Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H:13]([C:17]2[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C(Cl)Cl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C@@H:13]([C:17]2[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alaninate (slower-eluting diastereomer, 10 mg, 0.018 mmol) in ethanol (2 mL) was added LiOH (2.0 N in water, 0.5 mL, 1.0 mmol), then the reaction mixture was stirred for one hour. The mixture was diluted with DCM (20 mL) acidified with 2.0 N HCl (aq). The organic layer was dried over MgSO4, concentrated, then the residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound. 1H NMR (499 MHz, CDCl3): δ 8.27 (d, J=8.5 Hz, 1H); 8.13 (d, J=8.2 Hz, 1H); 7.67-7.49 (m, 5H); 7.20 (m, 3H); 6.95 (dd, J=8.3, 2.5 Hz, 2H); 6.76 (m, 1H); 6.51 (d, J=8.3 Hz, 2H); 4.86 (d, J=11.3 Hz, 1H); 3.76 (m, 2H); 3.60 (s, 3H); 3.58 (m, 1H); 2.65 (t, J=5.8 Hz, 2H); 1.70 (m, 2H); 1.07 (m, 2H); 0.76 (t, J=7.2 Hz, 3H). LC1 1.19 min. [M+]+ 514.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C@@H:36](O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To an argon-flushed flask containing a solution of 3.01 g (15 mmol) of p-benzyloxy-phenol and 1.25 eq of triphenylphosphine in 220 ml in dry dichloromethane, was added a solution of 4.91 g (15.14 mmol) of (R)-2-octanol in 30 ml of dry dichloromethane via syringe. Then 1.20 eq of diethyl azodicarboxylate dissolved in 60 ml of dry dichloromethane was added dropwise for 30 min. The reaction mixture was stirred at room temperature for 19 h, Then 5 drops of water were added and the mixture was stirred for 1 h. The solvent was then evaporated and the residual crude product was triturated in a mixture of hexanes/ethyl acetate [70/30] for 1 h and filtered through a short silica gel pad. The filtrate was evaporated and the product was purified by flash chromatography on silica gel using dichloromethane/hexanes [10/90] as eluent, affording 3.32 g (71%) of (S)-p-Benzyloxy-(1-methylheptyloxy)benzene (Compound 18, Scheme III, R2 =(S)-OCH(CH3)C6H13) as a colorless liquid: Rf [dichloromethane/hexanes 10/90]: 0.13; 1H NMR (300 MHz, CDCl3): δ 0.87(t, 3H, J=6.6 Hz), 1.20-1.60(m, 12H), 1.70(m, 1H), 4.21(m, 1H), 5.00(s, 2H), Distorted AA'BB' System [6.82(d, 2H) 6.88(d, 2H)], 7.30-7.46(m, 5H); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.77, 22.55, 25.52, 29.26, 31.77, 36.51, 70.63, 74.95, 115.77, 117.35, 127.49, 127.87, 128.55, 137.39, 152.53, 153.01; IR (CHCl3): 3010, 2940, 2850, 1600, 1500, 1475, 1450, 1375, 1230, 1200, 1125, 1025, 925, 825 cm-1 ; Mass spectrum, m/z (rel.Intensity): 312(M+ 7), 212(15), 91(100), 71(5), 57(8), 43(10).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2Cl)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
80.0 g (0.403 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 221.3 g (0.399 mol, 23% strength) of toluenic 2-chloroaniline solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 20° C. with a ramp of 10° C./h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 105 g (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:13])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[C@@H:26]([CH:27]=[O:28])[CH2:25][O:24][C@@H:23]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[C@@H:26]([C@@H:27]([OH:28])[C@@H:9]([N+:10]([O-:12])=[O:11])[CH2:8][C:6]2[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:25][O:24][C@@H:23]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Reactant: O=[N+]([O-])CCc1cc(F)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(Cl)c2)[N+](=O)[O-])CO1
Yield: 58.9 %

Procedure:
Add 1-chloro-3-fluoro-5-(2-nitroethyl)-benzene (0.343 g, 1.68 mmol) in dry tetrahydrofuran (2 mL) to a solution of (2R,5R)-2-(2,2-dimethylpropoxy)-5-formylmorpholine-4-carboxylic acid tert-butyl ester (0.462 g, 1.53 mmol) in tetrahydrofuran (7 mL). Add tetrabutylammonium fluoride (0.77 mL, 0.765 mmol, 1.0 M in tetrahydrofuran) and stir at room temperature for 1 hour. Dilute with ethyl acetate and wash with saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 2:98 ethyl acetate:dichloromethane) to give the desired compound as a white foam (0.455 g, 59%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=1>O1CCCC1>[C:14]1([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[O:7][C:5]([C@H:4]2[C@H:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[O:29]2)=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2O[C@H]2C(=O)O[C@@H]2CCCC[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A 5.0-L three-necked flask equipped with a stirrer, a gas bubbler, a thermometer, an addition funnel and condenser was charged with 100 g (3.33 mole) of NaH (80% in mineral oil), and triturated with 3×500 mL=1.5 L of hexane. Each portion of hexane was decanted when the NaH had settled. Under an argon atmosphere, 1.5 L of tetrahydrofuran was added followed by a solution of 568 g (2.247 mole) of (-)-(1R,2S)-2-phenylcyclohexyl chloroacetate, 352 g (2.589 mole) of anisaldehyde and 250 mL of tetrahydrofuran over 0.5 hour via addition funnel. A vigorous evolution of H2 gas ensued along with an exotherm to about 55°. After the initial reaction subsided, the mixture was then stirred under argon at ambient temperature overnight. The mixture was heated at 55-60° for 1 hour and then quenched into 8.0 L of ice water. The pH was adjusted to 7 with 390 mL of 3N H2SO4 and the resulting mixture was extracted first with 4 L followed by 2×2 L for a total of 8.0 L of methylene chloride. The combined organic layers were dried (Na2SO4) and evaporated in vacuo to an oily, partially solid residue which on crystallization from 0.5 L of (9:1) hexanes-ethyl acetate afforded colorless needles. These crystals were collected by filtration, washed with 2×200 mL=400 mL of 9:1 hexanes-ethyl acetate followed by 2×500 mL=1.0 L of cold hexanes and finally dried in vacuo to afford 403 g (51%) of the title compound, m.p. 146-148° C., [α]D20 =-146°(c=1; CHC13).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1F)#[N:2].O.[NH2:14][NH2:15]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: N#Cc1ccc(C(=O)O)cc1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 110 °C
Yield: 26.3 %

Procedure:
To a solution of 4-cyano-3-fluorobenzoic acid (500 mg, 3.0 mmol) in n-butanol (9 mL) was added hydrazine monohydrate (0.5 mL, 10 mmol). The reaction was heated to 110° C. overnight. The reaction was cooled to room temperature and the precipitate was collected by filtration. The solid was then dissolved in 1 N aqueous sodium hydroxide (2 mL) and extracted with ethyl acetate (2×). The aqueous layer was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (140 mg, 26%) as a red solid. +ESI (M+H) 178.2; 1H NMR (400 MHz, CD3OD, δ): 7.99-8.01 (m, 1H), 7.73 (dd, J=8.4, 0.8 Hz, 1H), 7.61 (dd, J=8.5, 1.3 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NCC1CCCCC1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (11.6 mg, 38%) having the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=O)[CH:12]=[O:13]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=CC(=O)O
Solvent: CCO
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Yield: 90.4 %

Procedure:
4,5-Dichloro-1,2-phenylenediamine (25 g, 141.2 mmol) was suspended in 780 ml EtOH, and 13 g (142.0 mmol) of glyoxylic acid (HO2CCOH/H2O) was added. The mixture was heated at reflux for 3 hours, and then cooled and filtered, yielding 27.45 g of 6,7-dichloroquinoxalin-2-one as a solid. The product (25 g, 116.3 mmol) and 230 ml (911.7 mmol) of phosphorous oxychloride (POCl3) were stirred at reflux (100° C.) for 3 hours. The mixture was cooled and ice/H2O added. The resulting brown/grey solid was filtered, and dried in an oven, yielding approximately 25 g of 2,6,7-trichloroquinoxaline.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: CCCCS
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CCCCSc1cc(C)cc(C)c1
Yield: 94.7 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 1-butanethiol (107 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the n-butyl 3,5-dimethylphenyl sulfide (184 mg, 95% yield) as colorless oil. Column chromatographic solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.77 (s, 1 H), 2.89 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.41-1.65 (m, 4 H), 0.92 (t, 3 H, J=7.5 Hz). 13C NMR (CDCl3, 75 MHz) δ 138.5, 136.7, 127.7, 126.6, 33.5, 31.6, 22.4, 21.7, 14.1. IR (neat, cm−1) 3083, 3050, 3011, 2965, 2867. MS (EI) m/z (relative intensity) 194 (70), 138 (100). Anal Cald for C12H18S, Cald. C, 74.16; H, 9.34. Found C, 73.89; H, 9.32.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[CH3:18][S-:19].[Na+]>>[CH3:18][S:19][CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCl
Reactant: C[S-]
Agent: [Na+]
Product: CSCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 78.9 %

Procedure:
Using the general method of Example 21 Part D, N-(2-chloroethyl)-3-nitroquinolin-4-amine (6.0 g, 23.84 mmol) was reacted with sodium thiomethoxide (2.11 g of 95%, 28.61 mmol) to provide 4.95 g of N-[2-(methylthio)ethyl]-3-nitroquinolin-4-amine as a dull yellow solid.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23](OC(C)(C)C)=O)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1>>[CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:38][C:39]3[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCCCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (77d) (16.3 mg, 0.038 mmol), sodium carbonate (40 mg, 0.38 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (1f) (13.2 mg, 0.046 mmol), to obtain 15.5 mg of the title compound (76%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[CH:5][CH:4]=1.C(O[CH:21](OCC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12
Temperature: 60 °C
Yield: 56.7 %

Procedure:
28% aqueous HCl (0.3 mL, 2.26 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(2-cyclopentyl-ethyl)-hydrazine (0.54 g, 2.26 mmol) in ethanol (2.5 mL) and water (1 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated at reflux for 2.5 h. The reaction was cooled to 60° C. and then more 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and then more 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated to reflux for a further 3.5 h. The reaction was cooled and concentrated under reduced pressure. The red brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give the product (0.318 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH2:15][CH3:16])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: CCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (4.5 g., 0.023 mole), the product of Example 1, was stirred with triethyl orthopropionate (50 ml.) at 100° C. for one hour. The mixture was cooled to room temperature and the white precipitate was collected by filtration and washed with cyclohexane to give 4.5 g. (85% yield) of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 158°-160° C. Mass spectrum: m/e, 232 (P).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N1CCCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:11][CH2:12]2)=[CH:4][C:3]=1[Cl:10]
Reactant: CCN(CC)CC
Reactant: ClCc1ccc(Br)c(Cl)c1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Clc1cc(CN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03 mmol) and Et3N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. was stirred overnight at r.t. and was then concentrated in vacuo. The residue was taken up into water and extracted with CH2Cl2 (3×100 ml). The combined organic layer was washed with saturated NaHCO3 and brine, and was then dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude product; used in next reaction step, without further purification).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]#[N:15])([CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 20 mmol) in THF (50 mL) was added LHMDS in THF (24 mL, 24 mmol) at 0° C. After stirring at 0° C. for 1 hour, MeI (5.7 g) was added. The reaction mixture was kept at 0° C. for 2 hours, then partitioned between EtOAc and H2O. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to give the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[N+:18]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:21](=[O:23])[CH3:22])[C:7]3[C:16]([S:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1cc([N+](=O)[O-])ccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of 3,7-dinitrophenothiazine (MW 289.27, 24.0 g, 82.96 mmol), acetic anhydride (MW 102.09, 151 g, 1.48 mol) and pyridine (100 cm3) was stirred at reflux for 18 hours. The warm solution was then cooled to room temperature and poured carefully over ice water. The precipitate formed was filtered to give the title compound (MW 331.26, 21.14 g, 63.81 mmol, 77%) as a sand coloured solid which was recrystallised from acetone to give light yellow needles.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])C.S(=O)(=O)(O)O.[C:27](O)(=O)C>[Pd]>[CH3:18][O:17][C:9]1[C:10]2[O:16][CH2:15][O:14][C:11]=2[CH:12]=[C:13]2[C:8]=1[CH2:7][N:6]([CH3:27])[CH2:5][CH2:4]2
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reactant: CC(=O)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Yield: 93 %

Procedure:
1.19 g (5 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (1) obtained in Reference Example 1 or 2 was dissolved in 15 ml of acetic acid, to which 0.33 ml (6 mmol) of 97% sulfuric acid and 500 mg of 5% palladium on carbon catalyst were added to carry out catalytic reduction at 75° C. for 2 hours. The catalyst was filtered out and 2 ml of 25% aqueous sodium hydroxide solution and 5 ml of water were added to the reaction mixture, which was concentrated under vacuum. 10 ml of water was added to the residue, the solution was made basic with 25% aqueous sodium hydroxide solution and extracted with 10 ml and then 5 ml of methylene chloride successively. The liquid extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate and then concentrated under vacuum to obtain 1.03 g of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. Yield 93%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH2:28][CH2:29]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1cc(N2CCNCC2)cs1
Product: CCc1cc(NC(=O)N2CCN(c3ccsc3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-thiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:32]([O:39][CH3:40])(=[O:38])[CH2:33][CH2:34][C:35]([O-])=[O:36]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:35](=[O:36])[CH2:34][CH2:33][C:32]([O:39][CH3:40])=[O:38])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: COC(=O)CCC(=O)[O-]
Product: COC(=O)CCC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 86.5 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 202 mg; 0.46 mmol) and monomethyl succinate (165 mg; 0.92 mmol), 220 mg (86%) of the title compound was obtained as a yellow oil after purification by reverse phase flash chromatography.