Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=2)[N:12]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:11]=1[C:44]([O:46]CC)=[O:45])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:17]=2)[N:12]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:11]=1[C:44]([OH:46])=[O:45])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(OCCCCN3CCOCC3)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(OCCCCN3CCOCC3)cc12

Procedure:
A mixture of EXAMPLE 149A (36 mg), 1-chloro-4-iodobutane (0.043 ml) and cesium carbonate (116 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature overnight. The inorganic salt was filtered off. To the N,N-dimethylformamide solution was added morpholine (0.2 ml) and the resulting mixture was heated at 60° C. for 5 hours. The reaction mixture was concentrated and the residue was purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 column to give ethyl 3-(2-isopropylphenyl)-5-(4-morpholinobutoxy)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in a mixture of tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.52 (s, 1H), 8.20 (d, J=8.29 Hz, 1H), 7.87 (d, J=7.98 Hz, 1H), 7.59 (d, J=8.90 Hz, 1H), 7.43-7.57 (m, 3H), 7.30-7.43 (m, 3H), 7.14-7.23 (m, 1H), 7.06 (d, J=7.36 Hz, 1H), 6.89 (dd, J=9.05, 2.30 Hz, 1H), 6.85 (d, J=7.67 Hz, 1H), 6.43 (d, J=2.45 Hz, 1H), 4.88 (t, J=7.21 Hz, 2H), 4.15 (t, J=5.83 Hz, 2H), 3.89-4.03 (m, J=11.97 Hz, 2H), 3.75-3.89 (m, 2H), 3.55-3.70 (m, 2H), 3.07-3.17 (m, 2H), 3.02 (s, br, 2H), 2.61-2.78 (m, 2H), 2.23-2.45 (m, 2H), 1.60-1.85 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:12]([OH:14])=O)[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)=O.[NH2:29][CH:30]1[C:58](=[O:59])[N:32]2[C:33]([C:55]([OH:57])=[O:56])=[C:34]([CH:37]([S:49][C:50]3[NH:54][N:53]=[N:52][N:51]=3)[CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:35][S:36][C@H:31]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC(C)=O.O.CN(C)C=O>[F:22][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:12]([NH:29][CH:30]2[C:58](=[O:59])[N:32]3[C:33]([C:55]([OH:57])=[O:56])=[C:34]([CH:37]([S:49][C:50]4[NH:51][N:52]=[N:53][N:54]=4)[CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:35][S:36][C@H:31]23)=[O:14])[N:10]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)C(=NOC1CCCC1)c1csc(NC(=O)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3CCCC3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 76.2 %

Procedure:
2-[2-(2,2,2-Trifluoroacetamido)thiazol-4-yl]-2-cyclopentyloxyiminoacetic acid (syn isomer, 1.5 g.), dry N, N-dimethylformamide (0.4 g.), phosphoryl chloride (0.8 g.), 7-amino-3-[1-(3-tert-butoxycarbonylaminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.0 g.), sodium bicarbonate (1.4 g.), water (12.0 ml.), acetone (12.0 g.), and dry ethyl acetate (0.4 g.) were treated in a similar manner to that of Example 11-(1) to give 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-cyclopentyloxyiminoacetamido]-3-[1-(3-tert-butoxycarbonylaminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.60 g.).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([N:22](CC)[CH2:23]C)C>CN(C)C=O>[N:1]1([C:10]2[N:18]=[C:17]([N:22]([CH3:23])[CH3:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CN(C)C=O
Product: CN(C)c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 90 °C

Procedure:
300 mg of product obtained in stage 1 above are mixed with 3 ml of DMF (dimethylformamide) and 0.17 ml (1.1 equivalents) of TEA (triethylamine). The mixture is heated at 90° C. for 2 hours. The precipitate is filtered off. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-9 mixture for eluent. 298 mg of expected product are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.00 g, 49.93 mmol) and triethylamine (20.88 mL, 149.8 mmol) in CH2Cl2 (100 mL) at 0° C. (ice bath) was treated dropwise with benzyl carbonochloridate (10.54 mL, 74.90 mmol) and stirred at 0° C. After 2 hours, the mixture was diluted with CH2Cl2 (50 mL) and successively washed with ice cold 10% HCl (2×30 mL), water (1×30 mL), saturated NaHCO3 (1×30 mL), and brine (1×30 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 60) eluting with 20% EtOAc/hexane (3 L). The fractions containing the product were pooled, concentrated in vacuo and dried under high vacuum for 18 hours to provide (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate as a solid. LCMS (APCI+) m/z 335 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>CN(C=O)C.CO>[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:41]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCCCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([NH:30][S@@](C(C)(C)C)=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:37][CH3:38].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)([NH2:30])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc([C@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl
Solvent: CO
Product: COc1cc([C@@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
To a solution of (R)-N-((S)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (1.1 g, 2 mmol) in MeOH (50 mL) was added 4N HCl (2.5 mL). The reaction mixture was stirred at room temperature for 20 minutes. The organic solvent was removed under reduced pressure. To the residue was added saturated NaHCO3, and the aqueous portion was extracted with ether. The separated organic portion was dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-60%) over 18 min to give (S)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine as a colorless oil (540 mg, 59% yield). LCMS: RT=1.74 min, [M+H]−17=439.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:26])=[O:25]
Reactant: O=C(CCCCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of benzyl 5-hydroxypentanoate (2.01 g, 9.65 mmol) in anhydrous dichloromethane (30 mL) under nitrogen at −15° C. was added triethylamine (2.7 mL, 19.3 mmol) followed by a solution of methanesulfonyl chloride (1.5 mL, 19.3 mmol) dropwise over 20 minutes. The reaction was stirred at room temperature overnight and then diluted to 75 mL using dichloromethane. The organic layer was washed three times with saturated NaHCO3 and the combined aqueous layers backextracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×1″W; eluted with a gradient of 100% hexanes→10%→20%→25% diethyl ether in hexanes) to afford the product as a pale yellow oil (1.39 g, 50%).
Reaction SMILES: [N:1]#[C:2]Cl.[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5].C([N:14](CC)CC)C>C(O)(C)C>[O-:5][C:2]#[N:1].[O-:8][C:7]#[N:14].[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5]
Reactant: N#CCl
Reactant: CCN(CC)CC
Agent: Oc1cccc(O)c1
Solvent: CC(C)O
Product: N#C[O-]

Procedure:
A solution of 271 g (4.4 mols) of cyanogen chloride in 1.1 liter of isopropanol is introduced at 0° to -5° C. into a 3 liter glass vessel equipped with a stirrer and a thermometer. By means of a metering pump, a solution of 220 g (2 mols) of resorcinol and 420 g (4.04 mols) of triethyl amine in 750 ml of isopropanol is introduced with stirring through an inlet pipe projecting below the surface. The pumping rate is adjusted in such a way that the reaction temperature can be kept at -5° C. to +3° C. On completion of the reaction, the crystalline sludge formed is filtered off under suction from the isopropanol. The filter residue is thoroughly stirred with 1.1 liter of water and filtered off under suction again. The residue thus obtained is then thoroughly washed with water and dried in a stream of air at 25° to 30° C. 276 g (86% of the theoretical) of resorcinol dicyanate are obtained in this way. Mp: 81° C., nD90 :1.4980
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[C:7]([O:17][CH3:18])=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[C:7]([O:17][CH3:18])=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([Cl:25])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Cl)cc1Cc1cccc(Cl)c1F
Temperature: 75 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Under a nitrogen atmosphere, 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid (4.7 g) was dissolved in DMF/toluene solution (25 mL) (DMF concentration: 300 ppm). Thionyl chloride (2.1 g) was added dropwise to this solution at 75° C. After stirring at 75° C. for 1 hr, completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. Toluene (20 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure to give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid chloride (5.07 g). THF (15 mL) was added thereto to give a suspension of acid chloride (5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid chloride) in THF, which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3s2)cc1
Yield: 64.3 %

Procedure:
2-aminothiophenol 9.01 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 13.43 g of product (yield=64.3%).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1.[NH3:19]>CO>[OH:1][CH:2]1[CH:6]([C:7]([NH2:19])=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: N
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1O
Solvent: CO
Product: NC(=O)C1CN(Cc2ccccc2)CC1O
Yield: 22.1 %

Procedure:
A solution of 11.0 g (44.0 mmol) of 3-hydroxy-4-ethyloxycarbonyl-1-phenylmethyl pyrrolidine (prepared according to E. Jaeger and J. H. Biel in J. Org. Chem. 1965, 30, (740) in 40 g of 25% ammonia in methanol was heated at 100° C. under pressure overnight. The solution was cooled and evaporated to dryness. The oily residue was purified by chromatography using dichloromethane-methanol (85:15) to yield 2.14 g (22%) of the title compound. M.P. 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1N1CCC(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 81.3 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-nitropyridine (122 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (118 mg), a yellow solid, in 81% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.Cl[CH:32]([CH2:36][CH3:37])[C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][CH:32]([CH2:36][CH3:37])[C:33]([NH2:35])=[O:34])=[CH:27][C:21]=2[S:20](=[O:29])(=[O:30])[N:19]=1
Reactant: CCC(Cl)C(N)=O
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC(C)C)c1=O)N2)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of the product of Example 321C (20 mg, 0.0467 mmol) in N,N-dimethylformamide (2 mL) was added 2-chlorobutyramide (8.5 mg, 0.070 mmol), tetra-n-butylammonium iodide (1.7 mg, 0.0047 mmol) and cesium carbonate (61 mg, 0.187 mmol). The mixture was stirred at 25° C. for 18 hours, then heated to 80° C. for 3 hours. After cooling to 25° C., 1N aqueous hydrochloric acid (10 mL) was added and the mixture extracted with ethyl acetate (10 mL). The resulting organic layer was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (24 mg, 100%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 512 (M−Na)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (t, J=7.7 Hz, 3H), 1.03 (d, J=6.3 Hz, 6H), 1.83 (m, 3H), 2.50 (m, 1H), 2.75 (m, 1H), 4.46 (m, 1H), 5.94 (m, 1H), 7.08 (m, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.32 (s, 1H), 7.58 (m, 2H), 7.64 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 16.23 (bs, 1H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:7]1[C:15]2[C:10](=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=O)C.[BH4-].[Li+]>O1CCCC1>[CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:5][CH2:4][OH:3])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(C(C)C)cccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cccc2c(CCO)c[nH]c12
Temperature: 90 °C

Procedure:
To a solution of (7-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.97 g. 3.7 mmol) in tetrahydrofuran was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated at 90° C. for 5 hours. It was quenched with 5% HCl, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 2-(7-isopropyl-1H-indol-3-yl)-ethanol. ESI (+) MS m/e=204 (MH+), ESI (−) MS m/e=202 (MH−).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:23])=[O:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Yield: 94 %

Procedure:
10-Oxo-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid (2 g; 6.94 mmoles) is partially dissolved in methanol (20 mL) and is treated with excess diazomethane in ether. The resulting solution is evaporated to dryness, triturated in methanol to yield 1.98 g (94%) of methyl 10-Oxo-8-fluoro-dibenzo [b,f]thiepin-3-carboxylate, m.p. 129°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CCOCC>[CH:13]1([NH:16][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: NC1CC1
Solvent: CCOCC
Product: COC(=O)C=C(CC(=O)OC)NC1CC1
Yield: 83.5 %

Procedure:
This compound was prepared as described in Step A of Example 94: 190.6 g (1.09 mol) of dimethyl acetonedicarboxylate and 75 g (1.3 mol) of cyclopropylamine in 200 ml of ether were reacted affording 194 g of clear oil. Trituration with petroleum ether gave 171.5 g (74%) of the enamine diester as a white solid: mp 64°-70° C. Crystallization from cyclohexane afforded an analytical sample; mp 73°-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(OCC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nccc(OC[C@H]3CC[C@H](N)CC3)c2c1

Procedure:
A solution of tert-butyl [4-(6-methoxy-quinolin-4-yloxymethyl)-cyclohexyl]carbamate (438 mg, 1.13 mmol) and TFA (1.5 ml) in dichloromethane (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice/ammonium hydroxide and extracted with dichloromethane. The organic extracts were dried over Na2SO4 and concentrated.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.BrBr.[NH2:9][C:10]([NH2:12])=[S:11].C(O)C>O1CCOCC1>[NH2:12][C:10]1[S:11][C:3]([CH:2]([CH3:6])[CH3:1])=[CH:4][N:9]=1
Reactant: CC(C)CC=O
Reactant: NC(N)=S
Agent: BrBr
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)c1cnc(N)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
2 ml (18.6 mmol) of 3-methylbutyraldehyde were dissolved in 15 ml of dioxane. 40.4 ml (18.6 mmol) of a solution 2% v/v of bromine in dioxane was dropped therein at 0° C. The mixture was maintained at room temperature under stirring for 2 hours, then 2.83 g (37.2 mmol) of thiourea and 5 ml of ethanol were added. After 6 hours at room temperature the solution was evaporated to dryness, the residue was dissolved in methylene chloride and the product extracted with 1M hydrochloric acid; the aqueous layer was made basic by using 30% ammonium hydrate and extracted again with methylene chloride. The organic phase was dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on a silica gel column, eluting with cyclohexane-ethylacetate to give 1.1 g (42% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]Br)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2ccc(CN3CCN(C)CC3)cc2c1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.2 g, 0.56 mmol) was dissolved in THF (1 ml), to this was added N-methyl piperazine (0.14 g, 1.4 mmol) as a solution in THF (1 ml) and the reaction mixture was stirred for 1 hour. Whereupon LC-MS indicated complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 90% EtOAC, 10% MeOH) to give the title compound (0.17 g, 84% yield) as a light yellow solid.