Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:34])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:34])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Temperature: 70 °C
Yield: 112.1 %

Procedure:
A solution of ethyl 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (10.62 g, 22.42 mmol) and 1 N NaOH (120 mL) in THF (100 mL) and MeOH (100 mL) was heated to 60° C. for 16 hrs. and then the reaction mixture was added 120 ml of 1 N NaOH solution and heated to 70° C. for 8 hrs. The reaction mixture was added 120 ml of 1 N NaOH solution and heated to 70° C. for 8 hrs which was concentrated to remove THF and MeOH. The aqueous layer was acidified with conc. HCl solution until pH about 4 at 0-5° C. The solid was collected to give 4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (11.2 g, 76% yield). HPLC retention time=3.020 min., LC/MS (M+H)+=446.3.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][C@H:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@@H:27]4[CH3:31])[CH2:22]3)=[CH:17][C:16]=2[F:32])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[Li]CCCC>C1COCC1>[F:32][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])[CH2:22]2)[CH:19]=[CH:20][C:15]=1[N:14]1[CH2:13][CH2:12][CH2:11][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:3]1=[O:2]
Reactant: COC(=O)C1(CCCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2F)CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N3CCCC4(CCOCC4)C3=O)c(F)c2)C1
Temperature: 0 °C

Procedure:
4-{3-[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamino]-propyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (40 mg, 0.1 mmol, 1 eq) was dissolved in 2 mL of THF and cooled to 0° C., where a 2.5 M solution of n-BuLi in heptanes (0.11 mL, 0.17 mmol, 3 eq) was added drop-wise and the ice bath was removed. After 30 min the reaction mixture was quenched with water, transferred to a separatory funnel and extracted with diethyl ether (2×50 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (40 g column, 10% MeOH in CH2Cl2; 35 mL/min). This gave 38 mg (98%) of the title compound as an off-white gum.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][C:14]=1[NH:22][C:23](=[O:41])[CH2:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[O:39][CH3:40])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:12])([CH3:11])[CH3:10].S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.C(OC(C)C)(C)C>C(#N)C.C(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][C:14]=1[NH:22][C:23](=[O:41])[CH2:24][CH:25]([C:31]1[CH:36]=[C:35]([Cl:1])[C:34]([O:37][CH3:38])=[CH:33][C:32]=1[O:39][CH3:40])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:10])([CH3:11])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cc(Cl)c(OC)cc1OC
Temperature: 50 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
181 mg (1.36 mmol) of N-chlorosuccinimide were added to a solution of 504 mg (1.11 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Example 2) in a mixture of 10 ml of acetonitrile and 4 ml of methylene chloride, and the resulting mixture was stirred at 50° C. for 15 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature, after which a 1M aqueous solution of sodium sulfite was added to decompose any excess of the reagent. The mixture was then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, after which it was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using ethyl acetate as the eluent, to give 434 mg (yield 80%) of the title compound as crystals, melting at 161.5-163.5° C. (from ethyl acetate-isopropyl ether).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])=[O:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C=O)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6.5 h

Procedure:
To 3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (2.05 g), toluene (20 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.70 mL) were added, and then the mixture was stirred at 60° C. for 6.5 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (2.42 g) as a brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C=O.[C:35](O)(=O)C.[BH3-]C#N.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:35])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.N.[Na].[Cl-].[NH4+]>C(O)C>[OH:8][CH2:7][C:6]1[CH2:5][CH:4]=[C:3]([O:2][CH3:1])[CH2:10][CH:9]=1
Reactant: COc1ccc(CO)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC1=CCC(CO)=CC1
Reaction time: 2 h

Procedure:
Using the method of Birch, J. Proc. Roy. Soc. New South Wales, 83, 245 (1949), 27.6 g of 4-methoxybenzyl alcohol in 93 ml of dry ethanol was added to 600 ml of liquid ammonia and reduced with 23 g of sodium added in pieces. After 2 hrs stirring, the excess sodium was discharged by cautiously adding 60 g of ammonium chloride. The ammonia was allowed to evaporate, water was added to the residue, and the product was extracted with dichloromethane. The extracts, dried and evaporated, afforded 12.1 g, bp 72°-74° (0.1 mm), identified by nmr.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]=[N:7][NH:8][C:9]=1[SH:10])(=[O:4])[NH2:3].CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O>>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:10][C:9]3[NH:8][N:7]=[N:6][C:5]=3[C:2](=[O:4])[NH2:3])[CH2:25][S:24][C@H:19]12
Reactant: NC(=O)c1nn[nH]c1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na]
Product: NC(=O)c1nn[nH]c1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Reaction of 4-carbamoyl-1,2,3-triazole-5-thiol sodium salt and 7-aminocephalosporanic acid as described hereinabove gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([CH2:15][CH2:16][OH:17])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[Si:28]([O:17][CH2:16][CH2:15][C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C:12]([OH:14])=[O:13])([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: Cc1c(N[C@H](CCO)C(=O)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O)ccc(C#N)c1Cl
Temperature: 0 °C

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar and a septum was added (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-4-hydroxybutanoic acid (1.49 g, 5.55 mmol). This was dissolved in dry DMF (68 mL) under an atmosphere of nitrogen. This mixture was cooled to 0° C. followed by addition of imidazole (3.02 g, 44.36 mmol) and TBDMSCl (4.18 g, 27.75 mmol). The reaction was allowed to slowly warm to room temperature overnight quenched by slow addition of aqueous ammonium chloride (sat) (60 mL). The solution was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with (5%) aqueous citric acid (100 mL) (×2), water (80 mL) then dried over Na2SO4, filtered, and concentrated under reduced pressure to reveal a yellow oil (4.2 g). This material was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1B(O)O.C(C1C=CC(B(O)O)=CC=1)(O)=O.Br[C:26]1[CH:27]=[C:28]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1>>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:30]2[CH:31]=[CH:26][CH:27]=[C:28]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)[CH:29]=2)[CH:5]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Brc1cccc(-c2nnn[nH]2)c1
Agent: O=C(O)c1ccc(B(O)O)cc1
Product: COc1ccc(Cl)cc1-c1cccc(-c2nnn[nH]2)c1

Procedure:
Following the procedure of Example 1b), except substituting 2-methoxy-5-chlorophenylboronic acid; for 4-carboxyphenylboronic acid;, and substituting 5-(3-bromophenyl)-1H-tetrazole for the compound of 1a), the title compound was prepared (1.36 g; 100%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 8.16(s, 1H), 8.05(d, J=7.6 Hz, 1H), 7.7(d, J=6.6 Hz, 1H), 7.67(t, J=7.7 Hz, 1H), 7.48(m, 2H), 7.2(d, J=9.1 Hz, 1H), 3.8(s, 3H), MS(ES) m/z 287 [M+H]. b) 5-(5′-chloro-2′-hydroxybiphenyl-3-yl)-1H-tetrazole
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[C:20]=2[CH:21]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(F)cc12
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1ccc(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (87%): mp 224-226° C.; 1H NMR (300 MHz, DMSO-d6) δ10.65 (s, 1H), 7.23 (ddd, J=7.7, 7.7, 0.9 Hz, 1H), 7.09 (d, J=7.0 Hz, 1H), 7.06-6.87 (m, 4H), 6.58 (dd, J=8.0, 2.7 Hz, 1H), 4.80 (d, J=9.3 Hz, 1H), 4.67 (d, J=9.3 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 178.2, 158.9, 157.1, 142.3, 132.4, 131.3, 131.1, 129.5, 124.3, 122.8, 116.5, 116.2, 111.0, 110.9, 110.7, 110.4, 80.2, 58.4; MS (ES+) m/z 260.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16]N=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](OC(N1CCN(C2C=CC(Br)=CN=2)CC1)=O)(C)(C)C.FC1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:27]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: OB(O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Yield: 99 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)-pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromo-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.151 g) and 4-fluorophenylboronic acid (0.068 g), to give the title compound as a white solid (0.155 g, 99%).
Reaction SMILES: [Na].C1C2C(=CC=CC=2)C=CC=1.[OH:12][CH:13]([CH2:32][OH:33])[CH2:14][N:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)S(C1C=CC(C)=CC=1)(=O)=O.Cl>COCCOC.O>[C:26]1([NH:15][CH2:14][CH:13]([OH:12])[CH2:32][OH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(O)CO)c2ccccc2)cc1
Agent: Cl
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: O
Solvent: COCCOC
Product: OCC(O)CNc1ccccc1
Yield: 83.4 %

Procedure:
250 Grams of 40% sodium dispersion in mineral oil was added to a solution of 600 g of naphthalene in 1.8 l of 1,2-dimethoxyethane ("Glyme") stirred under nitrogen and maintained at a temperature between 20° to 30° C. After all the sodium was added, the mixture was stirred 20 minutes, and then 305 g of N-(2,3-dihydroxypropyl)-4-methyl-N-phenylbenzenesulfonamide was added through a powder addition funnel while maintaining the temperature of the reaction mixture below 35° C. After all of the solid was added, the mixture was stirred one hour. Water was then added until the color of the mixture faded from dark green or black to yellow; then concentrated hydrochloric acid was added until the solution was strongly acidic. The mixture was extracted twice with toluene and then three times with hexane, was sparged with nitrogen to remove the hexane, saturated with sodium chloride and then made basic with concentrated ammonium hydroxide. The product was extracted with dichloromethane, and the extract was dried over potassium carbonate. The filtered dichloromethane was concentrated to yield 132.3 g of 3-phenylamino-1,2-propanediol, a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCOCC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Morpholine (0.04 ml; 0.46 mmol; 1.40 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (13) is obtained as white-off solid (15 mg; 19%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.46 (s, 3H), 2.96 (m, 4H), 3.67 (m, 4H), 7.33 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.35 (s, 1H). M−(ESI): 386.17; M+(ESI): 388.46. HPLC, Rt: 3.21 min (purity: 99.7%).
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])C(=O)[O-])(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1cccnc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccnc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 20 h
Yield: 68.4 %

Procedure:
To a solution of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(3-pyridinylmethyl)ethyl]carbamate (796.7 mg, 2.1 mmol) in DCM (10 mL) at RT was added 1M HCl in dioxane (10 mL). After 20 h, the solution was concentrated affording the title compound (404 mg, 68%) as the HCl salt: LCMS (ES) m/z 282 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](O)=[O:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[NH2:41][C@H:42]([C:49]([NH:51][C@H:52]([CH:57]=[N:58][NH:59][C:60]([NH2:62])=[O:61])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][NH:12][C:13]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([CH:57]=[N:58][NH:59][C:60]([NH2:62])=[O:61])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:43][C:44]2[N:48]=[CH:47][NH:46][CH:45]=2)=[O:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NCc1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.6 %

Procedure:
A mixture of 102 mg of (±)-2-(1-naphthylmethylcarbamoyl)-3-phenylpropionic acid and 50 mg of 1,1'-carbonyldiimidazole was added to 5 ml of dichloromethane, and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was added to a solution of 202 mg of L-histidyl-L-leucinal semicarbazone.2p-toluenesulfonic acid salt and 0.09 ml of triethylamine in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 24 mg of N-[(±)-2-(1-naphthylmethylcarbamoyl)-3-phenylpropionyl]-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].[CH2:33](Br)[C:34]#[CH:35]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:35][C:34]#[CH:33])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C#CCN(C(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccnc(CC)c1Cl
Temperature: 25 °C

Procedure:
1.0 g (2.3 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of N,N-dimethylacetamide, and the solution was stirred at room temperature. Then, 0.067 g (2.8 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 10.3 (2.5 mmol) of propargyl bromide was added thereto, and the mixture was stirred for one hour at room temperature. Then, 0.3 g (2.5 mmol) of propargyl bromide was further added thereto, and the mixture was stirred for one hour at a temperature of from 50° to 60° C. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then purified by high performance liquid chromatography to obtain 0.5 g of the desired product as a brown viscous substance (refractive index nD20 =1.35619).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:8][C:9]=1[OH:10])[CH:6]=O.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>O>[OH:10][C:9]1[CH:8]=[C:5]2[C:4](=[CH:3][C:2]=1[OH:1])[O:11][C:18](=[O:19])[C:17]([C:15]([OH:16])=[O:14])=[CH:6]2
Reactant: O=Cc1cc(O)c(O)cc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
4,5-dihydroxy-salicylaldehyde (213.0 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 271.0 mg of 6,7-dihydroxy-3-carboxy-coumarin in an 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:22]3[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C@@H:21]3[N:13]3[CH2:14][C:15](=O)[N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23.B.C1COCC1.CC1C=CC=CC=1C.C=CCCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C@@H:22]3[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C@@H:21]3[N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17]([CH:18]=1)=[C:12]23
Reactant: CN1C(=O)CN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]12
Agent: B
Solvent: C=CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: CN1CCN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]12
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a solution of tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (100 mg, 0.21 mmol) in THF (5.0 mL), BH3-THF (1M in THF) (0.82 mL, 0.82 mmol) was added dropwise. After addition was completed, the resulting reaction mixture was refluxed for 4 h, cooled to room temperature, and quenched cautiously with water (1.0 mL). The mixture was evaporated to dryness under reduced pressure and the residue obtained was treated with o-xylene (10 mL) and 1-octene (5 mL) and heated at reflux for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to give tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a white solid (50 mg, 58%).