Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:4][OH:5].[CH3:12][O:13][CH:14]([OH:19])[C:15](OC)=O.C(O)(=O)C>CO.[Pd]>[CH:6]1([CH:3]([CH2:4][OH:5])[CH2:2][NH:1][CH2:15][C:14]([O:13][CH3:12])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(O)OC
Reactant: NCC(CO)C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CNCC(CO)C1CCCCC1
Yield: 53.4 %

Procedure:
A solution of 3-amino-2-cyclohexyl-1-propanol (1 g, 6.37 mmole) and methyl glyoxylate methylhemiacetal (790 mg, 6.56 mmole; see Tetrahedron, 881, 1977) in methanol (9 ml) was stirred at room temperature under argon for 24 hours. The resulting solution was transferred to a Parr bottle, treated with additional methanol (22 ml), acetic acid (3.6 ml), and 10% Pd on carbon (857 mg) and hydrogenated at 50 psi overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo. Acetic acid was removed by evaporation from toluene. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was extracted with additional HCl and the combined aqueous extracts were washed with ethyl acetate. The pH of the product rich aqueous solution was raised to 10.2, and sodium chloride was added to saturation. Extraction with ethyl acetate followed by drying (sodium sulfate), filtration and concentration in vacuo produced 780 mg (53%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1)=[O:12].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH3:26])[C:10]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:16]([O:22][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:12]
Reactant: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 53.8 %

Procedure:
The tide compound was prepared according to the procedure in Example 4 using [2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (95% CH3CN/H20) gave 0.23 g (54%) of the title compound as an off white solid, mp 148° C. 1H NMR (DMSO-d6) δ1.06 (d, 12 H), 1.80 (s, 3 H), 2.21 (s, 3 H), 3.08 (septet, 2 H), 3.87 (s, 2 H), 1 H), 7.21 (t, 1 H), 7.25 (s, 1 H), 7.38 (d, 1 H), 7.44 (s, 1 H), 7.48 (dd, 1 H), 7.51 (s, 2 H), 8.06 (d, 1 H). IR (KBr) 3400, 2950, 1680, 1650 and 1180 cm−1. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. for C33H33BrO8 S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.86; H, 4.93; N, 0.07.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[F:52])(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:53]([C:48]2[CH:49]=[CH:50][C:51]([F:52])=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:55])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)ccc1F
Yield: 39.3 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamido-4-fluorobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.013 g of a white solid. MS (ES): 661 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].Cl.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1cc(C(=O)O)cc(O)c1OC
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(O)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (27.2 mmol) of 3-Hydroxy-4,5-dimethoxy-benzoic acid was added at 0° C. to 100 ml of a saturated solution of HCl in MeOH. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (2/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:30])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Fc1ccccc1C1=CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
20.2 g of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one are dissolved in 110 ml of hexamethylphosphoric acid triamide and treated with 13.8 g of 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The mixture is warmed to 100° for 1 hour, again cooled to room temperature and poured into 2.2 l of water. The mixture is extracted three times with ethyl acetate and the organic extracts are washed with water, sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 400 g of silica gel. By elution with toluene and toluene/chloroform (19:1) and recrystallization of the resulting material from diisopropyl ether there is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepine-2-thione of melting point 179°-181°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:14]([NH2:16]=O)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[ClH:31]>C(OCC)(=O)C.[Pd]>[ClH:31].[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: O=C([NH2+][O-])C1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccc(F)cc2)CCNCC1
Temperature: 25 °C

Procedure:
1-Benzyl-4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid amide N-oxide (5.3 g, 16.3 mmol) and 10% palladium-on-carbon (0.6 g) and acetic acid (100 mL) were combined in a pressure vessel. The reaction mixture was treated with hydrogen on a Parr apparatus at an initial pressure of 53 psi of hydrogen. When hydrogen consumption stopped the catalyst was removed by filtration. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (150 mL), acidified by the addition of 12M aqueous hydrochloric acid solution (5 mL), and heated to reflux for 10 minutes. The mixture was cooled to ambient temperature to give a solid which was collected by filtration, rinsed with ethyl acetate, recrystallized from methanol/ethyl acetate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 4-fluoro-2-methyl-benzoic acid (13 g, 84 mmol) in MeOH (500 mL) was added SOCl2 (20 g, 168 mmol) dropwise at 0° C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. When TLC indicated that no starting material was left, the mixture was concentrated under reduced pressure to give a crude product (12.7 g, yield 90.7%), which was used in the next step reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=O)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CCN(CC)CC.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][NH:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(Cc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-ethyl-carbamic acid tert-butyl ester (240 mg, 0.806 mmol), cyclopropylamine (0.085 mL, 1.2 mmol) and Et3N (0.169 mL, 1.21 mmol) in MeOH (2.7 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (76.2 mg, 2.01 mmol) was added. The mixture was stirred for 1 h at rt, and aq. sat. NaHCO3 was added. The mixture was extracted several times with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (125 mg, 46%). LC-MS: tR=0.78 min; ES+: 380.20.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:20][OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:31]([C:33]1[CH:34]=[CH:35][C:36]([O:44][CH3:45])=[C:37](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:38]=1)#[N:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([NH:2][C:41](=[O:42])/[CH:40]=[CH:39]/[C:37]3[CH:38]=[C:33]([C:31]#[N:32])[CH:34]=[CH:35][C:36]=3[O:44][CH3:45])[CH2:20][OH:21])[CH2:10][CH2:9]2)=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Reactant: N[C@H](CO)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CO)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone hydrochloride (1.8 g, 5.7 mmol) and diisopropylethylamine (2.0 ml, 11.4 mmol) in dichloromethane (45 ml) is added (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (1.1 g, 5.7 mmol) followed by 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (1.83 g, 5.7 mmol). The reaction mixture is stirred at ambient temperature for 4.5 hours, then filtered and the filtrate washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml). The organic phase is dried over magnesium sulphate, the solvent evaporated and the residue purified by flash silica chromatography (dichloromethane:methanol; 98:2 to 92:8 elution gradient) to afford the product, [MH]+466.1.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH:8]=[CH:9][CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[C:6]([CH2:7][CH:8]=[CH:9][CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC=CCc1c(O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC=CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 81.6 %

Procedure:
3-Hydroxy-4-(2-butenyl)-5-phenylisoxazole (215 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (292 mg, 82%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 510.3 and 512.2 (M+H)+, 410.1 and 412.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][P:26]([C:31]1[CH:32]=[C:33]([CH2:49][CH2:50][C:51]([OH:53])=O)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][P:39]([O:45][CH:46]([CH3:48])[CH3:47])([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].[C:54]([C:57]1[CH:58]=[C:59]([CH:71]([NH2:73])[CH3:72])[CH:60]=[CH:61][C:62]=1[O:63][CH2:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1)(=[O:56])[NH2:55]>C(Cl)Cl.CN(C=O)C>[CH2:29]([O:28][P:26]([C:31]1[CH:32]=[C:33]([CH2:49][CH2:50][C:51](=[O:53])[NH:73][CH:71]([C:59]2[CH:60]=[CH:61][C:62]([O:63][CH2:64][CH:65]3[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]3)=[C:57]([C:54](=[O:56])[NH2:55])[CH:58]=2)[CH3:72])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][P:39]([O:45][CH:46]([CH3:47])[CH3:48])([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])(=[O:27])[O:25][CH2:23][CH3:24])[CH3:30]
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)O)ccc1OCP(=O)(OC(C)C)OC(C)C
Reactant: CC(N)c1ccc(OCC2CCCCC2)c(C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cc(CCC(=O)NC(C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)ccc1OCP(=O)(OC(C)C)OC(C)C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
HOBt (94 mg, 0.69 mmol) and EDC.HCl (140 mg, 0.73 mmol) were dissolved in 2.5 mL of dry DCM at 0° C. 3-(3-Diethylphosphono-4-diisopropylphosphonomethoxyphenyl)propionic acid (200 mg, 0.42 mmol) in 1.2 mL of dry DMF was added dropwise with stirring. After 5 min, racemic 1-(3-carbamoyl-4-cyclohexylmethoxyphenyl)ethylamine (120 mg, 0.43 mmol) in 0.8 mL of dry DMF was added dropwise. Stirring was continued at 0° C. for 1 hr. The reaction was quenched with 1 mL of saturated NH4Cl, diluted with 17 mL of EtOAc. The organic layer was separated and washed with H2O, 1 N HCl, H2O, 5% NAHCO3, and saturated NH4Cl. The organic layer was dried over Na2SO4 and concentrated to give 253 mg (yield 66%) crude product as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-:30].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
4-(N-Benzyl-N-methylamino)-1-cyano-1,1-diphenylbutane (2%--see Preparation 2) was dissolved in 90% sulphuric acid (11 l) and the solution heated at 100° for 3 hours. The solution was allowed to cool to room temperature then poured slowly into water (100 ml). The mixture was made basic (pH 10) by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to leave the title compound as a colourless foam, yield 1.9 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][C:30]12[CH2:37][CH:34]([NH:35][CH2:36]1)[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:35]3[CH2:36][C:30]4([CH3:29])[CH2:37][CH:34]3[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]4)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.132 g). 1H NMR (400 MHz, CHCl3-d; 80° C.); □ 7.6 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.0 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 3.0 (m, 1H), 2.9 (m, 1.9 (m, 2H), 1.7 (m, 1H), 1.6-0.9 (m, 26H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CS(C)=O>[NH2:1][C@@H:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([O:15][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 68 h
Yield: 53.9 %

Procedure:
To a suspension of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid (20.7 g, 81 mmol) in a mixture of dichloromethane (250 ml) and dimethyl sulfoxide (250 ml) was added dropwise a solution of diphenyldiazomethane (17.53 g, 90 mmol) in dichloromethane (150 ml). The mixture was stirred at room temperature for 68 h, filtered, the filtrate was concentrated under reduced pressure. The residual sticky mass was taken in ethyl acetate (250 ml) and washed successively with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate; solvent was removed under reduced pressure to give a residue which was purified over a silica column using dichloromethane-ethyl acetate (1:1) to give 18.4 g (54%) of a mixture of Δ2 and Δ3 -cephems. The mixture was directly used for the next step without further separation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Reactant: Brc1nccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(Nc3nccs3)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 90 °C
Yield: 45 %

Procedure:
(P-443): In an 8 mL vial equipped with a stir bar was placed 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) synthesized above (100 mg, 0.293 mmol), 2-bromothiazole (52.1 μL, 0.585 mmol), 10% aqueous ethanol (1.5 mL) and concentrated hydrochloric acid (48.8 μL, 0.585 mmol). The mixture was heated to 90° C. for 18 hours and then cooled to room temperature. After water (30 mL) and 5% aqueous potassium carbonate (30 mL) were added, the aqueous portion was extracted with ethyl acetate (2×35 mL) and the organic portions were combined, washed brine (30 mL), dried (magnesium sulfate) and concentrated. The crude material was purified by column chromatography utilizing 3% acetone/dichloromethane as the eluent to produce 57 mg of [4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-yl-amine. (P-443) as white solid in 45% yield. 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.94 (s, 2H), 6.62 (d, J=4 Hz, 1H), 6.70 (dd, J=8, 1 Hz, 1H), 7.10 (t, J=9 Hz, 1H), 7.20-7.22 (m, 2H), 7.26-7.40 (m, 8H) ppm; MS (APCI+): 425.0 (M+1), LC-MS: 89%
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[C:7]([NH:16][C:17]([C:19]2([CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[CH2:27]([CH:26]([CH2:29][CH3:30])[CH2:25][C:19]1([C:17]([NH:16][C:7]2[C:6]([S:5][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:28]
Reactant: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2S)CCCCC1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C(C)C)CCCCC1
Reaction time: 1 h

Procedure:
To a chloroform solution of the product obtained in step B) are added 1.05 mol equivalents of isobutyryl chloride and 2.5 mol equivalents of pyridine at room temperature. The mixture is stirred for 1 hour, concentrated and then n-hexane is added. The solids are filtered off and the filtrate is concentrated. The remaining residue is purified by silica gel column chromatography to obtain the desired title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chlorothiophenol (91 mg) in 6 mL of DMF was cooled to 0° C. under N2. Sodium hydride (60%, 30 mg) was added and the reaction stirred for 30 minutes. The product from Step A above in 3 mL of DMF was added and the reaction allowed to warm to room temperature while stirring overnight. This was diluted with EtOAc, washed with saturated NaHCO3 and brine and dried over Na2SO4. Concentrating in vacuo gave the titled compound. ESI+ MS: 202 [MH-Boc]+.