Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]([NH:25][CH2:26][CH3:27])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH:23]([N:25]([C:29](=[O:31])[CH3:30])[CH2:26][CH3:27])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNC(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(=O)Cl
Product: CCN(C(C)=O)C(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-(1-ethylamino-ethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [N:1]1[N:2]2[CH2:11][CH2:10][CH2:9][C:3]2=[CH:4][C:5]=1[C:6]([O-])=[O:7].[K+].CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl.O>[CH3:28][O:27][N:26]([CH3:25])[C:6]([C:5]1[CH:4]=[C:3]2[CH2:9][CH2:10][CH2:11][N:2]2[N:1]=1)=[O:7]
Reactant: O=C([O-])c1cc2n(n1)CCC2
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc2n(n1)CCC2
Temperature: 5.5 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a cooled (5-6° C.), stirred suspension of crude potassium 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (21.9 g, 115 mmol) in dichloromethane (180 mL) containing N,N-dimethylformamide (2.5 mL, 32.3 mmol), is added, dropwise, oxalyl chloride (19.0 mL, 218 mmol) over a period of 10 minutes. The reaction is exothermic with gas evolution. After the addition, the ice-bath is removed and the reaction mixture stirred at room temperature. After 5 hours, the solution is added to a cooled, stirred (10-12° C.) suspension of N,O-dimethylhydroxylamine hydrochloride (17.6 g, 180 mmol) in dichloromethane (80 mL) containing N,N-diisopropylethyamine (100 mL, 574 mmol). After 18 hours at room temperature, water (150 mL) is added. The two layers are separated. The organic layer is extracted with water (3×150 mL), and the organic layer dried over anhydrous sodium sulfate, filtered and concentrated under diminished pressure to give a brown solid which is recrystallized from ether (35 mL) to give 15.6 g (69%) of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide as a brown solid having HPLC purity, 91.3% (HPLC conditions described in Example 17).
Reaction SMILES: [CH3:1][CH:2]([CH:9]([CH:21]([CH:23]([CH2:25][OH:26])[OH:24])[OH:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1.C(#N)C>[CH3:1][CH:2]([CH:9]([C@@H:21]([CH:23]([CH2:25][O:26][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:24])[OH:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCC(C(C)CCCCCC)C(O)C(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(C(C)CCCCCC)[C@H](O)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
17 grams of 1-(2-octyl)dodecyl-glycerol (dried by azeotropic distillation with benzene) was dissolved in a mixture of dry THF (400 ml) and dry acetonitrile (160 ml). Triphenylchloromethane (15.8 grams) and dry triethylamine (14 ml) were added, and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (1 kilogram), transferred to a separatory funnel and extracted with diethyl ether (3×200 ml). The combined organic phase was washed consecutively with water (200 ml), dilute (1.5%) sulfuric acid (2×100 ml), water (200 ml), concentrated aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the obtained crude product was purified by chromatography on a silica gel (350 grams) column. 26 grams of pure (S)-1-(2-octyl)dodecyl-3-trityl-glycerol was eluted by hexane followed by a mixtures of hexane and chloroform (50-100%) as a yellow oil. The yield was 92.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([CH3:21])=[CH2:20])[N:18]=1)[C:12]([O:14]C)=[O:13].[BH4-].C([N+](CC)(CC)CC)C.[OH-:32].[Na+].Cl>CO.COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([OH:32])([CH3:21])[CH3:20])[N:18]=1)[C:12]([OH:14])=[O:13]
Reactant: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(F)cc2F)n1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [BH4-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(O)c1cc(C(=O)O)cc(-c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a solution of methyl 2-(2,4-difluorophenyl)-6-isopropenylisonicotinate (0.29 g, 1.01 mmol) in methanol (5.1 mL) and DME (5.1 mL) was added cobalt(II)mesotetraphenylporphine (6.8 mg, 10.1 mmol). The mixture was stirred at ambient temperature. After 18 h, tetraethylammonium borohydride (73.5 mg, 0.51 mmol) was added. After 15 min, additional tetraethylammonium borohydride (0.14 g, 1.01 mmol) was added. After 1.5 h, sodium hydroxide (1.0 M in water; 2.03 mL, 2.03 mmol) was added. The mixture was heated to 50° C. After 1 h, HCl (0.17 mL, 2.03 mmol) was added and the mixture was concentrated. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (0.22 g). MS 294.1 (M+1).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:37])[CH2:10][C@@:11]1([C:27]2[S:28][C:29]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[CH:30][CH:31]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:38]>CO.C(OCC)(=O)C>[ClH:38].[OH:7][NH:8][C:9](=[O:37])[CH2:10][C@@:11]1([C:27]2[S:28][C:29]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[CH:30][CH:31]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccco3)s2)S(=O)(=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C[C@]1(c2ccc(-c3ccco3)s2)CCNCCS1(=O)=O)NO
Reaction time: 1 h

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(2-furyl)-2-thienyl)-4-tert-butoxycarbonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (160 mg) in methanol (5 ml) was added 4M hydrogen chloride in ethyl acetate (5 ml) at room temperature. After being stirred for 1 hour, the mixture was concentrated in vacuo. The resulting residue was triturated with diethyl ether to afford N-hydroxy-2-[(S)-7-(5-(2-furyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide hydrochloride (75 mg) as a powder.
Reaction SMILES: C(OC(/[N:8]=[C:9](\[NH:32]C(OC(C)(C)C)=O)/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@@H:13]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C@@H:12]1[NH:26][C:27](=[O:31])[CH:28]([F:30])[F:29])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:29][CH:28]([F:30])[C:27]([NH:26][C@@H:12]1[C@@H:11]([NH:10][C:9]([NH2:32])=[NH:8])[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@H:13]1[O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:31]
Reactant: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(=O)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](NC(=N)N)[C@H]1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b (250 mg) in dioxane (5 ml) 5% solution of lithium hydroxide (2.5 ml) was added and the reaction mixture was stirred at room temperature for 45 min. Then lithium hydroxide was passivated by adding acetic acid (300 mcl), the solvents were evaporated in vacuo. The solid was extracted with isopropyl alcohol, the extract was dried over Na2SO4 and evaporated in vacuo. It gives (3R,4R,5S)-5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 8b (200 mg, 84%). LCMS (M+H): found 563; calculated 562.62. The obtained acid 8b (200 mg) was dissolved in 10% solution of trifluoroacetic acid in methylene chloride (2 ml) and stirred at room temperature for 12 h. Then the solvents were evaporated in vacuo. (3R,4R,5S)-4-(2,2-Difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 1.4 was separated by HPLC method. LCMS (M+H): found 363; calculated 362.28. 1H NMR (DMSO-d6), 400 MHz: 8.68 (d, J=8.4 Hz, 1H), 7.6 (d, J=10 Hz, 1H), 7.26 (br, 2H), 6.91 (br, 2H), 6.63 (s, 1H), 6.27 (t, J=53.6 Hz, 1H), 4.18 (d, J=8 Hz, 2H), 4.09 (m, 1H), 3.54 (q, J=10 Hz, 1H), 3.39 (m, 2H), 2.57 (dd, J1=18 Hz, J2=6 Hz, 1H), 2.31 (m, 1H), 1.44 (m, 4H), 0.85 (t, J=8 Hz, 3H), 0.795(t, J=7.6 Hz, 3H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](Cl)=[O:34]>>[F:30][C:31]([F:37])([F:36])[CH2:32][C:33]([NH:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)CC(F)(F)F)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 30 mg (0.2 mmol) 3,3,3-trifluoropropionylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 32 mg (33%) 3,3,3-trifluoro-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-propionamide as a yellow solid. MS ISP (m/e): 482.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.39 (s, 1H), 8.50 (d, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.24 (d, 1H), 7.03 (s, 1H), 7.01 (d, 1H), 6.64 (s, 1H), 4.92 (q, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.75 (m, 1H), 1.62 (m, 2H), 0.91 (d, 3H), 0.88 (d, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:24]=[CH:23][CH:22]=[C:14]([C:15]([N:17]([CH3:21])[CH2:18][CH:19]=O)=[O:16])[CH:13]=2)=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:2].[N:47]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:45]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([N:17]([CH2:18][CH2:19][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:48][CH2:49]2)[CH3:21])=[O:16])=[O:25])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:46]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCN(C(=O)OC(C)(C)C)CC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To a mixture of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-oxoethyl)isophthalamide (0.162 mmol, 100 mg) in ethanol (1 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (0.324 mmol, 65 mg) and HOAc (0.324 mmol, 19.4 mg). The mixture was stirred at room temperature for 20 minutes, and then sodium cyanoborohydride (0.81 mmol, 51 mg) was added. The mixture was stirred for an additional 1 h, diluted with ethyl acetate, washed with sat. aqueous NaHCO3 and brine, dried, concentrated and purified by column to give a product (70 mg, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Temperature: 80 °C
Yield: 75.5 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 ml, of N,N-dimethylformamide. The mixture was heated to 80° C. for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[N:4][NH:3]1>CCO.[Pd]>[NH:11]1[CH2:10][CH2:9][CH:8]([C:7]2[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccn[nH]c2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]nccc1C1CCNCC1
Yield: 90.1 %

Procedure:
A solution of benzyl 4-(3-oxo-2,3-dihydropyridazin-4-yl)piperidine-1-carboxylate (0.90 mg, 2.88 mmol) and 10% Pd/C (500 mg) in EtOH (25 mL), was hydrogenated under a balloon for 4 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (465 mg). MS 180.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=[O:5])[CH3:4].O.Cl>C(O)C>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH:3]([OH:5])[CH3:4]
Reactant: CC(=O)c1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1C(C)O
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Sodium borohydride (1.41 g) was added portionwise, at 0° C., to a solution of 4-acetyl-5-methyl-2-phenyloxazole (15.0 g) in ethanol (100 ml). The mixture was stirred for 1 hour at the same temperature, and then for 1 hour at room temperature. The reaction mixture was poured into water, which was neutralized with 2N HCl to obtain 1-(5-methyl-2-phenyl-4-oxazolyl)ethanol (13.0 g, 86%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.101-102° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCOCC2)c1
Temperature: 55 °C
Reaction time: 32 h
Yield: 22 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (437 mg, 1 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 55° C. for 32 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 22%) as a white solid: LC/MS m/e calcd for C23H27N3O4 (M+H)+: 410.49, observed: 410.2.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C([O-])(O)=O.[Na+].[C:36]([C:39]1[C:40]2[N:41]([N:46]=[N:47][N:48]=2)[N:42]=[C:43]([SH:45])[CH:44]=1)([OH:38])=[O:37].Cl>O>[C:36]([C:39]1[C:40]2[N:41]([N:46]=[N:47][N:48]=2)[N:42]=[C:43]([S:45][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:44]=1)([OH:38])=[O:37]
Reactant: O=C(O)c1cc(S)nn2nnnc12
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)c4nnnn4n3)CS[C@H]12)c1csc(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) (0.456 g, 0.001 mole) and NaHCO3 (0.143 g, 0.0017 mole) in water (10 ml), 8-carboxy-6-mercapto-tetrazolo[1,5-b]pyridazine (0.138 g, 0.0007 mole) was added. A slow stream of nitrogen was passed through the solution, and the mixture was heated at 50° C. for 12 hours, while keeping the pH at 6.8. After cooling, the solution was acidified with 10% HCl, the precipitate collected by filtration, washed with water and then with ethanol. There was thus obtained 0.245 g of the title compound which was shown by N.M.R., T.L.C. and I.R. to be identical to the product described in Example 4, apart a minor contaminant of the anti-isomer.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)[N:7]=1
Reactant: FC(F)(F)COc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (10 g, 40.3 mmol) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g, 40.3 mmol) and Hunig's Base (7.04 mL, 40.3 mmol). The resulting mixture was stirred for 16 h. After removal of most THF, the precipitate was filtered and washed with THF, then washed with water and dried to give the product tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10.6 g) as white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([OH:42])([C:40]#[CH:41])[CH3:39])=[CH:34][CH:33]=1.CCN(CC)CC.[NH4+].[Cl-]>C1COCC1.[Cu]I.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>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:41]#[C:40][C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)([OH:42])[CH3:39])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:27])([CH3:28])[CH3:29]
Reactant: C#CC(C)(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccc(C#CC(C)(O)c3ccc(F)cc3)cc2c1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (70 mg, 0.14 mmol) in THF (2 mL) was added 2-(4-fluorophenyl)but-3-yn-2-ol (46 mg, 0.28 mmol), CuI (5 mg, 0.028 mmol), Pd(PPh3)4 (17 mg, 0.014 mmol), and Et3N (80 μL, 0.57 mmol). The reaction mixture was stirred at 70° C. for 1 h. A saturated solution of NH4Cl was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 7.56-7.66 (m, 4H), 7.29 (m, 6H), 6.97 (m, 2H), 5.02 (s, 1H), 4.06 (q, J=7 Hz, 2H). 2.54 (s, 3H), 1.76 (s, 3H), 1.10 (s, 9H), 0.80 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][CH2:12][CH2:13][CH3:14])[C:6](OCC)=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[CH2:1]([CH:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCCC)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CO)CCCC
Temperature: 25 °C

Procedure:
Compound 16 (54.1 g, 270 mmol) was dissolved in anhydrous THF (450 mL) and cooled in an ice/water bath under nitrogen protection. Lithium aluminum hydride (LAH) (15.3 g, 404 mmol) was added into the reaction flask in small portions. The temperature of the reaction solution was increased to room temperature and then refluxed overnight. The reaction mixture was cooled down to room temperature and poured very slowly into the ice/water solution. The solution was acidified using a 2N HCl aqueous solution, extracted with Et2O (150 mL×3), and then concentrated via rotary evaporation. The resulting crude oil was purified via vacuum distillation. The compound 17 was collected as colorless oil (32.6 g, 76.2%). 1H NMR (CDCl3): δ 0.87-0.92 (6H, m), 1.17-1.42 (12H, m), 1.40-1.50 (1H, m), 3.53 (2H, d). MS (EI): calcd, 158.3. found M+H+, 159.2.