Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][NH:18][CH2:12][C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:7]=2[CH:8]=1
Reactant: O=Cc1ccc2c(c1)OCCCC2
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)CNCc1ccc2c(c1)OCCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.3 %

Procedure:
To a mixture of 0.48 g (2.7 mmol) of 2,3,4,5-tetrahydro-1-benzoxepine-8-carbaldehyde and 1.33 mL (13.5 mmol, 5 equiv) of isobutylamine in 22 mL of 1,2-dichloroethane was added 0.86 mL (15.0 mmol, 5.5 equiv) of acetic acid. The mixture was stirred under nitrogen at ambient temperature for 20 minutes and 0.64 g (3.0 mmol, 1.1 equiv) of sodium triacetoxyborohydride was added. The mixture was stirred overnight then diluted with 125 mL of ethyl acetate and washed with 60 mL each of saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 0.67 g of a yellow oil. Purification by flash chromatography (0-10% methanol in ethyl acetate) gave the product as a colorless oil. MS (m+1)=234.2; 1H NMR (400 MHz, CDCl3) 7.07 (d, 1H, J 8 Hz), 7.09 (d, 1H, J 1.5 Hz), 6.99 (m, 1H), 3.99 (m, 2H), 3.72 (s, 2H), 2.70 (m, 2H), 2.43 (d, 2H, J 7 Hz), 1.95 (m, 2H), 1.77 (m, 1H), 1.71 (m, 2H), 1.5 (br s, 1H), 0.91 (d, 6H, J 7 Hz).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=5)[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2cn(Cc3ccc(Cl)cc3)nn2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.09 mmol) (from Example 36 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered, washed with methanol and dried to give 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34.5 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[CH:7]([CH3:18])[CH2:6]1.FC(F)(F)C(O)=O.CC1C=CC=C(C)C=1CN1C2C(=CC=C(CC(O)=O)C=2)[C@H](C)C1>CCCCCC.C(O)(C)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C@@H:7]([CH3:18])[CH2:6]1
Reactant: Cc1cccc(C)c1CN1CC(C)c2ccc(CC(=O)O)cc21
Agent: Cc1cccc(C)c1CN1C[C@@H](C)c2ccc(CC(=O)O)cc21
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1CN1C[C@H](C)c2ccc(CC(=O)O)cc21
Yield: 57.7 %

Procedure:
The compound [78] obtained in Example 78 (26 mg) was optically resolved by chiral column chromatography (CHIRALCEL (registered trademark) OD (CHRALCEL OD) manufactured by Daicel Corporation, 2 cm×25 cm; 0.1% trifluoroacetic acid, hexane/isopropyl alcohol=85/15; flow rate 20 mL/min). (3R*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic acid [79A] (15 mg) as a pale brown solid was obtained from the preceding fraction (retention time: 5.3 minutes), and (3S*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic acid [79B] of the same (16 mg) as a pale brown solid was obtained from the posterior fraction (retention time: 10.8 minutes). (Both of them were un-identified, and thus one of them was referred to as 3R*, and the other one as 3S* for convenience.)
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1([CH3:54])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:52][CH2:53][C:48]([CH3:54])([CH3:47])[CH2:49]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC1(C)CCCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC(C)(C)C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,3-dimethylpiperidine (Chmsrv-As) to give the title product. LC-MS (ES+) 760 [(M+H)+].
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[Cl:8][C:9]1[C:14]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=[CH:11][N:10]=1.O.[OH-].[Na+]>C1COCC1>[Cl:8][C:9]1[C:14]([N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:20][CH2:21]2)[C:6]([NH2:5])=[O:7])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2cccnc2Cl)CC1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(c1cccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
530 mL (6.1 mol) chlorosulphonyl isocyanate were placed in 6 L THF and cooled to −15° C. A solution of 1.25 kg (3.63 mol) benzyl 4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate in 7 L THF was then added dropwise to this mixture within one hour such that the temperature of the reaction mixture did not exceed −7° C. The mixture was stirred for 90 minutes at approx. −8° C. and then 700 mL water were added dropwise within 30 minutes. The mixture was stirred for 30 minutes at approx. 10° C. and then slowly combined with 8.1 L sodium hydroxide solution (2 mol/L). The reaction mixture was then heated to 50° C. and the phases were separated. The organic phase was washed with 2 L water. Then 10 L solvent were distilled off from the organic phase, 15 L butyl acetate were added to the residue and another 8 L were distilled off. The product was crystallised by slow cooling to 0° C. The precipitate was suction filtered, washed with 2 L butyl acetate and dried at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[N:16]([CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][C:31]([Cl:37])=[CH:32][CH:33]=3)[N:28]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=2)[N:16]([CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][C:31]([Cl:37])=[CH:32][CH:33]=3)[N:28]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc(N)cc23)c(OC)c1
Yield: 105.7 %

Procedure:
A solution of the nitroindole from Step 1 (185 mg, 0.36 mmol) in THF (3 ml) containing NaBH4 /S (200 mg) was heated at reflux for 1 hr. The solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried, evaporated, and concentrated to give the crude amine (185 mg) which was used directly in the next step.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)n1nc(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12

Procedure:
1-tert-butyl-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (21 mg, 0.082 mmol) was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 257.1, found 257.3.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 169.1, (116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na2CO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon, PdCl2(dppf) (9 mg, 0.013 mmol) was added and the RM subjected to MW irradiation at 100° C. for 2 h. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give a residue that was purified flash chromatography (RediSep® Silica gel column, EtOAc/EtOAc-MeOH (98:2)), from 50% to 100% EtOAc-MeOH (98:2)) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=4.71 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV 210 nm) tR=60.52 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.82-2.92 (m, 1H) 3.15-3.26 (m, 2H) 3.33-3.41 (m, 1H) 4.15-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz, 2H) 8.03-8.13 (m, 1H) 8.78 (m, J=2.35, 0.78 Hz, 1H) 8.87 (s, 2H) 9.18 (d, J=0.78 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(C)c4)nc23)ccn1
Yield: 51.8 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (113 mg, 52%). MS (ISP) 437.5 [(M+H)+]; mp 237° C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[ClH:33].CCOCC>O1CCOCC1>[ClH:33].[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[O:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(NC(=O)c4ccc(F)cc4)n[nH]c3c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2cc(C3CNCCO3)ccc12)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Tert-butyl 2-(3-(4-fluorobenzamido)-1H-indazol-6-yl)morpholine-4-carboxylate (40 mg, 0.09 mmol) was dissolved in dioxane (0.2 ml) and a solution of HCl in dioxane (4M, 0.34 ml, 1.36 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether (2 ml) was added, the mixture was stirred for 30 min and the solid was filtered off. It was washed with ether and dried in vacuo to afford 4-fluoro-N-(6-(morpholin-2-yl)-1H-indazol-3-yl)benzamide hydrochloride (22 mg, 66%) as an off-white solid. MS (ISP): 341.2 ([M+H]+).
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][CH2:60]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[CH:4]1([N:7]([CH2:40][C:41]2[CH:42]=[C:43]([O:52][CH2:60][CH2:59][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][N:53]=3)[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:5][CH2:6]1
Reactant: OCCc1ccccn1
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCc2ccccn2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in toluene (0.1 M) was added 2-pyridin-2-ylethanol (1.2 eq.) and 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.). The resulting orange solution was deoxygenated before tributylphosphine (1.2 eq.) was added. The now yellow-orange solution was heated at 100° C. for 14 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a red oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[N:17][C:10]3[N:9]([CH3:34])[C:8](=[O:35])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=3[C:14]=2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
To a solution of 3-(6-(4-chlorophenoxy)-5-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.10 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (10 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(4-chlorophenoxy)-5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 37% yield) as a white solid. 1H NMR (CDCl3) δ: 8.31 (s, 1H), 7.31-7.27 (m, 2H), 7.22 (dd, J=8.6, 5.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 6.83-6.77 (m, 2H), 4.72 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.70 (s, 3H), 3.55 (dd, J=11.7, 6.2 Hz, 2H), 3.04 (t, J=6.9 Hz, 1H), 2.01-1.86 (m, 2H). LCMS: MH+ 470 and TR=2.811 min
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[CH:13]([C:19]([O:21][CH3:22])=[O:20])[C:14](=[CH2:17])[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(CCl)CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: O
Solvent: C1CCOC1
Product: C=C1CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N2C1C(=O)OC
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 96 %

Procedure:
To a solution of 48 ml of SmI2 in THF (0.1M), a solution of 0.8 g of methyl 7β-benzoylamino-3chloromethyl-3-cephem -4-carboxylate in 100 ml of dry THF, was added by dropping at -78° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. After the usual work-up and column chromatography, the title product was isolated in 96% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:21]([CH:23]1[CH:28]([CH3:29])[CH:27]([CH2:30][O:31][Si](C)(C)C)[CH2:26][CH2:25][C:24]1=[O:36])[CH3:22].Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2([OH:36])[CH2:25][CH2:26][CH:27]([CH2:30][OH:31])[CH:28]([CH3:29])[CH:23]2[CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: CCC1C(=O)CCC(CO[Si](C)(C)C)C1C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1C(C)C(CO)CCC1(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Benzyloxy4-iodo-benzene (5.70 g, 18.37 mmol) was dissolved in anhydrous THF (36 mL) at −10° C. Isopropyl magnesium chloride (1.0 M, 18.37 mL) was added and the mixture was stirred for 3 h. A solution of 2-ethyl-3-methyl-4-trimethylsilanyloxymethyl-cyclohexanone (12.0 g in 50 mL THF) was added slowly over 30 min by syringe pump. The reaction mixture was stirred for 30 min at 25° C. and then refluxed for 30 min. The reaction mixture was then cooled to 25° C., HCl (1.0 N, 80 mL) was added slowly, followed by addition of ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL), dried over MgSO4 and purified on SiO2 (10˜15% ethyl acetate/hexane) to yield 1-(4-benzyloxy-phenyl)-2-ethyl-4-hydroxymethyl-3-methyl-cyclohexanol.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC(=O)NC)COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCCCCCCCCC.C(SCC(OC)CNS(CCC[I:111])(=O)=O)CCCCCCCCCCCCCCC>>[I:111][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methylcarbamoyloxy-1-octadecylcarbamoyloxypropane III c2 is allowed to react and worked up by the same procedure as described in (5). m.p. 97°-99° C. The summary of the experimental condition and the physical data of the product are listed in the Table 8.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([C:35](=[O:40])[CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH3:38]/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=1)=[O:40]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1cccc(C)c1
Product: C/C(=C/C(=O)c1cccc(C)c1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 48 mg (0.27 mmol) of Intermediate 21 to yield 104 mg of Example 46. 1H NMR (DMSO-d6, 400 MHz) δ11.47 (d, 1H, J=9.06), 7.95 (m. 2H), 7.65 (m, 2H), 7.54 (m, 3H), 7.31 (m, 2H), 7.19 (d, 2H, J=8.51), 6.88 (d, 2H, J=8.51), 5.64 (s, 1H), 4.23 (m, 1H), 4.23 (m, 3H), 3.21 (m, 1H), 2.96 (m, 2H), 2.86 (m, 1H), 2.60 (s, 3H), 1.80 (s, 3H); low resolution MS (ES) m/e 525.2 (MH+); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 50-100% CH3CN in H2O) with 0.1% HCO2H buffer 30 minutes; 1 mL/min: tf15.57 min (to=1.43).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:18][OH:19].C(O)(C)C.O>CC(C)=O>[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:18]([OH:3])=[O:19]
Reactant: CC(C)=O
Reactant: CON=C(CO)c1ccccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CON=C(C(=O)O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
10 ml of Jones reagent (chromic anhydride in dilute sulfuric acid) were added to a solution in acetone of 0.40 g of 2'-chloro-2-hydroxyacetophenone O-methyloxime (the less polar isomer prepared above). The resulting mixture was stirred at room temperature for an hour and then 10 ml of isopropanol were added to it with ice-cooling. The reaction mixture was poured into 100 ml of water and extracted three times with 10 ml portions of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give 320 mg (75%) of the title compound as a crude product.