Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(#N)C.O>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: [C-]#N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol) in acetonitrile (186 mL) was treated with a solution of sodium cyanide (1.0 g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) in water (24 mL). The reaction mixture was heated at reflux for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting solution was washed with chloroform (1×50 mL). The aqueous layer was acidified to pH=3 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1, 3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-cyanomethyl-benzoic acid (0.79 g, 26.3%) as a white solid: mp 193–195° C.; EI-HRMS m/e calcd for C9H7NO2 (M+) 161.0476, found 161.0483.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc2occ(CCN3CCN(c4cccc5cccnc45)CC3)c2c1

Procedure:
A mixture of 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline(213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as brown solid. mp 78° C.; Yield: 120 mg (31%); (M+H): 388; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.7 Hz, J2=1.7 Hz,, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.51˜6.88 (m, 8H); 3.68 (s, 3H); 3.68˜2.82 (m, 12H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]2[C:33]#[N:34])=[CH:23][CH:22]=1>CS(C)=O>[C:3]([N:8]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1)[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]2[C:33]#[N:34])=[CH:25][CH:26]=1)(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: N#Cc1cc(Cl)cn1-c1ccc(CBr)cc1
Reactant: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(=O)N(Cc1ccc(-n2cc(Cl)cc2C#N)cc1)c1nccc(C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (114 mg, 60% oil dispersion) in dimethyl sulfoxide (5 ml) was added dropwise a solution of 2-butyrylamino-4-methyl-3-nitropyridine (605 mg) in dimethyl sulfoxide (10 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred at the same temperature for one hour and a solution of 1-(4-bromomethylphenyl)-4-chloropyrrole-2-carbonitrile (800 ml) in dimethyl sulfoxide (10 ml) was added therein. The reaction mixture was stirred at ambient temperature for 2 hours and quenched with ice water. The separated oil was extracted twice with ethyl acetate. The combined extracts were washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted by n-hexane/ethylacetate (2/1-1/1) to yield 2-[N-butyryl-N-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]amino]-4-methyl-3-nitropyridine (723 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:23]([O:25][CH3:26])=[O:24]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(C#N)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#N)c2ccccc12
Temperature: 0 °C

Procedure:
To a solution of 4-methyl-1-cyanonaphthalene (4.35 g, 25.9 mmol) in THF (100 mL) was cooled to −78° C. and treated with commercially available LDA (2 M, 60 mL). The reaction mixture was then warmed to 0° C. and maintained at 0° C. for 30 min. The resulting red-colored solution was cooled to −78° C. and methyl chloroformate (10 mL, 130 mmol) was added. The reaction mixture was stirred while warming to rt until the displacement was complete (4 h) and then quenched with sat'd NH4Cl. The THF layer was evaporated and extracted with EtOAc (3×20 mL). The EtOAc was dried over Na2SO4 and concentrated in vacuo to afford an oil.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1.CCN(CC)CC>ClCCl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:12][CH2:13][C:14]2([C:17]#[N:18])[CH2:16][CH2:15]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
TsCl (7.25 g, 38 mmol) was added in one portion to a stirred solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (3.1 h, 32 mmol) in dichloromethane (75 mL) at 0° C. Et3N (4.1 g, 40 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was diluted with dichloromethane, washed with water, 0.5 N NaOH, brine. The organic extract was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 18A (6.43 g, 81% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.[NH2:46][NH2:47]>N1C=CC=CC=1.Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[C:4]3[C:3](=[C:2]([Cl:1])[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=3)[NH:47][N:46]=2)[CH:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[O:30])=[CH:41][CH:42]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: NN
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(Cl)cc(C(F)(F)F)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of the minor diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 71 mg, 0.108 mmol) in pyridine (5 mL) was added hydrazine hydrate (0.053 mL, 1.1 mmol). The mixture was stirred at 80° C. for one hour in a sealed tube. The mixture was diluted with 1 N HCl (aq), then extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, then concentrated to afford the title compound. This material was used directly in the next step without further purification. LC2 1.57 min. (M-tBu+H)+ 592.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:34]=[N:35][NH:36][N:27]=4)[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 44.9 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzenesulfonamide (1.00 g, 2.15 mmol), sodium azide (1.40 g, 21.5 mmol), and ammonium chloride (1.15 g, 21.5 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool the reaction to room temperature and dilute with water (120 mL). Filter the resulting mixture, wash the filtered material several times with water and dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a tan solid (490 mg, 45%): 1H NMR (DMSO-d6) δ 0.80 (t, 3H), 1.42 (sextet, 2H), 2.49 (s, 3H), 2.50 (t, 2H), 5.16 (s, 2H), 6.59 (d, 1H), 7.10 (d, 1H), 7.12 (d, 1H), 7.24 (s, 1H), 7.25 (t, 1H), 7.70 (d, 1H), 7.73 (t, 1H), 7.87 (d, 1H), 8.22 (d, 1H), 8.49 (s, 1H), 10.56 (s, 1H), 12.82 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 506 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:8]2[C:27]([C:28]([F:29])([F:30])[F:31])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution 2-chloro-6-hydrazinopyridine (1.00 g, 6.97 mmol) and triethylamine (971 mL, 6.97 mmol) in acetonitrile (35 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.36 mL, 6.97 mmol). After 20 min, the reaction mixture was placed in a 60° C. oil bath. After 30 min, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) gave the title compound (PCT publication WO 2009/032249): LCMS m/z 319.9 [M+H]; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1 H),7.88 (t, J=7.5 Hz, 1 H),7.58 (d, J=8.0 Hz, 1 H),7.47 (d, J=8.0 Hz, 1 H),4.38 (q, J=7.0 Hz, 2 H), 1.38 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH3:16])=[CH:4][N:3]=1.CN(C=O)C>CCOC(C)=O.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH3:16])[N:8]([CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CC#Cc1cnc(Cl)nc1NC(CC)CC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(C)cc2cnc(Cl)nc21
Temperature: 160 °C
Yield: 19.7 %

Procedure:
To a microwave vial are added (2-chloro-5-prop-1-ynyl-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.22 g, 0.92 mmol), anhydrous DMF (3 mL), and CuI (53 mg, 0.27 mmol). The reaction is heated at 160° C. for 1 h by employing microwave. The reaction mixture is diluted with EtOAc, washed with NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:4) gives 43 mg of 2-chloro-7-(1-ethyl-propyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][N:24]([CH3:41])[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=[C:28]([S:25](=[O:26])(=[O:27])[N:24]([CH3:41])[CH3:23])[CH:29]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 132, intermediate a) and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 90:10), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Light brown foam (13%). MS (ESI): m/z=598.104 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([C:33]2[CH:42]=[C:41](O)[C:40]3[C:35](=[CH:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)[N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([O:13][C:41]2[C:40]3[C:35](=[CH:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)[N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:42]=2)[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
Compound 35 (73 mg, 0.199 mmol) was dissolved in dry THF (4 mL) and 2-phenyl-7-methoxy-4-quinolinol (86 mg, 0.342 mmol) and triphenylphosphine (141 mg, 0.538 mmol) were added. The mixture was cooled to 0° C. and DIAD (0.567 mmol) dissolved in 1 mL THF was added dropwise. The mixture was stirred for 48 h at room temperature. The solvent was evaporated and the crude product was purified by flash column chromatography gradient elution (toluene/EtOAc 9:1, 6:1, 4:1) to give the title compound (81 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].Cl.[NH2:12][OH:13]>>[CH3:1][O:2][C:3]([CH:5]1[C:9](=[N:12][OH:13])[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1CSCC1=O
Agent: Cl
Product: COC(=O)C1CSCC1=NO

Procedure:
Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]#[C:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1>C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[NH:3][N:2]=2)=[CH:7][CH:6]=1
Reactant: O=C(C#Cc1cccs1)c1ccc(Cl)cc1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Hydrazine hydrate (228 mg, 4.6 mM) and pyridinium p-toluenesulfonate (50 mg) were added to a solution of 1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one (750 mg, 3.0 mM) in ethanol (30 ml), and this mixture was heated under reflux for 2 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (50 ml). This solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 634 mg of 3-(4-chlorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 217° C., in an 80% yield.
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH2:19]>O.C(Cl)Cl>[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH:19][C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(OCCN)c(C)c1
Reactant: CSCc1ncnc(Cl)c1SC
Solvent: O
Solvent: ClCCl
Product: CSCc1ncnc(NCCOc2ccc(C)cc2C)c1SC
Yield: 47.2 %

Procedure:
4.4 g (0.02 mol) of 4-chloro-5-methylthio-6-methylthiomethylpyrimidine and 7.4 g (0.045 mol) of 2-(2,4-dimethylphenoxy)ethylamine were heated for 2 hours at 100° C. The mixture was worked up using a water/methylene chloride mixture, and the organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel (mobile phase, ethyl acetate/methanol (19:1)). 3.3 g (47.2% of theory) of 4-[2-(2,4-dimethylphenoxy)ethyl amino)-5-methylthio-6-methylthiomethylpyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5])C>NCCO>[OH:5][CH2:4][CH2:6][NH:7][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Solvent: NCCO
Product: O=C1CC(c2cccc(-c3nc(C(=O)NCCO)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Yield: 83.9 %

Procedure:
A solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (49 mg, 0.1 mmol) in 2-amino-ethanol was heated to 40° C. for 40 min. The cooled solution was partitioned between ethyl acetate and H2O and the organic layer was dried over Na2SO4 and evaporated in vacuum. The residue was triturated with ethyl acetate to give to give the title compound as light yellow solid (21 mg).
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[N:41]1[CH2:45][CH2:44][N:43]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)[C:42]1=[O:55]>CN(C=O)C>[CH3:2][NH:3][C:50](=[O:52])[C:49]1[CH:48]=[CH:47][C:46]([N:43]2[CH2:44][CH2:45][N:41]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][C:35]=3[CH3:34])[C:42]2=[O:55])=[CH:54][CH:53]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccncc1N1CCN(c2ccc(C(=O)O)cc2)C1=O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
EDCI (176.4 mg, 0.9205 mmol), HOBt (5.8 mg, 0.2525 mmol), DIPEA (0.3 mL, 2.3006 mmol) and methylamine hydrochloride (62 mg, 0.9205 mmol) were added to a stirred solution of 4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid (228 mg, 0.7668 mmol) in dry DMF (10 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 155 mg of the product (65.4% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9].CN(C)C=O.[N-:15]=[N+:16]=[N-:17].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[N:15]([CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nccn1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCN=[N+]=[N-]

Procedure:
To a solution of 8 parts of 1-(2-chloroethyl)-2-methylimidazole (U.S. Pat. No. 3,882,136) in 200 parts of N,N-dimethylformamide is added a slurry of 5 parts of sodium azide in 100 parts of N,N-dimethylformamide. The resultant mixture is stirred for 2 hours at approximately 65°, then cooled and thereupon diluted with 600 parts of water. Sufficient potassium carbonate is added to insure basicity. The mixture thus obtained is extracted with chloroform. The chloroform extract is dried over anhydrous magnesium sulfate and stripped of solvent by vacuum distillation, affording 1-(2-azidoethyl)-2-methylimidazole as the residue. The product has the formula ##SPC4##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br)[C:8]=1[CH2:29][CH2:30][CH3:31])[CH3:2].[OH:33][C:34]1[C:39]([CH2:40][CH2:41][CH3:42])=[C:38]([OH:43])[CH:37]=[CH:36][C:35]=1[C:44](=[O:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:43][C:38]2[CH:37]=[CH:36][C:35]([C:44](=[O:46])[CH3:45])=[C:34]([OH:33])[C:39]=2[CH2:40][CH2:41][CH3:42])[C:8]=1[CH2:29][CH2:30][CH3:31])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 15 h
Yield: 39.5 %

Procedure:
A mixture of 2.55 g (0.005 mole) of [4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.97 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.00 g (0.0062 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone was stirred at reflux for 15 hours. An additional 0.5 g of potassium carbonate was added and reflux was continued for 15 hours. The solvent was removed in vacuo and the residue was chromatographed on 300 g of silica gel. Elution with 30% ethyl acetate-toluene gave 1.25 g (40% yield) of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.