Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][N:28]=4)[CH2:31][CH2:32]3)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2c(S(=O)(=O)Cl)c(OC)ccc12
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(OC)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To a solution of compound from step 3 (50 mg, 0.14 mmol) in THF (2 mL) was added 1-[5-(trifluoromethyl)-2-pyridinyl]piperazine (32 mg, 0.14 mmol), followed by triethylamine (39 μL, 0.28 mmol). The reaction solution was stirred for 4 hours at room temperature. The solvent was evaporated and the residues were purified by silica gel chromatography to afford 22 mg of desired compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46]>C(Cl)Cl>[CH2:2]([O:4][C:5]([C:7]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[C:45]([O:47][CH2:48][C:49]([Cl:52])([Cl:51])[Cl:50])=[O:46])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a 0° C. solution of 3.0 g (5.83 mmol) (R,R)-5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester hydrochloride salt and 60 mL CH2Cl2 was added 2.54 mL (1.88 g, 14.57 mmol) of i-Pr2NEt followed by 0.84 mL (1.30 g, 6.12 mmol) of 2,2,2-trichloroethyl chloroformate. After stirring at room temperature for 6 h, the reaction mixture was quenched with 10 mL sat. aq. NaHCO3, and extracted with 3×100 mL Et2O. The combined organics were washed with 1×100 1N HCl, 1×100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (4/1 to 2/1), gives 3.46 g (5.30 mmol, a 91% yield) of the title compound (Rf =0.32; 2/1 hexanes/EtOAc) as an oily, off-white solid; 1H NMR 300 MHz, CDCl3): δ 1.20-1.39 (complex m, 9H), 2.60-2.80 (m, 1H), 2.80-2.91 (m, 1H), 3.01-3.19 (m, 1H), 3.23-3.31 (m, 1H), 3.40-3.53 (m, 1H), 4.10-4.23 (m, 1H), 4.30-4.42 (complex m, 4H), 4.70-4.89 (m, 3H), 6.65-6.88 (complex m, 4H), 7.15-7.39 (complex m, 3H); MS (ES) m/z (relative intensity): 654 (M+ +H, 100).
Reaction SMILES: [O:1]=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[OH-].[Na+:34]>CO>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O-:11])=[O:10])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O-:28])=[O:27])=[O:1].[Na+:34].[Na+:34]
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccc1C(=O)[O-])C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To methanol (2 ml), 2,2'-[(1,3-dioxo-2-phenylmethylene-1,3-propanediyl)diimino]bisbenzoic acid (500 mg) and 1N.NaOH (2.32 ml) were added, and the mixture was stirred at room temperature for 1 hour. Solvent was removed from the reaction mixture, and the residue was treated with acetone and crystallized to give the title compound (478 mg, 87%) in white solid. m.p. 283° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[C:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)(=[O:18])=[O:17])=[CH:14][C:5]2[O:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[C:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)(=[O:18])=[O:17])=[CH:14][C:5]2[O:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3cccc(F)c3)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Oc2cc(Cl)c(S(=O)(=O)c3cccc(F)c3)cc2O1

Procedure:
22.8 g (0.059 mole) of ethyl 5-chloro-6-(3-fluorophenylsulfonyl)-1,3-benzodioxole-2-carboxylate are covered with 90 ml of 2-n sodium hydroxide solution and the batch is heated for half an hour in a boiling water bath, cooled, acidified with hydrochloric acid and then extracted with ethyl acetate. The extract is concentrated by evaporation, affording 5-chloro-6-(3-fluorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid. Melting point 161°-163° C. (crystallisation from ether/toluene).
Reaction SMILES: [N:1]1[N:5]2[C:6]([CH:10](O)[CH3:11])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH:10]([C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(O)c1ccnc2ncnn12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1ccnc2ncnn12
Reaction time: 2 h

Procedure:
A solution of 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (1 g, prepared in an similiar manner to that described above) in dichloromethane (30 ml) was added dropwise over 30 minutes to a solution of thionyl chloride (0.5 ml) in dichloromethane (50 ml), heated under reflux, and the heating was continued for a further 2 hours. Further thionyl chloride (0.5 ml) was added and the heating continued overnight. The dichloromethane was removed by distillation and the residue dissolved in further dichloromethane (50 ml). The solution was washed with a mixture of water (20 ml) with 1M sodium bicarbonate (3 ml), and the aqueous washings were extracted with dichloromethane (20 ml). The dichloromethane solutions were combined, washed with brine (40 ml), dried over magnesium sulphate and the solvent was evaporated to give, as a light brown solid, 7-(1-chloroethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.00 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:16]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1csc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)CC(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (5.00 g), isovaleryl chloride (4.52 mL) and nitromethane (50 mL) was added aluminum (III) chloride (8.98 g) at 0° C., and the mixture was stirred at 0° C. for 30 min then at room temperature for 4 hr. The reaction mixture was poured into ice-cooled water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title object compound (7.72 g, 99%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][CH2:4][O:5][C:6](=[O:50])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3=[C:18]([CH:49]=2)[N:19]=[C:20]([NH:41]C(OC(C)(C)C)=O)[CH2:21][C:22]([C:24](=[O:40])[N:25]([CH2:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH2:26][CH2:27][CH3:28])=[CH:23]3)=[CH:10][CH:9]=1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:51][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:50])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3=[C:18]([CH:49]=2)[N:19]=[C:20]([NH2:41])[CH2:21][C:22]([C:24](=[O:40])[N:25]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:26][CH2:27][CH3:28])=[CH:23]3)=[CH:12][CH:13]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCN(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 2-(dimethylamino)ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. Step 2: 2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.59-7.64 (m, 2H), 7.48-7.51 (m, 1H), 7.28-7.38 (m, 4H), 6.87 (s, 1H), 4.19-4.24 (m, 2H), 3.58-3.74 (m, 6H), 3.44-3.52 (m, 2H), 2.84 (s, 2H), 2.54-2.61 (m, 2H), 2.27 (s, 6H), 1.79-1.86 (m, 2H), 1.65-1.76 (m, 2H), 0.89-0.97 (m, 3H); m/z (APCI-pos) M+1=507.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[S:15][CH3:16])=O.COC1C=CC(/C=[C:32]2/[C:33]([NH:35][C:36]([S:38]/2)=[NH:37])=[O:34])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:37][C:36]1[S:38]/[C:32](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[S:15][CH3:16])/[C:33](=[O:34])[N:35]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CSc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-methylsulfanyl-quinoline-3-carbonitrile (example 55b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 327 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:25])[C@H:19]([CH2:21][CH2:22][S:23][CH3:24])[NH:20][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:16]
Reactant: CCOC(=O)[C@@H](N)CCSC
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)[C@H](CCSC)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure G′ above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])=[O:4])[CH3:2].CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>C(OCC)(=O)C>[CH2:23]([O:22][C:19]([N:5]=[S:3]([CH2:1][CH3:2])([C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:4])=[O:21])[CH3:24]
Reactant: CCS(=N)(=O)c1cccc(C)c1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)N=S(=O)(CC)c1cccc(C)c1
Yield: 92 %

Procedure:
According to GWP 3, the conversion of (RS)-S-ethyl-S-(m-tolyl)sulphoximide (2.55 g, 13.91 mmol) and chromatographic purification (silica gel, hexane/ethyl acetate: 0→100% ethyl acetate) gives the desired product in 92% yield (3.27 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][NH:15][CH3:16])=[CH:4][CH:3]=1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][N:15]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: CNCC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CN(C)CC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-acetamide (157 mg, 0.47 mmol) was dissolved in CH2Cl2 (5 mL), treated with isobutyraldehyde (43 mL, 0.47 mmol), stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3 (150 mg, 0.71 mmol), and stirred overnight at room temperature. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 168 mg (92%) of the desired product as a sticky solid. MS: 389.3 (M+1 for C23H30N2O1F2); sticky solid; TLC (SiO2), Rf 0.44 (6% MeOH/CH2Cl2); HPLC (7:3 CH3CN/H2O with 0.1% TFA, C-18 column) 100%, RT=2.067 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:10]=1)[CH:8]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:8]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
5-Methoxy-2-[3-(4-morpholinyl)propoxy]benzaldehyde (33.4 g) and 14.5 g of phenethylamine are refluxed in 120 ml of toluene for about 1 hour. After cooling to about 50° C., the solvent is removed using a rotary evaporator and the oily residue is distilled to give 42.1 g of the title compound, boiling point 240°-245° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])(=[O:3])[CH3:2].OC(COC1C2C(=CC=CC=2)C=CC=1)CN[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2>>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2)(=[O:3])[CH3:2]
Reactant: OC(CNc1ncnc2[nH]cnc12)COc1cccc2ccccc12
Reactant: CC(=O)c1cccc(OCC(O)CN)c1
Product: CC(=O)c1cccc(OCC(O)CNc2ncnc3[nH]cnc23)c1

Procedure:
By substituting 3-(3-acetylphenoxy)-2-hydroxypropylamine (3.65 g, 0.0174 moles) for the starting material of Example 2 and following the method of Example 2, the desired compound is obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To 2′,4′-dihydroxy-3′-propyl acetophenone (3.0 g, 15.4 mmol) and 4-nitrobenzyl bromide (3.6 g, 17 mmol) in acetone (62 mL) is added K2CO3 (3.2 g, 23 mmol). The reaction mixture is refluxed for 1 h and cooled to room temperature. The precipitate is filtered, washed with water (5×70 mL), and dried to give the title compound (4.8 g, 94%). LC-MS (m/z): 328 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1.[OH-].[K+]>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1CN(CCCCC(c2ccc(F)cc2)c2cccnc2)CCN1
Reaction time: 96 h
Yield: 67.6 %

Procedure:
A mixture of 12 parts of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]2-methyl-1-piperazinecarboxylate, 16 parts of potassium hydroxide and 128 parts of 2-propanol was stirred for 4 days at reflux temperature. After cooling, the reaction mixture was evaporated. Water was added to the residue and the mixture was evaporated till all traces of 2-propanol were removed (this was repeated twice). The residue was taken up in water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6.7 parts (67.6%) of 1-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-3-methylpiperazine as a residue (int. 39).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[Li+]>C(O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Yield: 95.7 %

Procedure:
To a suspension of ethyl 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (12.1 g, 48.5 mmol) in ethanol (250 ml) was added a solution of lithium hydroxide (5.8 g, 242 mmol) in water (100 ml). The mixture was stirred at reflux for 2.5 hours. It was allowed to cool and concentrated to 50% of its volume before 5M hydrochloric acid (47 ml) was added. After stirring for 15 minutes, the resulting white solid was filtered off and further 5M hydrochloric acid (3 ml) was added to the filtrate and the resulting solid was filtered and the combined solids were washed with water and diethyl ether and then dried under vacuum to give the title compound (10.27 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]2N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC[C@H]2NS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Methyl 1-amino-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-02) (0.2 g, 0.881 mmol, 1 eq) was dissolved in dichloromethane and triethylamine (2.5 eq) under nitrogen, and 2-chlorobenzenesulfonic acid chloride (0.185 g, 0.881 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then concentration was carried out under reduced pressure, and the residue was diluted with ethyl acetate, washed with 10% ammonium chloride solution and sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:EA 4:1) and the desired product (R)-methyl 1-(2-chlorophenylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-01) was thus obtained. Yield: 87%
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([C:6]#[N:7])=O.C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[N+]([O-])(O)=O.N>CS(C)=O>[NH2:20][C:19]1[N:18]=[N:17][C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:2]=2[Cl:1])=[C:6]([NH2:7])[N:21]=1
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: N
Agent: O=C(O)O
Solvent: CS(C)=O
Solvent: O=[N+]([O-])O
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 2,3-dichlorobenzoyl cyanide (32 g, 0.16M) in dimethylsulphoxide (80 ml) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (81.67 g. 0.6M) which had been treated with 8N aqueous nitric acid (400 ml) at a temperature of ca 25° C. The mixture was stirred for 3 hours, then left to stand at room temperature for 7 days. The cooled mixture was stirred and basified with 0.880 aqueous ammonia (400 ml) at 20° C., then stirred with ice cooling for 30 minutes. The resulting solid was separated by filtration, washed thoroughly with water and finally dried in vacuo. The above solid was added to a 10% w/v solution of potassium hydroxide pellets in methanol (400 ml) and the solution heated to reflux for 11/2 hours. When cool the solution was evaporated down in vacuo, treated with ice water (800 ml) then stirred for 30 minutes and filtered. The residue was dried and recrystallised from isopropanol to give 3,5-diamino-(2,3-dichlorophenyl)-1,2,4-triazine Yield 6.8 g (15.6%), m.p. 216°-218° C. (uncorrected).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1>ClCCl>[CH:15]12[CH2:1][CH:16]1[CH2:17][CH2:18][CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: COC(=O)C1CC=CCC1
Reactant: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCC2CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of diethyl zinc (1.0 M in hexanes, 35 mL, 35.00 mmol) in anhydrous dichloromethane (34 mL) was added trifluoroacetic acid (3.99 g, 35.0 mmol) in 17.2 mL anhydrous dichloromethane at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and then added a solution of diidomethane (9.37 g, 35.00 mmol) in anhydrous dichloromethane (17 mL) at 0° C. The reaction mixture was further stirred at the same temperature for another 1 hour. To this mixture was added a solution of methyl cyclohex-3-enecarboxylate (2.45 g, 17.50 mmol) in anhydrous dichloromethane 17 mL) at 0° C. The resulting mixture was warmed to ambient temperature and further stirred for 4 hours. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and separated the organic layer. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (30%) to afford the title compound as yellow oil (2.56 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 2.31-1.92 (m, 3H), 1.84-1.65 (m, 2H), 1.54 (t, J=12.9 Hz, 1H), 1.19-1.04 (m, 1H), 0.93-0.86 (m, 2H), 0.63-0.55 (m, 1H), 0.05-0.00 (m, 1H).