Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.Br[CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]4[C:46]3=[O:55])[CH2:21][CH2:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)c2c1
Yield: 57.6 %

Procedure:
A mixture of 80 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 46 mg N-(2-bromoethyl)phthalimide, 19 mg sodium carbonate, and 8 mL acetonitrile was heated overnight under reflux. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 61 mg of the title compound as a colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][Br:15]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(CO)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(CBr)c1
Yield: 230.6 %

Procedure:
By the method of Example 1, Step B, 61.90 grams (0.279 mole) of 2,3-dichloro-5-nitrophenylmethanol and 26.41 grams (0.098 mole) of phosphorus tribromide were reacted in 800 mL of toluene, yielding 64.38 grams of 2,3-dichloro-5-nitrophenylmethyl bromide as a golden oil which solidified upon standing. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]=[C:21]([NH2:23])[NH2:22].C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:23][C:21]1[N:20]=[C:12]2[N:13]([C:8](=[N:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:11]2
Reactant: NC(N)=Nc1nc2ccccc2s1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1nc(=Nc2ccccc2)n2c(n1)sc1ccccc12

Procedure:
Phenyl isocyanide dichloride (0.18 g) in dry tetrahydrofuran (5 ml) was added to a stirred solution of 2-benzothiazolylguanidine (0.2 g) and diisopropylethylamine (0.27 g) in dry tetrahydrofuran (10 ml). The mixture was refluxed for sixteen days and on cooling the title compound was obtained as a white crystalline solid (23 mg) mp>250°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](Cl)=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Cc1ccccc1F)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-fluorophenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 526.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1C=C[C:11]([O:14]C)=[C:10](OC)[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].O1C=CC=C1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[O:14][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccco2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)furane was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 10 mmol) and 2-furoyl chloride (1.1 mL, 10 mmol) with a reaction time of 2 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 112-114° C.; 1H NMR (CDCl3) δ 7.78-7.66 (m, 2 H), 7.59-7.52 (m, 1 H), 7.26-7.17 (m, 1 H), 6.96-6.90 (m, 1 H), 6.63-6.55 (m, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ 180.9, 153.0, 152.5, 148.9, 146.5, 129.8, 124.0, 119.6, 112.0, 111.7, 110.0, 56.0, 55.9; Anal. Calcd for C13H12O4. Theoretical: C, 67.23; H, 5.21. Found; C, 67.09; H, 5.21.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][N:18]([C:10]2[S:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[N:3][C:2]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[CH:7][N:6]=3)[N:9]=2)[CH2:19][C@H:20]1[O:35][CH3:36])=[O:26]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(N2CCN(C)CC2)cn1
Temperature: 85 °C
Yield: 82.8 %

Procedure:
Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 100 mg, 0.1748 mM) was added to a solution of 1-methylpiperazine (87.93 mg, 0.874 mM) and N,N-diisopropylethylamine (67.12 mg, 0.5244 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and the resulting reaction mixture was stirred for over night at 80-90° C. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the obtained solid was filtered and dried to afford ethyl 2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate 92 mg (82%) as off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(CCCc1ccccc1)c1ccc(O)cc1O
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(N=C(CCCc3ccccc3)c3ccc(O)cc3O)cc2)=NN1
Temperature: 150 °C

Procedure:
A mixture containing 0.2 g of 1-(2,4-dihydroxyphenyl)4-phenylbutan-1-one and 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 24 h at 150° C. The product was treated with ethyl acetate. Yield 0.2 g (88%), m.p. 274°-280° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26].C(OCC)(=O)C>O1CCOCC1>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([F:31])=[C:22]([F:21])[CH:23]=2)=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCCc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(CCNC(=O)c2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
480 mg (2.649 mmol) of 4-(2-aminoethyl)-2-nitrophenylamine are dissolved in 30 ml of dioxane, and 1.102 ml (7.950 mmol) of triethylamine are added. 0.334 ml (2.650 mmol) of 3,4-difluorobenzoyl chloride are then added dropwise, and the mixture is stirred at room temperature for 30 min. Ethyl acetate is added to the reaction mixture, which is then washed 3× with water, dried using sodium sulfate, filtered and distilled off to dryness, giving N-[2-(4-amino-3-nitrophenyl)ethyl]-3,4-difluorobenzamide; EI-MS [M]+ 321, which is hydrogenated further under standard conditions, giving N-[2-(3,4-diaminophenyl)ethyl]-3,4-difluorobenzamide; HPLC-MS [M+H]+ 292.2.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH2:7])[N:3]=[CH:2]1.[CH3:8][C:9]([O:12][C:13]([N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:16]([C:24]1[C:29]([F:30])=[C:28](Cl)[N:27]=[C:26]([Cl:32])[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])([CH3:11])[CH3:10].C(N(CC)CC)C>C1COCC1.O>[CH3:11][C:9]([O:12][C:13]([N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:16]([C:24]1[C:29]([F:30])=[C:28]([NH:7][CH2:6][C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[N:27]=[C:26]([Cl:32])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:14])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NCc1cscn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2cscn2)c1F
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a suspension of (1,3-thiazol-4-ylmethyl)amine (0.1491 g, 1.308 mmol) in THF (10 mL) was added a solution of tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.649 g, 1.308 mmol) and triethylamine (0.22 mL, 1.5784 mmol) in THF (2 mL). Additional THF (3 mL) was added, and the reaction was stirred overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated. The resulting crude material was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a yellow oil (0.51 g, 68%). LCMS: (M-2Boc)=375.0.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[Br:20][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc2ccccc12
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
1-Naphthalene methanol (2.0 g, 12.7 mmol) was dissolved in toluene (30 mL) and pyridine (1.02 mL, 12.7 mmol) was added. The solution was cooled to 0° C. PBr3 (1.19 mL, 12.7 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give 1-(bromomethyl)naphthalene (1.5 g, 53%) as a colourless oil, This intermediate was used in the following reaction. Sodium ethoxide (169 mg, 2.49 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (438 mg, 2.49 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temperature. To this mixture 1-(bromomethyl)naphthalene (500 mg, 2.26 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine (2×50 mL), water (2×50 mL) and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 43 (200 mg, 28%) as a white solid. Mpt=181-183° C. H1 NMR (500 MHz, acetone-d6): δ=8.10 (1H, d, ArH), 8.00-7.99 (2H, m, Ar), 7.97-7.71 (2H, m, ArH), 7.70-7.53 (3H, m, ArH), 7.24 (1H, s, ArH), 7.09 (1H, d, CH), 6.23 (1H, s, CH), 5.68 (2H, s, CH2), 2.40 (3H, s, CH3).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][CH:8]([C:12]([CH3:14])=[O:13])[C:9]([O-:11])=[O:10].Cl[C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:24][CH3:25])[C:19]([N+:26]([O-:28])=[O:27])=[CH:18][CH:17]=1.[NH4+].[Cl-]>CO.CS(C)=O>[CH2:1]([O:10][C:9](=[O:11])[C:8]([C:16]1[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH:24][CH3:25])[C:21]=1[C:22]#[N:23])([CH3:7])[C:12](=[O:13])[CH3:14])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)C(C)C(=O)[O-]
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(NC)c1C#N
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
To a 1 L two-neck round bottom flask equipped with a magnetic stir bar and internal thermometer was added potassium tert-butoxide (5.0 g, 45 mmol) and dimethylsulfoxide (100 mL). To the rapidly stirred suspension was added 2-methylacetoacetate (7.13 g, 49.5 mmol) dropwise over 5 minutes. After the addition was complete the mixture was clear and slightly yellow. To the reaction mixture was then added 6-chloro-2-methylamino-3-nitro-benzonitrile (8.6 g, 41 mmol) from Step 1 in portions over 15 minutes. The reaction mixture immediately became deep red in color and the temperature rose to 40° C. The reaction mixture was stirred for 1.5 hours, then poured into a saturated solution of NH4Cl (100 mL). The mixture was extracted with EtOAc (3×150 mL). The organic layers were combined and washed with brine (3×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to produce a deep red oil. Methanol (40 mL) was added and the mixture was stirred for 1.5 hours with cooling over an ice bath. The resulting precipitate was recovered by filtration and washed with cold methanol to provide 2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (7.13 g, 40.6%) as a yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, 1H, J=9.0 Hz), 8.10-8.05 (m, 1H), 6.64 (d, 1H, J=9.0 Hz), 4.28-4.19 (m, 2H), 3.17 (d, 3H, J=5.5 Hz), 2.36 (s, 3H), 1.81 (s, 3H), 1.22 (t, 3H, J=7.0 Hz).
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([O:24][CH3:25])=[CH:11][C:10]=1[O:26][CH3:27])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH3:27][O:26][C:10]1[CH:11]=[C:12]([O:24][CH3:25])[C:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14][C:9]=1[P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(OCC)c1cc(Cc2ccc(CC)cc2)c(OC)cc1OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Cc2cc(P(=O)(O)O)c(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a solution of [2,4-dimethoxy-5-(4-ethylbenzyl)phenyl]phosphonic acid diethylester (1.00 g) in dichloromethane (13.4 mL) was added bromotrimethylsilane (1.3 mL) at 0° C., and the reaction mixture was stirred for 17 hr at room temperature. Methanol (4.1 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.78 g) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:24])[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1
Reactant: O=C(CC1CCN(Cc2ncc[nH]c2=O)CC1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: O=c1[nH]ccnc1CN1CCC(CC(O)c2ccccc2F)CC1
Reaction time: 1 h
Yield: 82 %

Procedure:
After dissolving 217 mg of 3-[4-[2-(2-fluorophenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one in 30 ml of methanol, 25 mg of sodium borohydride was added while stirring on ice, and the stirring was continued for 1 hour. Acetone was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol) to obtain the title compound (179 mg, 82% yield).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1.I[CH3:27]>>[CH3:27][N:17]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:20])[CH2:4][O:3][C:2]([CH3:1])([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)[C:8]=3[CH:9]=2)=[CH:14][CH:15]=[C:16]1[C:18]#[N:19]
Reactant: CC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: CI
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccsc1)OCC(=O)N2

Procedure:
Prepared from 5-[5-methyl-2-oxo-5-(3-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.16 (s, 1H), 7.56 (dd, J=2.92, 5.02 Hz, 1H), 7.42 (dd, J=1.90, 8.42 Hz, 1H), 7.28-7.23 (m, 3H), 7.09 (dd, J=1.06, 4.83 Hz, 1H), 7.01 (d, J=4.06 Hz, 1H), 6.30 (d, J=4.08 Hz, 1H), 4.20 (d, J=15.95 Hz, 1H), 4.05 (d, J=15.93 Hz, 1H), 3.65 (s, 3H), 1.96 (s, 3H); MS (ES) m/z 362 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].BrCC[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[C:23](#N)[CH3:24]>>[CH2:23]([C:15]1[CH:14]=[CH:13][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1)[CH3:24]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1cccc2ccccc12
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Product: CCc1ccc2ccccc2c1-n1cnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
4,5-Dichloroimidazole (0.137 g, 1 mmol) was dissolved into 1 mL of acetonitrile. Potassium hydroxide (0.061 g, 1.1 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-(2-bromoethyl)-naphthalene (0.142 mL, 0.235 g, 1 mmol) was added and the solution was allowed to reflux for 2.5 h. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and the solution was allowed to cool to room temperature to yield a tan crystalline material (0.085 g, 29% yield). 1H NMR (500 MHz, DMSO-d6) 8.13 (1H, d, Ar), 7.93 (1H, d, Ar), 7.84 (1H, d, Ar), 7.69 (1H, s, NCHN), 7.58 (2H, m, Ar), 7.42 (1H, t, Ar), 7.27 (1H, d, Ar), 4.31 (2H, t, NCH2), 3.49 (2H, t, CH2). 13C{1H} NMR (125 MHz, DMSO-d6) 135.9 (NCN), 133.4 (Ar—Cl), 133.3 (Ar—Cl), 131.3 (Ar—Cl), 128.6 (Ar—Cl), 127.4 (Ar), 126.9 (Ar), 126.3 (Ar), 125.7 (Ar), 125.5 (Ar), 124.0 (Ar), 123.3 (Ar), 111.9 (Ar), 46.2 (CH2), 32.8 (CH3). MS: m/z=290.04 (theor for C15H12Cl2N2=291.0).
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1(C)[O:20][CH2:19][C:14]2(OCCO2)[CH2:13][O:12]1.C1C2(CO[CH:39]([CH2:42][O:43]C3C=CN=C(CO)C=3C)[O:38]C2)C1.N1[C:57]2C=C3OCCOC3=C[C:56]=2N=C1S>>[Na:1].[CH2:56]1[C:14]2([CH2:19][O:20][CH:11]([CH2:10][O:9][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]4[NH:29][C:28]5[CH:30]=[C:31]6[O:43][CH2:42][CH2:39][O:38][C:32]6=[CH:33][C:27]=5[N:26]=4)=[O:24])[C:3]=3[CH3:2])[O:12][CH2:13]2)[CH2:57]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CO
Reactant: Sc1nc2cc3c(cc2[nH]1)OCCO3
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CS(=O)c1nc2cc3c(cc2[nH]1)OCCO3
Yield: 55.6 %

Procedure:
The same procedure as in the steps (5f) to (5h) was repeated using the (4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methanol obtained in Example (2d) and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol to obtain the title compound (364 mg, total 55.6% yield) as a light pink solid.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)C(=O)O1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCOCC>[O:8]=[C:6]1[C:12]2[C:11](=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[CH:13]=2)[NH:10][CH:9]=[CH:5]1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1ccc2[nH]ccc(=O)c2c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Intermediate (a) (27.5 g, 0.101 mol) was slowly added over five minutes to refluxing Dowtherm A (200 ml). After an additional five minutes at reflux, the mixture was allow to cool to room temperature then ether (200 ml) was added. The product was filtered off, thoroughly washed with ether then air dried to afford the product as a gold coloured solid (16.2 g, 94%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[N:21]=[CH:20][C:19]=3[C:28]([O:30]CC)=O)=[C:14]([N+:33]([O-])=O)[CH:13]=2)=[C:7]([CH3:36])[CH:6]=1)([CH3:3])[CH3:2].O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[CH:1]([O:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[C:18]4[N:22]([C@H:23]5[CH2:27][CH2:26][O:25][CH2:24]5)[N:21]=[CH:20][C:19]=4[C:28](=[O:30])[NH:33][C:14]=3[CH:13]=2)=[C:7]([CH3:36])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OC(C)C)nc2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(OC(C)C)nc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn([C@H]3CCOC3)c12
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of ethyl 5-[4-(6-isopropyloxy-2,4-dimethylpyridin-3-yl)-2-nitrophenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (65.1 mg) in acetic acid (1.5 mL)-water (0.15 mL) was stirred at 80° C. for 15 minutes. Iron powder (45.1 mg) was added to the solution, and the mixture was stirred at the same temperature for two hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature, and ethyl acetate (5 mL) was added to the reaction mixture. The insoluble matter was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. A solution of the residue in ethyl acetate was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was suspended and triturated by adding MTBE. The precipitated solid was collected by filtration to give the title compound (35.1 mg).