBN were added to the reaction. After refluxing the reaction for another 5 h the reaction mixture was cooled to room temperature, washed with sodium sulfite solution and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.62 g (50%) of the desired product as a white solid. EI Mass Spec 413 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].CCOC(C)=O.CCCCCC>C(O)C.[Pt]>[CH3:18][C:2]([CH3:1])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/C(C)(C)COC1CCCCO1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCC(C)(C)COC1CCCCO1

Procedure:
A mixture of ethyl (2E)-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-enoate (23 g, 90 mmol) and 5% Pt on carbon (3 g, 14.65 mmol) in ethanol (200 mL) was shaken on the Parr under 45 psi of hydrogen for 5 days (complete conversion by TLC: 10% EtOAc/hexane-no UV active spots). The catalyst was filtered off catalyst and the filtrate concentrated. Drying under vacuum gave ethyl 4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentanoate as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.7 (t, 1H), 4.12 (q, 2H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (d, 1H), 3.0, (d, 1H), 2.3 (m, 2H), 1.8 (m, 1H), 1.7-1.5 (m, 6H), 1.9 (s, 3H), 1.88 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:52])[C:32](=[N:39][O:40][C:41](=[O:51])[C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:53])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:52])[C:32](=[N:39][O:40][C:41](=[O:51])[C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Yield: 19.4 %

Procedure:
A solution of diphenylmethyl 3-acetoxymethyl-7β-[2-(4-nitrobenzoyloxyimino)-2-phenylacetamido]ceph-3-em-4-carboxylate (syn-isomer) (1.0 g) in trifluoroacetic acid (10 ml.) was allowed to stand at room temperature for ten minutes. After evaporation of trifluoroacetic acid under reduced pressure, the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. A solid precipitated during the bicarbonate extraction and was collected, washed with water and ethyl acetate, and partitioned between ethyl acetate and 2 -N-hydrochloric acid. The phases were separated and the upper layer was washed with water, dried, concentrated to ca. 10 ml. and added dropwise with stirring to petroleum (b.p. 40°-60°; 200 ml.). The precipitated solid was filtered and dried to give 3-acetoxymethyl-7β-[2-(4-nitrobenzoyloxyimino)-2-phenylacetamido]ceph-3-em-4-carboxylic acid (syn-isomer) (0.150 g; 20%), [α]D +17° (c 0.8, DMSO), λmax. (EtOH) 266.5 nm (ε 33,000), νmax. (Nujol) 3270 (NH), 1780 (β-lactam) 1520 and 1338 (NO2), 1675 and 1520 cm.-1 (CONH), τ (DMSO-d6) values include 1.58 and 1.69 (two doublets J 8 Hz; p-substituted phenyl), 2.1 to 2.5 (multiplet; aromatic protons), 7.79 (singlet; OCOCH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[OH:34][CH:32]([CH3:33])[CH2:31][NH:30][C:19]([C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:17]=1)=[O:21]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(O)CNC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (2.00 g, 4.83 mmol) in THF (50 mL), was added 1-aminopropan-2-ol (543 mg, 7.23 mmol), EDCI (1.12 g, 5.84 mmol), HOBt (800 mg, 5.92 mmol) and DIPEA (2.48 g, 19.2 mmol). The reaction was stirred for 12 hours at 25° C. and then concentrated in vacuo and quenched by addition of water. The reaction was extracted with DCM (×3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 33% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford N-(2-hydroxypropyl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide as a yellow solid. LRMS (ESI) calc'd for C22H30N5O5Si [M+H]+: 472, found 472.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=O)[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH3:38])([CH3:37])[C:30](=O)[CH2:29][CH2:28]2>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:13]2[C:14]=1[C:6]1[CH2:7][C:8]3[CH:20]=[C:19]([Br:24])[C:18]([O:21][CH3:22])=[CH:17][C:9]=3[C:10]([CH3:15])([CH3:16])[C:11]=1[NH:12]2.[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:29]3[CH2:28][C:27]4[CH:26]=[C:25]([Br:24])[C:34]([O:35][CH3:36])=[CH:33][C:32]=4[C:31]([CH3:38])([CH3:37])[C:30]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cc(Br)ccc13)C2(C)C
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cccc(Br)c13)C2(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared (as a mixture) from Compound E1.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccccn1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(C2(Oc3ccccn3)CCNCC2)cc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution of 4-phenyl-4-piperidinol (7.1 g, 40 mM) in dry DMSO (50 ml) was treated with a 50% sodium hydride dispersion (2.0 g, 40 mM) and the mixture warmed to 80°, until a clear solution was obtained. The solution was cooled to room temperature and treated with a solution of 2-fluoropyridine (3.9 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured onto water (250 ml) and extracted with toluene (3×250 ml). After washing with brine, the organic phase was dried (MgSO4) and the solvents removed under reduced pressure. Recrystallisation from IPE gave the title compound (3.5 g) contaminated with traces of 4-phenyl-4-piperidinol. Fractional crystallisation from cyclohexane gave the title compound analytically pure and chromatographically homogenous (600 mg) m.p. 86°-7°.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([O:23]C)=O)[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:33][NH2:34].C(=O)=O>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:33][NH2:34])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: NN
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in (1) (430 mg) in DMF (10 ml) was added hydrazine monohydrate (1.0 ml) at room temperature and the solution was stirred overnight. To the reaction mixture was added dry-ice and the resulting solution was concentrated to give a residue, which was triturated with water to afford the product (406 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Na].[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21]>CN(C=O)C.C(Cl)Cl.CC(O)=O>[CH2:1]([C:5]1[N:14]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1cnccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2ccncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-butyl-6-methylquinazolin-4(1H)-one (1.0 eq.) from Example 1 in DMF at rt is added NaH (1.0 eq.) to generate the sodium salt. After 20 min, 3-cyano-4-(4-bromomethyl phenyl)pyridine (1 mL of a 2M solution in CH2Cl2, 2 eq.) is added and the mixture is stirred at rt for 3 h. HOAc (100 μL) is added, the excess DMF is removed in vacuo then the crude product is isolated by extraction with EtOAc from brine. Purification by flash chromatography will give the above titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[CH3:17][S:18]SC.S(=O)(=O)(O)O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:18][CH3:17])[C:3]=1[F:8]
Reactant: CSSC
Reactant: Fc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cccc(Br)c1F
Yield: 50 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.4 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at −78° C. was added lithium diisopropylamide (2.5 M in hexane, 6.28 ml, 15.4 mmol). The mixture was stirred for 5 minutes after which dimethyldisulfide (0.92 ml, 15.4 mmol) was added and the stirring was continued at −78° C. for an additional hour. The reaction mixture was brought to ambient temperature and aqueous sulfuric acid (10%, 50 ml) was added. The phases were separated and the aqueous phase extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.26 g). MS m/z (relative intensity, 70 eV) 222 (M+, bp), 220 (M+, 91), 189 (24), 187 (25), 126 (97).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:10][CH:9]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=1)([CH3:26])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1

Procedure:
In a similar manner to that described in Reference example 3 (g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (16.2 g), which is the product of Reference example 5(f), triethylamine (12.1 ml) and methanesulfonyl chloride (5.05 ml) and the reaction mixture was treated to afford the desired compound (19.6 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:18]([Br:19])=[C:17]([O:20]COC)[CH:16]=[C:15]([O:24]COC)[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Si](C=[N+]=[N-])(C)C.CCCCCC.C(O)(=O)C>CO>[CH3:28][O:14][C:12](=[O:13])[C:11]1[C:15]([OH:24])=[CH:16][C:17]([OH:20])=[C:18]([Br:19])[C:10]=1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCOc1cc(OCOC)c(C(=O)O)c(COCc2ccccc2)c1Br
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1c(O)cc(O)c(Br)c1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-3-bromo-4,6-bis(methoxymethoxy)benzoic acid (16 mg, 0.036 mmol) was dissolved in methanol (2 mL) and the obtained mixture was further added with 2.0 mol/L trimethylsilyldiazomethane-hexane solution (0.30 mL, 0.60 mmol) followed by stirring at a room temperature for 1 hour. After adding acetic acid (0.050 mL) to the reaction mixture, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (4 mL) and the obtained solution was added with concentrated hydrochloric acid (0.10 mL) followed by stirring at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain Compound 10 (11 mg, 82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH:28]([O:31][C:32](=[O:49])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:34]=1[CH3:48])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH:28]([O:31][C:32]([C:33]1[C:34]([CH3:48])=[C:35]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])=[NH:9])[S:11][C:12]=3[S:25][CH3:26])(=[O:17])=[O:16])[CH:19]=2)[CH:36]=[CH:37][CH:38]=1)=[O:49])([CH3:30])[CH3:29]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)OC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)OC(C)C)c2C)c1
Yield: 49.3 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid isopropyl ester ((Example 3: step b) 92 mg, 0.3 mmol), Na2CO3 (2M, 0.4 mL, 0.8 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.4 mL) and toluene (0.8 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (29 mg, 49%) as a colorless glass. 1H-NMR (CDCl3): δ 7.98 (dt, 1H, J=1.6, 7.6 Hz), 7.93 (m, 2H), 7.79 (t, 1H, J=1.7 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.53 (dt, 1H, J=1.6, 7.6 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J=4.5 Hz), 5.27 (heptet, 1H, J=6.2 Hz), 2.58 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H), 1.39 (d, 1H, J=6.2 Hz). ESI-MS (m/z): Calcd. for C28H32N2O6S3: 588.8; found: 588.9.