Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:28][CH3:29])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26]O[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:31]([CH:33]=O)C>CO>[C:2]1([S:8]([C:11]2[C:12]([S:28][CH3:29])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:31]([CH3:33])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CSc1nn2c(Cl)cc(CN3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.9 g (2 mmol) of 3-benzenesulphonyl-7-chloro-2-methylsulphanyl-5-morpholin-4-ylmethyl-pyrazolo[1,5-a]pyrimidine in 20 DMF and stirred at RT for 4 hrs. The DMF was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH/NH4OH 80:10:1) and crystallization from EtOH yielded 0.70 g (83%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 224-226°.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH3:22])[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:29]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:29])=[N:4][CH:5]=1)[CH2:21][CH3:22]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(C)ns2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2cc(C)ns2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (106 mg, 0.334 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (38 mg). MS found for C13H17N7O2S as (M+H)+ MS 336.2; UV 206.0, 275.0, 323.1 nm; t 0.365 min. 1H NMR: (CD3OD) δ 7.70 (s, 1H), 6.88 (s, 1H), 4.65 (br.s, 1H), 2.45 (s, 3H), 2.18-2.05 (m, 1H), 1.96-1.87 (m, 1H), 1.10 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl.O>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCCC1
Reaction time: 24 h

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (1.90 g, 5.60 mmol) in CHCl3 (43 mL) was added m-chloroperoxybenzoic acid (m-CPBA, 77% w/w, 1.26 g, 5.60 mmol) over 15 min. The reaction was monitored by thin layer chromatography (TLC) and more m-CPBA was added over 1 h until the starting material was consumed. Water (40 mL) and solid K2CO3 were added to the reaction mixture until the pH=10. The mixture was poured into a separatory funnel and extracted with chloroform, resulting in an emulsion. The aqueous layer was extracted with chloroform three times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated to yield a crude white solid (1.51 g). The white solid (1.51 g, 4.24 mmol) was dissolved in dichloromethane (25 mL) at rt and concentrated ammonium hydroxide (16 mL) was added, followed by p-toluenesulfonyl chloride (TsCl, 0.81 g, 4.24 mmol). The mixture was stirred 1 day (d). Water (25 mL) was added and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (25 mL) and were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 98:1:1 CH2Cl2/MeOH/NH4OH to 94:5:1 CH2Cl2/MeOH/NH4OH) then crystallized from acetonitrile to yield 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as pale orange crystals that were dried under high vacuum (0.32 g, 16% over two steps), mp 186-188° C. 1H NMR (300 MHz, CDCl3) δ 8.15 (dm, J=8.4 Hz, 1H), 7.81 (dm, J=8.4 Hz, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 5.38 (br s, 2H), 4.90 (br s, 2H), 4.74 (br s, 2H), 3.66 (q, J=7.0 Hz, 2H), 3.00 (s, 1H), 1.71-1.52 (m, 10), 1.25 (t, J=7.0 Hz, 3H). MS (APCI) m/z 355 (M+H+). Anal. calcd for C20H26O2N4: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.52; H, 7.57; N, 15.78
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([C:20](=[O:26])[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of naphthalen-2-amine (2 g, 14.0 mmol) in dichloromethane (30 ml) was added triethylamine (4.24 g, 41.9 mmol, 3 eq). Then, ethyl 2-chloro-2-oxoacetate (1.92 g, 14.1 mmol, 1 eq) was added dropwise to the solution kept at 0-5° C. using an ice-bath. The resulting solution was allowed to warm to room temperature while stirring. The reaction was then quenched by the addition of water (50 ml), the product was extracted with dichloromethane (2×50 ml), and the organic layers were combined. The organic solution was washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford ethyl[(naphthalen-2-yl)carbamoyl]formate as a black solid (3 g, 88%). (ES, m/z) [M+H]+ 244; 1H NMR (300 MHz, CDCl3): δ 9.06 (broad s, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.72-7.88 (m, 3H), 7.59 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.53 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.IC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: O=C(O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(I)cc1

Procedure:
6.12 g of 4-iodobenzoyl chloride—prepared by reacting 4-iodobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: C[N+](CC(O)=O)(C)C.[CH3:9][N+:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[C:12](O)[N:11]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl-:16].[CH3:9][N+:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[C:12]([Cl:21])[N:11]=1
Reactant: C[n+]1cc(Cl)c(Cl)c(O)n1
Reactant: O=S(Cl)Cl
Agent: C[N+](C)(C)CC(=O)O
Solvent: CN(C)C=O
Product: C[n+]1cc(Cl)c(Cl)c(Cl)n1
Product: [Cl-]
Yield: 72.7 %

Procedure:
10 parts of the betaine of 1-methyl-3-hydroxy-4,5-dichloropyridazinium salt: ##STR81## is boiled in 100 parts of thionyl chloride for two hours with an addition of 1 part of dimethylformamide. 9.5 parts (72.7% of theory) of 1-methyl-3,4,5-trichloropyridazinium chloride is obtained; C5H4N2Cl4, washed with acetonitrile.
Reaction SMILES: O.C(NC1CC(=O)[N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])N=1)(=O)C>C(O)C>[Cl:18][C:17]1[CH:16]=[C:15]([Cl:19])[CH:14]=[C:13]([Cl:20])[C:12]=1[NH2:8]
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)cc(Cl)cc1Cl
Yield: 57 %

Procedure:
The procedure was repeated using a mixture of 20% water and 80% ethanol as the solvent instead of the anhydrous ethanol used above. This time the yield of 3-acetamido-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one was very poor, i.e., only 8%, while a 57% yield of 2,4,6-trichloroaniline was obtained. This illustrates that, in contrast to the excellent yields produced in an organic medium, very poor yields are obtained when the rearrangement is run in an aqueous medium.
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[CH2:11]([N:18]1[CH2:22][CH2:21][C:20](=[CH2:23])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C(N(CC)CC)C>O>[CH2:11]([N:18]1[CH2:22][CH2:21][C:20]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C1CCN(Cc2ccccc2)C1
Reactant: ON=CC1(Cl)C=CC=CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC3(CC(c4ccccc4)=NO3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound C (3.9 g, 25.2 mmol, dissolved in abs. DCM (25 ml)) was added dropwise to a solution of 1-benzyl-3-methylenepyrrolidine (P) (2.18 g, 12.6 mmol) in abs. DCM (25 ml) at 0° C. within 10 min. A solution of triethylamine (14 ml, 10.2 g, 100.1 mmol) in abs. DCM (25 ml) was added to this mixture at 0° C. within 10 min. As the reaction was highly exothermic, cooling was carried out in an ice/sodium chloride mixture. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (50 ml) and water (70 ml) were added. The phases were separated. The aqueous solution was extracted with DCM (2×20 ml). The combined organic phases were washed successively with water (50 ml) and sat. NaCl solution (50 ml) and then dried and concentrated (5.3 g, yellow oil). The residue was purified by column chromatography [silica gel 60 (500 g); EtOAc/cyclohexane 1:2 (3 l)]. The desired compound Q was obtained as a solid in a yield of (2.4 g, 65%) having a melting point of 31-40° C.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17].[OH-].[K+]>CN(C=O)C>[CH3:1][N:8]1[C:4]([CH3:3])=[C:5]([CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[N:6]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CI
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC(C)(C)[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c(CC(C)(C)[N+](=O)[O-])nc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
Methyliodide (1.4 g) was added dropwise to a stirred mixture of 5-methyl-4-(2-methyl-2-nitro-propyl)-2-phenyl-1H-imidazole (2.0 g) and fine powdered potassium hydroxide (2.0 g) in DMF (30 ml) at 10-20° C. The reaction mixture was stirred at RT for 2 h, quenched with ice/water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The residue was purified on silica gel using methylene chloride/methanol 2 and 5% as eluent, to obtain the desired product (0.98 g) as a light yellow amorphous compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][OH:18])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].CCN(CC)CC.CNC1C=CC=C(NC)N=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2C(CO)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: CNc1cccc(NC)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
Combine [6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-yl]-methanol (1.45 g, 3.81 mmol), TosCl (0.80 g, 4.19 mmol), Et3N (1.2 mL, 8.38 mmol), 2,6-dimethylaminopyridine (140.0 mg, 1.14 mmol), and methylene chloride (30 mL), and stir under nitrogen atmosphere at room temperature. After 18 hours, concentrate reaction under vacuum and add ethyl acetate. Wash with water and then brine. Dry the organic phase with anhydrous sodium sulfate and concentrate to yield the titled compound (1.83 g, 95%) as a yellowish-white solid. TLC Rf=0.30 in 2:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.53 (d, 2H, J=8.4 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.06 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=2.2 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.66 (dd, 1H, J=8.8, 2.6 Hz), 4.34 (dd, 1H, J=9.7, 2.6 Hz), 4.03 (dd, 1H, J=9.7, 4.0 Hz), 3.85 (s, 6H), 3.48 (d, 1H, J=11.9 Hz), 3.20 (s, 1H), 3.09 (dd, 1H, J=12.1, 3.3 Hz), 2.46 (s, 3H), 1.89 (m, 1H), 1.61 (m, 3H), 1.41 (d, 2H, J=9.7 Hz), 1.14 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.O.[NH2:12][NH2:13]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:12][NH2:13])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: NN
Reactant: COc1ncc(Br)nc1Br
Solvent: CCO
Solvent: O
Product: COc1ncc(Br)nc1NN
Temperature: 80 °C

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromo-2-methoxypyrazine (0.50 g, 1.9 mmol), hydrazine hydrate (0.47 g, 9.4 mmol) and ethanol (5 mL). The resulting mixture was heated at 80° C. for 4 h. TLC indicated a complete conversion. Work-up: the reaction solution was concentrated in vacuo, to afford 0.5 g (crude) of the product as a brown solid, which was used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
TBTU (69 mg, 0.22 mmol) was added to a stirred solution of racemic 14b (60 mg, 0.0.144 mmol), morpholine (19 μL, 0.22 mmol), and N,N-diisopropylethylamine (300 μL, 1.7 mmol) in DMF (3 mL). The mixture was shaken at 22° C. for 18 hr. The resulting solution was injected on a Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave methyl 13-cyclohexyl-6,7-dihydro-6-(morpholinylcarbonyl)-5H-indolo[2,1-a][2]benzazepine-10-carboxylate as a colorless solid (60 mg, 86%). ESI-MS m/z 487 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>CO>[OH:9][C:10]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O-:14])=[O:13].[CH2:1]([NH3+:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(O)c1O
Reactant: NCc1ccccc1
Solvent: CO
Product: O=C([O-])c1cccc(O)c1O
Product: [NH3+]Cc1ccccc1

Procedure:
Benzylamine (1.07 g; 10 mmol) was added dropwise to a solution of 2,3-dihydroxybenzoic acid (1.54 g; 10 mmol) in methanol (10 cm3). An off-white solid formed almost immediately. The product was collected by filtration and recrystallized from water to produce white crystals. Found: C, 62.0%; H, 5.8%; N, 5.1%. Calculated for C14H15NO4 ; C, 64.30%; H, 5.74%; N, 5.36%. M.pt. 169°-170° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: OCCOCCOCCCl
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCOCCOCCO)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (6.70 g, 26.4 mmol) in N,N-dimethylformamide (100 ml) was added 2-(2-(2-chloroethoxy)ethoxy)ethanol (4.0 ml, 28 mmol) and cesium carbonate (8.06 g, 24.7 mmol). The suspension was heated to 70° C. for 17 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (3.32 g, 8.61 mmol, 33%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 6H), 1.95-1.99 (m, 2H), 2.51-2.56 (m, 3H), 2.71 (t, J=5.6 Hz, 2H), 3.55-3.79 (m, 10H), 4.85 (s, 1H), 5.05 (s, 2H), 7.2-7.4 (m, 5H); LRMS (ESI/APCI) m/z 386 [M+H]+, 408 [M+Na]+.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)(=O)[CH3:2].[CH3:25]C(O)=O.Cl.[Cl:30][C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1>COC(OC)N(C)C>[Cl:30][C:31]1[CH:32]=[C:33]([N:37]2[C:1]([C:4]3[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)=[CH:15][C:14]=4[F:24])[N:5]=3)=[CH:2][CH:25]=[N:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)O
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Reactant: NNc1cccc(Cl)c1
Agent: COC(OC)N(C)C
Agent: Cl
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2cccc(Cl)c2)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A suspension of 3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (393 mg, 1.20 mmol) in N,N-dimethylformamide dimethyl acetal (4.0 mL) was stirred at 100° C. for 1 h. The reaction mixture was concentrated in vacuo. To the residue were added AcOH (4 mL) and 3-chlorophenylhydrazine hydrochloride (429 mg, 2.40 mmol). The mixture was stirred at 100° C. for 1 h. After solvent evaporated, the residue was diluted with saturated NaHCO3 aqueous solution (25 mL) and extracted with AcOEt (25 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was crystallized from AcOEt to give a coarse solid, which was recrystallized from EtOH/hexane to give the title compound (242 mg, 44% yield) as an orange solid: mp 186-190° C.; NMR (300 MHz, DMSO-d6): δ ppm 3.80 (3H, s), 6.64 (1H, d, J=1.9 Hz), 7.05 (1H, d, J=1.9 Hz), 7.27-7.34 (1H, m), 7.44 (3H, dd, J=16.6, 10.2 Hz), 7.34-7.52 (1H, m), 7.84 (3H, dd, J=3.6, 1.7 Hz), 8.00 (1H, dd, J=12.3, 2.1 Hz), 8.56 (1H, d, J=1.9 Hz), 8.67 (1H, d, J=2.6 Hz): LC-MS (ESI) m/z 463 [M+H]+. Anal. Calcd for C23H16ClFN6O2.0.03H2O: C, 59.61; H, 3.49; N, 18.14. Found: C, 59.32; H, 3.50; N, 17.92.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[C:31]=2[F:38])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:39][CH:40]([CH:44]([CH3:46])[CH3:45])[C:41](O)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:39][CH:40]([CH:44]([CH3:46])[CH3:45])[C:41]([O:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=2)=[C:31]([F:38])[C:32]=1[F:37])=[O:42]
Reactant: CC(C)C(Cl)C(=O)O
Reactant: CCCCCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(OC(=O)C(Cl)C(C)C)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 0.1 mol of DCC in methylene chloride is added to a mixture of 0.1 mol of 4'-heptyloxy-2,3-difluorobiphenyl-4-ol, 0.1 mol of optically active 2-chloro-3-methylbutyric acid (prepared from valine) and a catalytic amount of DMAP in 250 ml of methylene chloride at 0° C. The mixture is then stirred at room temperature for 12 hours, the precipitate is subsequently filtered off with suction and the filtrate is worked up in the customary manner to give 4-(p-heptyloxyphenyl)-2,3-difluorophenyl 2-chloro-3-methylbutyrate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([OH:23])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C>[OH:23][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[CH:13]=[N:14][NH:15][C:3]=23)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1ccc(O)cc1
Yield: 54.5 %

Procedure:
Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (1.0 g, 0.004 mole) and p-aminophenol (1.0 g, 0.009 mole) were stirred together in ethyl acetate (200 ml) under nitrogen for 48 hours, the temperature being maintained between -10° and -5° C. The ethyl acetate was removed under reduced pressure to give a yellow solid. This solid was dissolved in aqueous ethanol and the pH adjusted to pH8 with 10% sodium carbonate solution. The resulting solid was filtered off washed with water and dried. Recrystallization from methanol/ethyl acetate gave the title compound as a pale yellow solid (650 mg, 50%), m.p. 286°-287° C. (decomposition)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2.4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)amide as a yellow solid (57.3 mg, 47%).