Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(C)c1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.851 g, 8.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.422 mL, 10.20 mmol). The solution was then cooled to 0° C. before 2,4-dimethylbenzoyl chloride (I53) (1.577 g, 9.35 mmol) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered, and analysis by LCMS showed impurities still to be present. The solid was thus further purified by flash chromatography (Isolera 100 g cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 1.482 g.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH:14]([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])[CH:3]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH:14]([CH3:21])[CH2:15][C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: CCOC(=O)CC(C)c1cc(F)c2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)CC(=O)O)cc(F)c2c1

Procedure:
The ester (9 g) was dissolved in methanol (180 ml) and 10% aqueous sodium hydroxide solution (90 ml) was added. The solution was heated under reflux for 2 hours. It was then poured into water (270 ml) and the suspension was acidified with dilute hydrochloric acid. The precipitate produced was extracted into ethyl acetate. The organic solution was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give 3-(4-fluoro-6-methoxy-2-naphthyl)butanoic acid as an oil which crystallised on standing (12.4 g., >100%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[Br:22]C1SC2C=C(C(N3C=CN=C3)C(N(C)C)CC)C=CC=2N=1.CN(C)C(CC)C(C1C=CC2N=C(C(OC)=O)SC=2C=1)N1C=CN=C1.CN(C)C(CC)C(C1C=CC2N=C(N)SC=2C=1)N1C=CN=C1.CN(C)C(CC)C(C1C=CC2N=C(NC(N)=O)SC=2C=1)N1C=CN=C1.C(N(C)C(CC)C(C1C=CC2N=C(NC(=O)C)SC=2C=1)N1C=CN=C1)C.CN(C)C(CC)C(C1C=CC2N=C(C(=N)OC)SC=2C=1)N1C=CN=C1.CN(C)C(CC)C(C1C=CC2N=C(C(N)=O)SC=2C=1)N1C=CN=C1.BrC1SC2C=C(C(N3C=CN=C3)C(N(CC)C)CC)C=CC=2N=1.ClC1SC2C=C(C(N3C=CN=C3)C(N(CC)C)CC)C=CC=2N=1.S1C2C=C(C(N3C=CN=C3)C(N(C)C)CC)C=CC=2N=C1>>[Br:22][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: CCC(CC)C(c1ccc2nc(N)sc2c1)n1ccnc1
Agent: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)CC
Agent: CCC(C(c1ccc2nc(C(=N)OC)sc2c1)n1ccnc1)N(C)C
Agent: CCC(C(c1ccc2nc(C(=O)OC)sc2c1)n1ccnc1)N(C)C
Product: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1

Procedure:
6-(2-Ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine; 1-(2-Bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine; Methyl 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylate; 6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine; 1-(6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea; N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide; Methyl 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carbimidate; 6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxamide; 1-(2-Bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine; 1-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine; 1-(Benzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine; and 6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-4)butyl)benzo[d]thiazol-2-amine.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[OH:17])=[N+]=[N-].[Cl-].[NH4+]>CCO.O.C(OCC)(=O)C.N.O.[Zn]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][C@H:5]1[OH:17]
Reactant: [N-]=[N+]=N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Yield: 66.9 %

Procedure:
201 mg of trans-4-azido-1-benzylpiperidin-3-ol (0.87 mmol) was dissolved in 3 ml of EtOH-water 3:1. To that solution 77 mg of zinc (12 mmol), 112 mg of ammonium chloride (2.1 mmol) were added and heterogeneous mixture was refluxed for 10 minutes. After cooling down reaction mixture was diluted with 8 mL of ethyl acetate and 0.5 mL of conc. ammonia in water, filtered off. Organic layer washed with brine, dried over sodium sulfate and evaporated. The residue was purified on silica gel column using DCM:MeOH 10:1 as eluent affording 120 mg of trans-4-amino-1-benzylpiperidin-3-ol.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[CH:25][N:24]=1)=O)C.[BH4-].[Na+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.C1COCC1>[F:32][CH:30]([F:31])[O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:21][OH:20])=[N:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(OC(F)F)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OC(F)F)cn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A toluene solution (13.8 mL, 13.8 mmols) of 1N diisobutylaluminium hydride was added to a THF solution (40 mL) of 2-ethoxycarbonyl-5-difluoromethoxypyridine (1.0 g, 4.6 mols) and stirred at 0° C. for 40 minutes. Successively sodium borohydride (174 mg, 4.6 mmols) and methanol (2 mL) were added and stirred at 0° C. for 30 minutes. Sodium sulfate decahydrate was added to the reaction liquid and stirred overnight at room temperature. Filtering the insoluble matter with Celite, the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (C-300, hexane:ethyl acetate=3:2-2:3) to provide the title compound (738 mg, 87%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:16]
Reactant: COc1ccccc1C(=O)O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added at room temperature to a stirred solution of 2-methoxy-benzoic acid (39.2 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123 mg, 0.64 mmol). After 2 minutes biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 60 mg (93.0% yield) of biphenyl-4-carboxylicacid {2-[4-(2-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 92.98%, HPLC Purity: 98.70%. 1H NMR: (CDCl3) δ 7.94 (d, 2H), 7.7-7.6 (q, 4H), 7.52-7.44 (t, 2H), 7.44-7.4 (m, 1H), 7.4-7.3 (m, 2H), 7.1-7.0 (t, 1H), 7.0-6.92 (dd, 1H), 4.4-4.24 (dd, 2H), 4.0 (s, 1H), 3.88 (d, 3H), 3.8 (s, 2H), 3.7-3.58 (m, 2H), 3.5-3.24 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7]([Cl:26])=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: COc1c(C(=O)N2CCCC2)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1c(C(=O)N2CCCC2)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoic acid (785 mg), toluene (8 mL) and oxalyl chloride (0.64 mL) were added, and then the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure and the obtained product was used for the synthesis of (d).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[CH3:38]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=2[CH3:38])[N:8]=1)=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.5 g, 6.72 mmol) in THF (30 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (6.5 ml, 6.50 mmol, Aldrich). The solution was stirred for 30 min. To the solution was added a solution of 1-(bromomethyl)-2-methyl-4-nitrobenzene (1.5 g, 6.52 mmol) in THF (20 ml). The resulting pale orange solution was stirred at ambient temperature under nitrogen over the weekend. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The phases were separated and the aqueous layer washed with ethyl acetate (25 ml). The combined organic phases were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (2.87 g). The sample was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.6 g); LCMS: (System 4) MH+=373, tRET=2.65 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].P(Br)(Br)[Br:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][Br:25])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc(Br)cc1C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccc(Br)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 5, 5-bromo-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide in chloroform to give 5-bromo-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([NH:27][C:28]#[N:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:27][C:28]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:6][CH2:7]1)=[NH:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: N#CNC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: N=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Yield: 40.4 %

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042 m) and benzoyl cyanamide (0.67 g, 0.0042 m) in toluene (100 cm3) were refluxed for 15 hours. The solvent was evaporated and the residue recrystallised from the minimum amount of isopropyl alcohol and recrystallised twice more from ethanol to give 0.65 g of the title compound, m.p. dihydrochloride quarter hydrate, m.p. 260°-262° C.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:31][CH:32]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(1-methyl-piperidin-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (47.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.042 g, 38%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=8.2 Hz. 1H), 7.85 (d, J=6.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.46 (m, 3H), 7.20 (d, J=8.5 Hz, 2H), 6.69 (t, J=7.4 Hz, 1H), 6.37 (s, 1H), 6.42 (d, J=7.6 Hz, 1H), 5.29 (t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.16 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.39 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.86-1.73 (m, 4H). MS=491 (MH)+.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:15]([NH:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: Cc1nnc(N)s1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nnc(C)s1
Yield: 89.1 %

Procedure:
To a mixture of toluene (20 ml) and triethylamine(2.63 g) was added 2-amino-5- methyl-1,3,4-thiadiazole (3.0 g) and acetic anhydride (3.2 g). The mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtrated, washed with water and dried. The title compound(3.65 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=N.Cl>O>[NH2:16][C:14]1[S:15][C:10]([C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:12][N:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S
Agent: Cl
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)s1

Procedure:
1-(1-Methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide (0.3 g.) is heated with 7 ml. of 6N hydrochloric acid for 15 minutes. The resulting solution is cooled and diluted with water. The solid is filtered, washed with water and dried affording 2-(2-amino-1,3,4-thiadiazol-5-yl)-1-methyl-5-nitroimidazole, melting point 266°-8°.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH3:22][O:23][CH:24]=O.S(OC)(OC)(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[CH:22]\[O:23][CH3:24])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(O)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(O)c1
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.558 g, 0.023 moles in DMF (20 ml) was added dropwise a solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (2.0 g; 0.0077 mol) in DMF (10 ml) and methylformate (10 g; 0.167 mol) After stirring for 45 minutes, water (100 mls) was added and the mixture was extracted with ether (50 mls). The aqueous layer was acidified with hydrochloric acid to pH 3-4 and the mixture was extracted with ether (2×40 mls). The combined ether extracts were washed with water (3×30 mls) and saturated brine (1×30 ml), and then dried. The ether was evaporated off and the residue was dissolved in DMF (20 ml), and anhydrous potassium carbonate. (0.64 g; 0.0046 moles) and dimethyl sulphate (0.55 g; 0.0044 moles) was added. The mixture was stirred at ambient temperature for 1 hour, then water (100 ml) was added, and the mixture was extracted with ether (2×40 ml). The combined ether extracts were washed with water (3×20 ml) and saturated brine (20 ml), dried, filtered, evaporate to dryness, then chromatographed using a mixture of ether and hexane as eluant to give (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (E) as an amber gum which, on trituration with a mixture of hexane and dichloromethane, gave a white solid, [0.7 g, 30% yield from methyl 2-(3-hydroxyphenoxy)phenylacetate (D)] m.p. 115°-116° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:9][CH:8]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:25])[N:15]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:16]3=[N:17]2)=[CH:12][CH:11]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1ccc2c(=O)n3c(nc2c1)CCCCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1c2ccc(C(O)Cc3ccccc3)cc2nc2n1CCCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-phenylacetyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one, obtained from Example 21.3 (100 mg, 0.3 mmol) and excess NaBH4 in CHCl3/MeOH (10 mL, 1:1) was stirred at room temperature for 2 h. After quenching with water, the reaction solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated. The residue was purified by silica gel chromatography to give the desired product. MS (ESI): 335 (MH+); 1H NMR (300 MHz, CDCl3) δ: 8.18-8.16 (d, J=8.19 Hz, 1H), 7.82 (s, 1H), 7.41-7.28 (m, 6H), 5.05-5.01 (t, J=7.65 Hz, 1H), 4.49-4.46 (t, J=5.01 Hz, 2H), 3.76 (brs, 1H), 3.36-3.33 (t, J=4.08 Hz, 2H), 3.23-3.20 (m, 2H), 2.00-1.86 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=1[CH3:27])=[O:14])=[O:10])([CH3:7])[CH:3]=[N:4][O:5][CH3:6].BrN1C(=O)CCC1=O.[Cl:40]N1C(=O)CCC1=O>>[Cl:40][C:31]1[C:11]([C:9]([NH:8][C:2]([CH3:1])([CH3:7])[CH:3]=[N:4][O:5][CH3:6])=[O:10])=[C:12]([CH:28]=[CH:29][CH:30]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=1[CH3:27])=[O:14]
Reactant: CON=CC(C)(C)NC(=O)c1ccccc1C(=O)Nc1ccc(OC(F)(F)F)cc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1Br
Product: CON=CC(C)(C)NC(=O)c1c(Cl)cccc1C(=O)Nc1ccc(OC(F)(F)F)cc1C
Yield: 63 %

Procedure:
2-(1,1-Dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-trifluoromethoxybenzanilide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-chlorosuccinimide, to obtain 3-chloro-2-(1,1-dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-trifluoromethoxybenzanilide (yield 63%, melting point 197° C.). Regioselectivity of chlorination into the 3-position was 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[NH:11])[N:9]([CH2:13][C:14]([C:16]3[CH:21]=[C:20]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=3)=[O:15])[N:10]=2)[N:7]=1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: Nc1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Cn2nc3ccc(Cl)nn3c2=N)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamin (W2.001a; 30 mg) was initially charged in DMF (3.5 ml) at RT while stirring, and 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone (O1.002; 58 mg) predissolved in DMF (0.5 ml) was added dropwise. The reaction mixture was stirred at RT for 30 min and was then heated to 60° C. for 5 h. After standing overnight, the solvent was removed under reduced pressure and the residue was purified by means of preparative HPLC (met. A). The clean product fractions were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 28 mg of the title compound were obtained. LC-MS rt: 1.28 min [M+H]+: 416.1 (met. a)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCCCc1ccc(N)nc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1

Procedure:
A solution of 2-amino-5-n-butylpyridine (3.72 g., 23.43 mmoles) and ethyl ethoxymethylenecyanoacetate (3.96 g., 23.43 mmoles) in toluene was heated for 10 minutes by means of an oil bath maintained at 100°. The solution was cooled and treated with Skellysolve B (200 ml.). The mixture was triturated for 18 hours at room temperature and then filtered. The collected title compound (4.3 g., 67.2%) had m.p. 69°-73°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:19])([CH3:18])[O:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=2)[O:9][C:8]1([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=Cc2cc(F)ccc2OC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1Cc2cc(F)ccc2OC1(C)C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
140 mg of palladium-on-carbon (5%) are added to a solution of 3.4 g (13 mmol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromene in 30 ml of absolute ethanol and the mixture is hydrogenated at normal pressure and room temperature for 90 minutes. The catalyst is then filtered off and the filtrate is concentrated by evaporation in vacuo, yielding 3.47 g of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-chroman in the form of a light-yellow oil.