Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]1[CH2:8][C@@H:7]([CH2:9][N:10](C(OC(C)(C)C)=O)[C:11]([NH2:20])=[N:12]C(OC(C)(C)C)=O)[CH2:6][N:5]1C(OC(C)(C)C)=O.[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]1[CH2:8][C@@H:7]([CH2:9][NH:10][C:11]([NH2:20])=[NH:12])[CH2:6][NH:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](CN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](CNC(=N)N)CN1

Procedure:
(4R)-1-(tert-Butyloxycarbonyl)-4-[N,N'-bis(tert-butyloxy-carbonyl)guanidinomethyl]-L-proline methyl ester (14 mg, 0.028 mmol) was treated with 4N HCl in dioxane (1 mL) at room temperature overnight. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether and several times with methanol. The product was dried under high vacuum; yield 7.6 mg (100%). Mass spectrum: m/z 201 (M+1); 400 MHz 1H NMR (CD3OD): δ2.19 (m, 1H); 2.42 (m, 1H); 2.68 (m, 1H); 3.11 (dd, 1H); 3.64 (dd, 1H); 3.87 (s, 3H); 4.60 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.BrC1C(OC)=CC2N=C[N:35](CC3C=CC4N=C(N[C@@H]5CCCC[C@H]5O)SC=4C=3)[C:34]=2C=1>>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2]([C:34]#[N:35])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Reactant: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1Br
Product: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1

Procedure:
1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was synthesized as a white powder (32 mg, 6%) using a procedure analogous to that described in Step 1 of Example 53, substituting (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from the previous step for (1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol used in Example 53. The product was further purified by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.22 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.62 (m, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.54 (s, 2H), 4.73 (d, J=5.3 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.56-1.67 (m, 2H), 1.10-1.35 (m, 4H); LCMS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 40 was prepared from 1-(4-fluoro phenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 2H), 7.42–7.36 (m, 2H), 7.30–7.20 (m, 2H), 7.05–6.96 (m, 3H), 6.85–6.79 (m, 1H), 3.28 (q, 2H, J=6.3 Hz), 2.95–2.87 (m, 2H), 2.57–2.41 (m, 2H), 2.36–2.28 (m, 4H), 2.06 (s, 1H), 1.96–1.84 (m, 4H), 1.83–1.75 (m, 2H), 1.71–1.54 (m, 9H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Br:15][C:16]1[CH:21]=[N:20][C:19](Br)=[CH:18][N:17]=1>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]2[CH3:1])=[N:20][CH:21]=1
Reactant: Brc1cnc(Br)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(Br)cn1
Temperature: 80 °C
Reaction time: 15 h
Yield: 10.6 %

Procedure:
A mixture of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (6.0 g, 30 mmol) and 2,5-dibromopyrazine (14.1 g, 60 mmol) was stirred at 80° C. for 15 h. It was then cooled to room temperature and purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 2:1) to afford 230a as a yellow solid (1.14 g, 19%). MS: [M+H]+ 359.1.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:9]([O:20][CH2:21][CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([C:32]3[CH:33]=[CH:34][C:35]4[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=4[CH:42]=3)=[O:31])[CH2:25][CH2:24]2)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2)=[O:7]>O1CCCC1.O>[CH3:19][O:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]([OH:7])=[O:5])[C:9]([O:20][CH2:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([C:32]4[CH:33]=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:25][CH2:24]3)=[N:10]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2nc1OCC[C@H]1CC[C@H](NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)c(OCC[C@H]3CC[C@H](NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Lithium hydroxide monohydrate (18 mg, 0.42 mmol, 1.5 eq) is added at room temperature to a stirred solution of 7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylic acid methyl ester (173 mg, 0.28 mmol, 1.0 eq) in a mixture of tetrahydrofuran/water (6 mL, 2:1, v/v). After stirring at room temperature for 15 hours, solvents are evaporated and the residue is acidified to pH 5 with 0.5N hydrochloric acid aqueous solution and the resulting aqueous layer is extracted with dichloromethane (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 7-methoxy-2-(2-{trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexyl}-ethoxy)-quinoline-3-carboxylic acid as an off-white lyophilizated powder (11 mg, 6% yield).
Reaction SMILES: Cl.[CH2:2]([CH:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7]1)[CH2:3][CH2:4][CH3:5].[OH-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>[Cl-].C[N+](CCCC)(CCCC)CCCC.C(Cl)Cl>[CH2:2]([C:6]1[N:10]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC1NC(=O)C2(CCCC2)N1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
A mixture of 28.9 g (125 mmoles) of 2-butyl-1,3-diazaspiro[4.4]nonan-4-one, hydrochloride, 1.3 mL of 75% aqueous solution of methyl tributylammonium chloride, 90 mL (10 N) of 33% aqueous sodium hydroxide and 90 mL of methylene chloride was vigorously stirred for 5 minutes at room temperature and then cooled to 7-12° C. To this vigorously stirred cooled mixture at 7-12° C. was added a solution of 36.04 g (132 mmoles, amount determined quantitatively by HPLC) in 300 mL of methylene chloride of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile over a period of 70 minutes. After that, the reaction mixture was allowed to warm up to room temperature and stirred additionally at room temperature for a half hour. Then the phases were separated and the organic phase was washed twice with 90 mL of water. The organic phase was concentrated under reduced pressure to the minimum agitation volume, and methyl tertiarybutyl ether was added. Concentration was continued to displace the dichloromethane, and the product was crystallized from the methyl tertiarybutyl ether solution. The crystals were collected on a filter, washed with cold 120 ml of methyl-tertiarybutyl ether and dried in a vacuum oven at 40° C. and a pressure of 3.1 mm Hg to give 39.9 g (82.4%) of the title compound having a laboratory HPLC of HI 99.8.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][CH2:35][O:36]C1CCCCO1.CO>O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:35][OH:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: BrCCOC1CCCCO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 142, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran, the crude product subjected to reverse phase HPLC (Gemini C18 column, gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 201 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.41 (s, 1 H); 8.28 (s, 1 H); 8.16 (s, 1 H); 7.80 (td, J=8.75, 5.92 Hz, 1 H); 7.62 (ddd, J=10.34, 9.02, 2.81 Hz, 1 H); 7.37-7.31 (m, 1 H); 7.28 (d, J=8.17 Hz, 1 H); 6.95 (d, J=1.73 Hz, 1 H); 6.89 (dd, J=8.25, 1.81 Hz, 1 H); 4.22 (t, J=5.03 Hz, 2 H); 3.69 (t, J=7.37 Hz, 2 H); 3.60 (dt, J=15.08, 7.40 Hz, 1 H); 3.39 (t, J=6.62 Hz, 1 H); 3.23 (t, J=7.74 Hz, 2 H); 3.14 (s, 2 H); 3.05 (t, J=5.14 Hz, 2 H); 2.61 (t, J=5.95 Hz, 2 H). LCMS: RT=7.11 min, M+H+=465
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[S:23]([CH3:26])(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH:10][C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[CH:16][C:17]=2[S:23]([CH3:26])(=[O:25])=[O:24])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)N)c1OC
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Yield: 30.6 %

Procedure:
A solution of 1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl amine (1.27 g, 5.89 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (1.25 g, 6.48 mmol) and N,N-diisopropylethylamine (2.1 mL, 11.78 mmol) in acetonitrile was stirred at 80° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water, dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (700 mg, 32%): 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, 1H), 6.82 (m, 2H), 6.73 (dd, 1H), 6.42 (dd, 1H), 6.24 (dd, 1H), 4.82 (m, 1H), 3.95 (s 3 H), 3.88 (s, 3H), 3.27 (3, 3H), 1.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. After 3 hours of stirring at room temperature, a solution of 4-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 18 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1→1:1) to provide the title compound as white powder (351 mg, yield 39%). 1H-NMR (DMSO-d6) δ: 3.68(3H,s), 5.73(2H,s), 7.30(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 8.71(1H,s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:24][CH2:25][OH:26])=[N+:21]([O-])[CH:22]=2)=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]>C(O)(=O)C.[Zn]>[F:33][C:2]([F:1])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:24][CH2:25][OH:26])=[N:21][CH:22]=2)=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(CCO)[n+]([O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(CCO)nc1
Yield: 90.3 %

Procedure:
To a solution of 5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-(2-hydroxyethyl)pyridine 1-oxide (2.29 g, 4.74 mmol) in acetic acid (24 mL), zinc powder (6.2 g, 94.7 mmol) was added, and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was filtered using celite, added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine and dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/acetone) and 2-(5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)pyridin-2-yl)ethanol (2.0 g, yield 90%) was obtained as a yellow oil.
Reaction SMILES: [CH:1](O)=O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=1)([O-:6])=[O:5].[OH-].[NH4+]>Cl>[CH:12]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:8][C:9]2[NH:14][CH:1]=[N:13][C:10]=2[CH:11]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2nc[nH]c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
15 ml of formic acid were added to a suspension of 15.3 g of 4-nitro-1,2-phenylenediamine in 150 ml of 10% hydrochloric acid and the mixture was stirred on a water bath at 80° C. for 3 hours and was cooled. The mixture was made alkaline with concentrated ammonium hydroxide solution and the mixture was filtered. The yellowish needles were washed with water and dried over P2O5 under reduced pressure to obtain 14.3 g (89% yield) of 5(6)-nitro-benzimidazole melting at 209°-211° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:21][CH2:22][CH3:23])=[C:10]([S:12]/[C:13](=[CH:17]\[C:18]([OH:20])=O)/[C:14]([OH:16])=[O:15])[CH:11]=1.ClS(O)(=O)=O>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:21][CH2:22][CH3:23])=[C:10]2[C:11]=1[C:18](=[O:20])[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[S:12]2
Reactant: CCCc1ccc(OCCC(C)C)cc1S/C(=C\C(=O)O)C(=O)O
Agent: O=S(=O)(O)Cl
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)O)sc12
Reaction time: 0.17 h

Procedure:
65 Parts of [5-(3-methylbutoxy)-2-propylphenylthio] fumaric acid was added portionwise to 240 parts of chlorosulphonic acid over a period of 20 minutes with stirring. The dark, orange solution was allowed to stand for 10 minutes before pouring cautiously into 2000 parts of ice. The resulting solid precipitate was allowed to settle under the gravity. The solid was filtered off, washed with water and sucked dry. At this point the material, became oily and it was extracted into ethyl acetate. The latter was dried over magnesium sulphate, filtered, concentrated in vacuo and allowed to crystallize in the refrigerator. The resulting yellow crystalline solid was collected and dried in vacuo to afford 8.4 parts of the desired product, mp 153° - 154°C (d). Recrystallization from ethyl acetate gave 6.0 parts of 5-(3-methylbutoxy)-8-propyl-1-thiachromone-2-carboxylic acid, mp 156°C (d).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
After N-bromosuccinimide (1.49 g, 6.63 mmol) and 2,2′-azobis(isbutyronitrile) (20 mg) were added to a solution of 4-bromo-1-methyl-2-(trifluoromethyl)benzene (2.0 g, 8.4 mmol) in carbon tetrachloride (20 ml), the mixture was heated under reflux for 5 hours. The temperature of the reaction mixture was returned to room temperature and the residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane) to give crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene. Potassium cyanide (365 mg, 5.6 mmol) was added to a solution of crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene obtained in the above in a mixture of ethanol-water (3:1, 12 ml), and the mixture was stirred at 70° C. for 3 hours. After the reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-5/1) to give [4-bromo-2-(trifluoromethyl)phenyl]acetonitrile as a solid (1.14 g, total yield: 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:27][O:28][C:29](=[O:38])[CH:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:30]([C:29]([O:28][CH3:27])=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reaction time: 15 h
Yield: 96.5 %

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.7 mmol) in DMF (18 mL) was added Cs2CO3 (1.5 g, 4.4 mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 mL, 4.0 mmol). After 15 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 1.6 g (96%) of the title compound. 1H NMR (CDCl3): 7.55-7.33 (m, 2H), 7.43-7.36 (m, 3H), 6.85 (d, J=1.2, 2H), 6.51 (t, J=1.2 Hz, 1H), 5.58 (s, 1H), 4.91-4.85 (m, 1H), 4.31-4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.89-3.74 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].S(=O)(=O)(O)O>>[CH3:3][CH:2]1[O:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4][CH2:1]1
Reactant: C=CCNC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1CN=C(c2ccccc2)O1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[C:7]([CH3:20])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:10]=1.CC[N+](CC)(CC)CC.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:7]1[C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:10][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[N:8]=1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1/C=C/C#N
Yield: 191.3 %

Procedure:
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solution was then diluted with ethyl acetate and washed with water (×2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60° C. for 4 h, 9 mg, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH2:18].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrCCCCBr
Reactant: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N)CC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2

Procedure:
1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (6 g, 19.88 mmol) was dissolved in acetonitrile (150 mL). 1,4-Dibromobutane (2.61 mL, 21.87 mmol) and triethylamine (6.1 mL, 43.7 mmol) were added and the reaction mixture heated under reflux for 3 h. The reaction mixture was poured on ice and extracted with dichloromethane. The combined organic extracts were successively washed with water and brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product (6.6 g) was used for the next step without further purification.