Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:28][CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:22][C:21]=3[CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3c(c2)OCO3)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and piperonylamine in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CO.C(N(CC)CC)C>[Pd]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][CH:2]=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (35.0 mg, 0.106 mmol) in Methanol (1.91 mL, 47.1 mmol) was added Triethylamine (0.0147 mL, 0.106 mmol) and Palladium (0.0113 g, 0.0106 mmol). The reaction was stirred overnight at room temperature under H2 atm. The reaction was filtered thru celite. The solute was concentrated then diluted with EtOAc, wash with H2O. The organic layer was dried Na2SO4, concentrated. The crude product was purified by isco column to give 364. MS: (ESI+)=297.1. 1H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.05 (d, J=5.7 Hz, 1H), 5.90 (dt, J=13.2, 6.5 Hz, 1H), 4.59 (dt, J=26.2, 13.1 Hz, 4H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:7]=1
Reactant: CC(C)(C)CNc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Product: CC(C)(C)CNc1cc(Cl)nc(N2CCCC2)n1
Yield: 75 %

Procedure:
The reaction of 2,4-dichloro-6-(2,2-dimethylpropylamino)pyrimidine with pyrrolidine as described in Example 12 affords the title compound in a yield of 75.0%, m.p.: 130°-135° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 721.4 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO.O>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)s1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(12-Methoxycarbonyl-dodecyl)-thiophene-2-carboxylic acid tert-butyl ester (75 mg, 0.13 mmol) was dissolved in methanol (2 mL). A 20% solution of NaOH in water (0.36 mL) was added and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was acidified by the addition of 2 mL of a 10% solution of NaHSO4 in water. The precipitate was isolated by centrifuge and dried in vacuo, to yield 5-(12-carboxydodecyl)-thiophene-2-carboxylic acid tert-butyl ester, which was contaminated with some starting material was used in the subsequent step without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([C:15]3[O:19][C:18]([NH:20][C:21]4[CH:26]=[C:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=4[O:32][CH3:33])=[N:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35]>>[CH2:30]([S:27]([C:25]1[CH:24]=[CH:23][C:22]([O:32][CH3:33])=[C:21]([NH:20][C:18]2[O:19][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH:34]([CH3:36])[CH3:35])[N:7]=3)=[CH:16][N:17]=2)[CH:26]=1)(=[O:29])=[O:28])[CH3:31]
Reactant: CC(C)N
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccnc(Cl)n4)c3)o2)c1
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccnc(NC(C)C)n4)c3)o2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
The title compound of Example 168 (40 mg) was treated with isopropylamine (2 mL) and stirred at 100° C. overnight in a sealed tube. The mixture was evaporated to dryness and purified by thin layer chromatography to afford the title compound (28 mg, 67% yield) as a yellow solid, which was isolated as the HCl salt 1H NMR (400 MHz, d6-DMSO): δ 9.77 (bs, 1H), 8.68 (s, 1H), 8.26 (d, J=6.4, 1H), 7.58 7.45 (m, 5H), 7.23 (d, J=8.4, 1H), 7.14 (m, 1H), 6.61–6.64 (m, 2H), 3.92 (s, 3H), 3.32 (m, 1H), 3.15 (q, J=7.3, 2H), 1.05 (m, 9H). MS (ES+, m/z)=510 (m+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].B1C2CCCC1CCC2.[OH:20][C:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=2)[O:23][C:22]=1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:35]([O:49][CH3:50])[CH:34]=1>O1CCCC1.[OH-].[Na+]>[OH:20][C:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:28]=2)[O:23][C:22]=1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:35]([O:49][CH3:50])[CH:34]=1
Reactant: C=CCCCCCCCC
Reactant: COc1cc(-c2oc3ccc(I)cc3c(=O)c2O)cc(OC)c1OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2c1
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a stirring solution of 1-decene (0.189 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon was added 9-BBN in tetrahydrofuran (0.5M, 2.8 ml, 1.4 mmol, 1.5 eq). The reaction was stirred for 8 hours then 3-hydroxy-6-iodo-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 56 (0.501 g, 0.9 mmol) in tetrahydrofuran (5 ml), 3M NaOH solution (1.26 ml) and dichloropalladium(dppf) (0.021 g, 0.03 mmol, 0.03 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether and acidified (6 M HCl). The organic layer was collected and the aqueous layer extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give a red oil. This was passed through a short plug of silica, eluting with ethyl acetate to give 3-hydroxy-6-decyl-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 58(0.369 g, 72%) as a red oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)([F:12])[F:11].FC(F)(C1C=CC=CC=1)COCCCCCC[N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>>[F:11][C:10]([F:12])([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Reactant: Cc1cccc(C(F)(F)COCCCCCCBr)c1
Product: Cc1cccc(C(F)(F)COCCCCCCN2C(=O)c3ccccc3C2=O)c1
Yield: 40 %

Procedure:
Obtained from Intermediate 30 (8.77 g, 26.2 mmol) by the procedure described in Intermediate 8. Purification by column chromatography with silica gel and methylene chloride as eluent gave the title compound (4.0 g, 40%) as oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)(O)[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCCl.CCO>[CH2:1]([NH:3][C:4]([CH:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)[CH2:9]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: CCO
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)C1CC(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 80 °C
Yield: 24.7 %

Procedure:
To Example 12, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethylamide (17 g, 53.1 mmol) in 200 mL of DCE at rt was added TFA (80.7 mL, 1.1 mol) and then the reaction was heated to 80° C. (oil bath). After 15 h the reaction was concentrated to approximately 45 g and used without further purification. The crude TFA salt from the above reaction was diluted with EtOH (500 mL), placed in a Parr bottle, purged with N2, and then 10% Pd/carbon (2.5 g, 14 wt %) was added. The resulting reaction mixture was hydrogenated with H2 (45 psi) at rt. After 1.5 h the reaction was purged with N2, then filtered through Celite™ and concentrated under reduced pressure. The resulting oil was diluted with EtOAc and then slowly quenched with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by re-crystallization. Crude title compound was taken up in a minimal amount of warm EtOAc and allowed to cool to approximately 0° C. (refrigerator). The solid was filtered, dried under reduced pressure to give the title compound (4 g, 24% yield) as a white solid: Rf=0.21 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C18H25FN2O, 304.4, found, 305.3; 1H NMR (300 MHz, CDCl3): δ 7.30 (apt t, J=7.9 Hz, 1H), 6.98 (dd, J=7.9, 1.6 Hz, 1H), 6.92 (dd, J=12.0, 1.6 Hz, 1H), 5.36 (bs, 1H), 3.67 (s, 2H), 3.42-3.26 (m, 3H), 2.94-2.85 (m, 1H), 2.57-2.50 (m, 6H), 2.42-2.33 (m, 2H), 1.82-1.74 (m, 4H), 1.14 (t, J=7.5 Hz, 3H); structure confirmed by x-ray crystallography and was determined to be cis.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.O.OC1C2N=NNC=2C=CC=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([OH:36])=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][N:3]([CH3:2])[C:34](=[O:36])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CNCC1CCCc2c(OC)cccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
The product from Example 17 (1.04 g), hydroxybenzotriazole hydrate (1.51 g) and thiopheneacetic acid (720mg) in dry THF (30 ml) at 0° C. was treated with dicyclohexylcarbodiimide (1.16 g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60 ml) washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml), dried (MgSPO4) filtered and concentrated. Chromatography on SiO2 afforded 1.58 g of product as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][OH:17])[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:18]([CH3:19])[CH3:20])[CH2:15][CH2:16][O:17][C:37](=[O:40])[CH2:38][CH3:39])[O:11][C:10]([CH3:21])([CH3:22])[N:9]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)Cl
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCC[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
1.0 g (2.43 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 50 ml of methylene chloride is treated with 0.38 ml (2.7 mmol) of triethylamine and 0.24 ml (2.7 mmol) of propionyl chloride and stirred at room temperature for 12 hours. After the usual working-up the crude product is purified by flash chromatography on silica gel with a 1:5 mixture of ether and petroleum ether, whereby there is obtained 1.0 g (88%) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-4-(propionyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 452 (M-CH3)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].Br[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CC(C)([O-])C.[K+].[I-].[K+]>CN(C=O)C>[O:10]=[C:2]1[N:3]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(=O)oc2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Combine 2-(3H)-benzoxazolone (0.4 g, 2.9 mmol), tert-butyl 2-bromoethylcarbamate (715.14 mg, 3.19 mmol), potassium tert-butoxide (508.7 mg, 4.35 mmol), potassium iodide (0.1 g, 0.6 mmol) in DMF (6 mL). Heat to 80° C. and stir the mixture overnight. Filter; collect the filtrate; and purify via HPLC conditions M (See below) to provide the title compound (0.53 g, 65.6%) as an oily solid. MS (m/z): 223 (M-tBu+1).
Reaction SMILES: [OH-].[NH4+:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1>ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:2])(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Br)cc1F
Reaction time: 2 h

Procedure:
To an ammonium hydroxide (28%, 80 ml) was added a solution of 4-bromo-2-fluorobenzenesulfonyl chloride (10 g) in dichloromethane (80 ml) dropwise for 1 hour at approximately 0° C. The reaction mixture was stirred vigorously for an additional 2 hours at the same temperature. The phases were separated. The aqueous phase was washed with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 4-bromo-2-fluorobenzenesulfonamide (8.0 g).
Reaction SMILES: C(OC([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([CH3:21])([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[F:19][C:13]1([F:18])[C:12]([CH3:20])([CH3:21])[C:11]2[C:10]3[CH2:22][CH2:23][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(C)C(F)(F)C3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1(C)c2c(ccc3c2CCNCC3)CC1(F)F
Temperature: 60 °C
Yield: 30.7 %

Procedure:
Into a glass vial containing the product from step (c) (20 mg, 0.061 mmol) dissolved in CHCl3 (2 ml), TMSI (84 μL, 0.619 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours. The volatiles were evaporated in vacuo and the residue diluted with 2M HCl (2 ml) and water (20 ml). The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a colorless oil (4.7 mg). 1H NMR (300 MHz, CDCl3) δ 6.99-6.96 (m, 2H); 3.28 (t, J=14.1 Hz, 2H); 3.03-2.90 (m, 8H); 1.89 (bs, 1H); 1.39 (s, 6H); MS: ESI (positive): 252 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C-]#N.[Na+].[OH2:24].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:24])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: COc1ccc2c(c1)C(c1cccc(Cl)c1)CCC2=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(O)(c1cccc(Cl)c1)CCC2
Temperature: 180 °C
Yield: 100 %

Procedure:
4-(3-Chlorophenyl)-6-methoxy-1-tetralone (0.85 g, 3 mmol) is dissolved in DMSO (10 mL). Crushed NaCN (0.73 g, 15 mmol) is added, and the reaction is heated at 180° C. overnight. The reaction is then poured into water (70 mL) and acidified to pH 2 using concentrated HCl. The resulting brown solid (0.8 g, 100% yield) is filtered and dried in a vacuum oven at 50° C. for 2 hours.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([Cl:17])=[O:14]
Reactant: O=C(O)c1cnc2ccccn2c1=O
Reactant: O=S(Cl)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(Cl)c1cnc2ccccn2c1=O

Procedure:
In a similar manner to that of Example 1--1), 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride, which was prepared from 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (1.8 g) and thionyl chloride (36 ml), was treated with a solution of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid formate (2.5 g) and bis(trimethylsilyl)acetamide (4.0 g) in methylene chloride (50 ml). Thus obtained reaction mixture was worked up in a similar manner to that of Example 1-4) to give powder (650 mg) of 7-[D-2-(4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)-2-phenylacetamide]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 103° to 105° C. (dec).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[CH:21]([CH3:22])[CH3:23])[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CNCc1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41.7 %

Procedure:
Diisobutylaluminum hydride (38 mL of a 1.0 M solution in toluene, 38 mmol) was added over 5 min to a solution of 2-isopropyl-malonic acid diethyl ester (3.84 g, 19.0 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (1.92 g, 12.14 mmol, 64%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.39 mL, 12.2 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.52 g, 24.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.36 g, 5.09 mmol, 42%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.93 (6H, d, J=7.2 Hz), 1.27 (3H, t, J=7.0 Hz), 1.92-2.01 (1H, m), 2.35-2.46 (1H, m), 2.73 (1H, dd, J=3.8 Hz, J2=11.6 Hz), 2.90 (1H, dd, J=10.2 Hz, J2=11.7 Hz), 3.74 (1H, d, J=13.2 Hz), 3.82 (1H, d, J=13.5 Hz), 4.15-4.21 (2H, m), 6.97-7.01 (2H, m), 7.26-7.30 (2H, m).
Reaction SMILES: CO.[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15].[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][O:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(O)c(CO)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1cc(C(=O)OC)ccc1O
Temperature: 130 °C
Yield: 445.2 %

Procedure:
To MeOH (100 mL) was added methyl 4-hydroxy-3-(hydroxymethyl)benzoate (10 g; 54.89 mmol; 1 eq.) and PTSA (1.89 g; 10.98 mmol; 0.20 eq.). The resulting suspension was heated to 130° C. for 1 hour. The reaction mixture was concentrated giving a yellow solid. It was dissolved in EtOAc (400 mL), washed with a saturated aqueous solution of NaHCO3 (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (9.59 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 10.48 (br s, 1H), 7.87-7.86 (d, J=2.11 Hz, 1H), 7.76-7.28 (dd, J=8.44 Hz, 2.31 Hz, 1H), 6.91-6.88 (d, J=8.48 Hz, 1H), 4.39 (s, 2H), 3.79 (s, 3H), 3.33 (s, 3H). LC/MS (Method B): 195.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]=[CH:12][C:13]#[N:14].N>[Ni].C(O)C>[NH2:14][CH2:13][CH2:12][CH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC)c(C=CC#N)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(OC)c(CCCN)c1
Reaction time: 3 h
Yield: 88.3 %

Procedure:
90 g of β-(2,5-Dimethoxyphenyl)acrylonitrile and 500 ml of ethanol containing about 100 g of ammonia were subjected to catalytic reduction inthe presence of Raney nickel under a hydrogen pressure of 80 atm. and at 130° C for 3 hours. After the reaction, distillation under reduced pressure gave 82 g of the end product having a boiling point of 105° ~ 107° C/l mmHg (yield 88.2%).