Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Cl)[O:22][CH3:23]>CO.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1ccc2cc(OC)ccc2c1Br
Temperature: 20 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
To a solution of 1-bromo-6-methoxynaphthalen-2-ol (described in U.S. 61/423,799) (2.90 g, 11.5 mmol) in MeOH (20 mL) and THF (20 mL) was added K2CO3 (3.18 g, 23.0 mmol) and MOMCl (1.10 g, 13.8 mmol). The resulting mixture was stirred at 20° C. for 48 hours and stirred at 30-40° C. for 5 days. An aqueous/EtOAc workup was followed by purification by silica gel column chromatography (PE to PE/EtOAc=200/1) to give the product (1.90 g, yield 56%) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH2:26][O:27][CH2:28][CH2:29][CH:30]=3)[NH:16]C(OC(C3CC3)C)=O)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH2:26][O:27][CH2:28][CH2:29][CH:30]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)C3CC3)C3=CCCOC3)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)C3=CCCOC3)[C@H]2S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of 2-methyl-7-[N-(Cl-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid (3.0 g) and formic acid (20 ml) was stirred for 3 hours at room temperature. After the reaction was completed, formic acid was removed from the reaction mixture under reduced pressure at room temperature. The residue was pulverized with acetonitrile and the powder was collected by filtration. The powder was in turn washed with acetonitrile and water, and dried to give 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid (2.20 g), mp 125° to 128° C. (dec.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>C(Cl)Cl.CCOC(C)=O.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:14][N:15]1[CH:19]=[C:18]([CH2:20][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[N:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cnc(C=O)c1
Agent: Cl[Ti+3]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cnc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.3 %

Procedure:
N-Boc-piperazine (0.470 g, 2.50 mmol, 1.1 eq) was dissolved in DCM (6.2 mL). To this solution, 1-methyl-1H-imidazole-4-carboxaldehyde (0.250 g, 2.27 mmol, 1 eq) was added followed by chlorotitanium triisopropoxide (1.19 mL, 5.0 mmol, 2.2 eq). The resulting solution was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 5 eq). The mixture was stirred at room temperature for 17 h and was diluted with EtOAc (12 mL). It was then poured into ammonia (35% sol. in H2O, 6 mL) and the resulting mixture filtered and washed with EtOAc. The organic phase was washed with H2O dried (MgSO4) and the solvent removed in vacuo. The crude material was purified by column chromatography on a Biotage SP1 system eluting with methanol (1-8%) in dichloromethane to give the title compound as a clear oil (0.390 g, 62%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 2.48 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.45 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 3.66 (s, 3H, imidazole Me), 6.80 (s, 1H, imidazole 5-H), 7.38 (s, 1H, imidazole 2-H); LC (Method B)-MS (ESI, m/z): 281 [(M+H+)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[CH3:18][C:19]1([CH3:27])[CH2:24][C:23](=[O:25])[CH2:22][C:21](=O)[CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:18][C:19]1([CH3:27])[CH2:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]3[OH:17])=[CH:22][C:23](=[O:25])[CH2:24]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1nnc2ccc(NC3=CC(=O)CC(C)(C)C3)cc2c1O

Procedure:
A mixture of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.), 5,5-dimethylcyclohexan-1,3-dione (2.24 g.) and p-toluenesulphonic acid (0.4 g.) in ethanol (100 ml.) was heated under reflux on a steam bath for 16 hours. The solution was evaporated in vacuo and the residue was applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave crystalline ethyl 6-[(5,5-dimethylcyclohexen-3-one-yl)amino]-4-hydroxycinnolin-3-yl carboxylate, m.p. 274° C.
Reaction SMILES: C(OC(=O)N[C@@H](C1C=CC(C2C=C(Cl)C=C(F)C=2C2N=C(C)ON=2)=CC=1F)C)(C)(C)C.BrC1C=C(Cl)C=C(F)C=1C1N=C(C)ON=1.ClC1C=C(F)C(C2N=C(C)ON=2)=C(C2C=CC([C@H](N)C)=C(F)C=2)C=1.C1C2C(COC(=O)[NH:87][C:88]3([C:92](=[O:117])[NH:93][C@@H:94]([C:96]4[CH:101]=[CH:100][C:99]([C:102]5[CH:107]=[C:106]([Cl:108])[CH:105]=[C:104]([F:109])[C:103]=5[C:110]5[N:114]=[C:113]([CH3:115])[O:112][N:111]=5)=[CH:98][C:97]=4[F:116])[CH3:95])[CH2:91][O:90][CH2:89]3)C3C(=CC=CC=3)C=2C=CC=1>>[Cl:108][C:106]1[CH:105]=[C:104]([F:109])[C:103]([C:110]2[N:114]=[C:113]([CH3:115])[O:112][N:111]=2)=[C:102]([C:99]2[CH:100]=[CH:101][C:96]([C@H:94]([NH:93][C:92]([C:88]3([NH2:87])[CH2:91][O:90][CH2:89]3)=[O:117])[CH3:95])=[C:97]([F:116])[CH:98]=2)[CH:107]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc([C@@H](C)NC(=O)C3(NC(=O)OCC4c5ccccc5-c5ccccc54)COC3)c(F)c2)no1
Agent: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc([C@@H](C)N)c(F)c2)no1
Agent: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc([C@@H](C)NC(=O)OC(C)(C)C)c(F)c2)no1
Agent: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc([C@@H](C)NC(=O)C3(N)COC3)c(F)c2)no1

Procedure:
The title compound was prepared in analogy to intermediate 5 synthesizing {(R)-1-[5′-chloro-3,3′-difluoro-2′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]ethyl}-carbamic acid tert-butyl ester in step A (using 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate 10) instead of 5-(2-bromo-4-chloro-6-fluorophenyl)-2-methyl-2H-tetrazole), (R)-1-[5′-chloro-3,3′-difluoro-2′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]-ethylamine in step B and (3-{(R)-1-[5′-chloro-3,3′-difluoro-2′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester in step C. White foam. MS: 449.1; [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5](C)[CH:4]=[C:3](C)[C:2]=1[Mg]Br.[C:12]1(=O)[CH2:18][CH2:17]C[CH2:15][CH2:14][CH2:13]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C1([Mg]Cl)C=CC=CC=1.Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCC>[C:1]1([C:11]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:18][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: O=C1CCCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: Cl[Mg]c1ccccc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
Mesitylmagnesium bromide (18.0 mL, 18.0 mmol, 1.0 M in THF) was added over 15 minutes to a solution of cycloheptanone (2.0 g, 17.8 mmol) and diphenyl chlorophosphate (1.1 eq.) in THF (5 mL) at 0° C. The solution was stirred at 0° C. for 30 min, whereafter the solution was allowed to reach room temperature. After stirring the solution for 30 min, dichlorobis(triphenylphosphine)palladium (126 mg, 1 mol %) was added and the solution was warmed to 65° C. Phenylmagnesium chloride (10.8 mL, 1.2 equivalents in THF) was added over 10 minutes, resulting in a gentle reflux of the solvent. After stirring at 65° C. for 30 minutes, the mixture was cooled to rt and poured into a mixture of 3 N HCl (30 mL) and pentane (30 mL). The phases were separated, and the aqueous portion was extracted with pentane (30 mL). The combined organic phase was washed sequentially with 3 N HCl (20 mL), 3 M NaOH (2×20 mL), and brine (20 mL), and dried over MgSO4. Evaporation of the solvent followed by distillation using a Kugelrohr apparatus (oven temperature 100-140° C., 0.065 torr) yielded 1-phenylcycloheptene (1.29 g, 43%).
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[CH:6]=[CH:5]1>N1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[N:2][OH:3])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: NO
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 11.6 %

Procedure:
Hydroxylamine hydrochloride (0.574 g) was added portionwise to a solution of 1H-indole-6-carbaldehyde (1 g) in pyridine (5 ml) are RT. The resulting solution was heated to reflux and stirred at that temperature for 1 hour. The solvent was evaporated. The residue was diluted with ethyl acetate (50 mL) and the resulting solution was washed with aqueous hydrochloric acid (0.5 M, 40 mL). The organic fraction was separated and dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford a brown oily solid. The residue was triturated with ether/hexane to afford 1H-indole-6-carbaldehyde oxime (D11) as a pink solid (128 mg). Solid was precipated out from the filtrate. The solid was collected to give another batch of 1H-indole-6-carbaldehyde oxime (D11) (818 mg). δH (DMSO-d6, 400 MHz): 6.44 (1H, m), 7.24 (1H, dd), 7.32 (1H, m), 7.55 (1H, dd), 7.57 (1H, s), 8.19 (1H, s), 10.88 (1H, s), 11.25 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([CH2:8][C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)ccc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(F)ccc1C(F)(F)F

Procedure:
A mixture of 2-(5-fluoro-2-trifluoromethyl-phenyl)-acetic acid (50 g), ethanol (100 ml) and concentrated sulfuric acid (4 ml) is heated at reflux for twelve hours. The solvent is distilled off in vacuo and the residue is diluted with ether. The mixture is neutralized with solid sodium bicarbonate and dried with anhydrous sodium sulphate and filtered. The filtrate is concentrated in vaouo to yield 54 g of the product.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)#[N:22]>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CNc1ccc(CCN)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CNc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1

Procedure:
920 mg of N-[p-(2-aminoethyl)phenyl]glycine methyl ester sulphate were reacted in analogy to Example 3 with 4-cyanobenzoyl chloride to give N-[p-[2-(p-cyanobenzamido) ethyl]phenyl]glycine methyl ester, melting point 161°-162° C. (from toluene).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:11][C@H:10]([NH2:12])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3].[F:19][C:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:2]([N:5]1[CH2:11][C@H:10]([NH:12][C:21](=[O:22])[C:20]([F:19])([CH3:35])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:32])[F:31])=[O:25])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3]
Reactant: CC(F)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C)c2ccccc21
Agent: Cl
Product: CC(=O)N1C[C@H](NC(=O)C(C)(F)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-5-acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and 2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white foam;
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1.[CH2:25]([OH:29])[CH2:26][CH2:27][OH:28].C(N(CC)C(C)C)(C)C>>[Cl-:2].[OH:28][CH2:27][CH2:26][CH2:25][O:29][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1
Reactant: OCCCO
Reactant: Clc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: OCCCOc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Temperature: 120 °C

Procedure:
A 2 mL microwave vial was charged with a magnetic stirring bar, 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (50 mg, 138 μmol), 1,3-propanediol (1 mL), and N,N-diisopropylethylamine (48 μL, 276 μmol). The vial was sealed, and the reaction mixture was magnetically stirred and heated under microwave irradiation to 120° C. for 10 minutes in a microwave reactor to give 4-(3-hydroxypropoxy)-2-morpholino-8-phenylchromenylium chloride (79).
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Cc1cc(O)ccc1C#Cc1ccccc1
Yield: 65 %

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5-(3H,4H)-dione, the product of Example 1A, (1.5 g, 5 mmole) was dissolved in MeOH (50 mL) and water (10 mL). Anhydrous potassium carbonate 7.1 g, 50 mmole) was added and the mixture was heated at reflux for 45 min. The reaction was quenched into ice cold 3N hydrochloric acid and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL) and brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel; 3:1::hexane:EtOAc) to give 0.84 g (65%) of the title compound as a light brown crystalline solid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O>[OH:11][NH:10][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: N=C(NO)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Nicotinonitrile (1 g; 10 mmol) and 1.3 g of hydroxylamine hydrochloride (19 mmol) were dissolved in 15 ml of water. Sodium carbonate (2 g; 24 mmol) in 10 ml of water was continuously added, the resulting solution was stirred and heated at app. 70° C. for 6 hours. Then no more starting material was left (checked by TLC), the reaction mixture was cooled to room temperature, added sodium chloride until saturation and extracted 4 times with 50 ml of ethyl acetate. The organic layer was dried with sodium sulfate and evaporated to a solid. Yield 1 g (76%) of white solid powder.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].[OH-].[K+]>C1COCC1>[C:19]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: c1ccc2c(c1)CNCCS2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-1,4-benzothiazepine (11 g) and triethylamine (13.5 g) were dissolved in THF (300 ml) and acryloyl chloride (9.5 g) was added dropwise thereto under ice cooling and agitated at room temperature for 30 minutes. A 10% potassium hydroxide aqueous solution was added thereto, agitated at room temperature and thereafter extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (60 parts) +ethyl acetate (40 parts) to give 4-acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (12.59).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:16][CH:15]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)cc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a refluxing solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (1.05 g, 6.14 mmol) in ethanol (25 mL) was added an ethanol (10 mL) solution of 4-chloroaniline (0.784 g, 6.14 mmol) by syringe pump over 2 h. The heating bath was removed, and the reaction stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and purified by chromatography oh SiO2 gel, eluting with 50% ethyl acetate in hexane to give the title compound. MS (ESI) m/z 252 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].O[CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:15][C:14](=[CH2:16])[C:13]([O:18][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:17]
Reactant: O=Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Reactant: C=C(C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
Firstly 9.4 ml of triethylamine and then 2.63 ml of methanesulphonyl chloride were added dropwise at −25° C. to a solution of 2.9 ml of methacrylic acid in 30 ml of tetrahydrofuran. Thereafter, the mixture was stirred at −25° C. for 1 hour and then a solution of 9.9 g of trans-4′-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carboxaldehyde and 1.1 g of 4-dimethylamino-pyridine in 50 ml of tetrahydrofuran was added dropwise. Thereafter, the mixture was left to react at 0° C. for 2.5 hours and then at room temperature for 18 hours. Thereupon, the reaction mixture was filtered over Celite, the filtrate was partitioned between ether and water, the ether phase was dried over magnesium sulphate and evaporated. This gave 11.5 g of crude trans-4′-[4-[3-(2-methyl-acryloyloxy)-propyl]-cyclohexyl]-biphenyl-4-carboxaldehyde in solid form.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2cnc(Br)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2cnc(Br)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (5)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate hydrochloride (Intermediate 62, 610 mg, 1.46 mmol, 1 equiv.) in acetonitrile (4 mL) was added 2-chloro-N,N-diethylethanamine hydrochloride (252 mg, 1.46 mmol, 1 equiv.) followed by potassium carbonate (1 g, 7.32 mmol, 5 equiv.). This was stirred in the microwave at 120° C. for 30 min. The reaction was cooled to room temperature and diluted with ethyl acetate. The precipitate was discarded, and the filtrate was concentrated to provide (S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (mg, %).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].C1COCC1.[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
The poorly soluble N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (19.3 mmol, 9.07 g) was dissolved in methanol (150 mL) and THF (20 mL) by gentle heating with a heat gun. To this solution, zinc dust (˜325 mesh, 193 mmol, 12.62 g, 10 equiv.) and ammonium chloride (289.5 mmol, 15.5 g, 15 equiv.) were added followed by water (75 mL) at room temperature. After the addition of water, an exothermic reaction ensued and the temperature rose to 45 to 50° C. The suspension was stirred for 1 h, at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered and the filter cake was washed with methanol (200 mL) and THF (100 mL). The volatiles were removed under vacuum and the organic residue was extracted into ethyl acetate (2×200 mL). The combined extracts were washed brine (250 mL) then were dried (MgSO4), filtered and evaporated to dryness to give 8.37 g (98%) of 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl)-L-phenylalanine methyl ester as a colorless gum which was used directly for next step. HRMS: Obs. mass, 441.1884. Calcd. mass, 441.1882 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][S:11][C:12]2[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([Si:25]([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]2[CH2:49][O:48]2)=[CH:41][CH:40]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>>[Si:25]([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]([OH:48])[CH2:49][NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([S:11][CH2:10][C:7]3[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=3)=[CH:20][CH:19]=2)=[CH:41][CH:40]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1nc(CSc2ccc(CCN)cc2)no1
Product: CC(C)(C)c1nc(CSc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)no1
Yield: 12.9 %

Procedure:
Following the procedure described in Example 14 using the amine of Example 30 (0.481 g, 1.565 mmol) and tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.697 g, 1.721 mmol) afforded 0.140 g of the title compound.