Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)[C:8]=2C)[N:3]=1.[CH3:28]N(C=NC1N=C(N=CN(C)C)C2C(=CC=C(C3C=C(C(F)(F)F)C=C(C(F)(F)F)C=3)C=2C)N=1)C>COC(OC)N(C)C>[CH3:28][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[C:16]([C:24]([F:26])([F:25])[F:27])[CH:15]=3)[CH:8]=2)[N:3]=1
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc2nc(N=CN(C)C)nc(N=CN(C)C)c12
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc2nc(N)nc(N)c12
Agent: COC(OC)N(C)C
Product: Cc1ncc2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.0026 mole) of 2,4-diamino-5-methyl-6-[3,5-di(trifluoromethyl)phenyl]quinazoline (Compound 63-prepared as in Example 1) in 20 mL of dimethylformamide dimethyl acetal was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was then triturated with petroleum ether, and the resulting solid was collected by filtration. The filter cake was washed with petroleum ether and dried, yielding about 1.1. grams of 2,4-di(dimethylaminomethyleneamino)-5-methyl-6-[3,5-di(trifluoromethyl)phenyl]quinazoline, mp 208°-210° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[Si]([O:14][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[CH3:22][CH2:23][CH2:24][CH2:25]CC>>[C:1]([CH2:2][CH2:22][CH2:23][CH2:24][CH2:25][OH:14])([OH:4])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: O=C(O)CCCCCO

Procedure:
The above solid is suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to 0° C., treated with 35 g of imidazole, stirred for 15 min at 0° C. and 15 min at ambient temperature, cooled to 0° C. and treated with 39 g of t-butyldimethyl silylchloride. The resulting solution is then allowed to warm to ambient temperature under a nitrogen atmosphere. After 26 hr, the resulting solution is treated with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol, with stirring maintained under a nitrogen atmosphere. After 13 hr, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts are then washed with 1 N aqueous sodium hydroxide. The basic extracts are then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine, and extracted with ethyl acetate. The ethyl acetate extracts are then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 22.6 g of a yellow liquid, 5-carboxypentanol, t-butyldimethylsilyl ether. Chromatography on 800 g of silica gel eluting with ethyl acetate and hexane (1:9 to 1:1) yields 14.8 g of 5-carboxypentanol, t-butyldimethylsilyl ether. NMR absorptions are observed at 0.05 (singlet) and 0.90 (singlet)δ. Infrared absorptions are observed at 3000 (broad) and 1700 cm-1.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[CH3:12])[O:17][CH2:13][CH2:14][O:4]1
Reactant: Cc1cc(Br)ccc1C(=O)CBr
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(Br)ccc1C1(CBr)OCCO1
Reaction time: 8 h

Procedure:
To a stirred mixture of 78.8 parts of 2-bromo-1-(4-bromo-2-methylphenyl)-1-ethanone and 200 parts of butanol are added 3 parts of 4-methylbenzenesulfonic acid and 225 parts of benzene. Then there are added dropwise 33.5 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred with 15 parts of a concentrated sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The combined organic layers are washed with water (till neutralization), dried, filtered and evaporated. The solid residue is crystallized from methanol, yielding 30.5 parts of 2-(bromomethyl)-2-(4-bromo-2-methylphenyl)-1,3-dioxolane; mp. 86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.[H][H]>ClCCl.C(OCC)(=O)C.[Pd]>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=1[CH2:7][N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CNCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1cc(Cl)ccc1N)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.15 g (4.2 mmol) of ethyl (5-chloro-2-nitrobenzyl)aminoacetate was dissolved in 20 ml of dichloromethane. 0.64 ml (5.1 mmol) of 4-chlorobenzoyl chloride and 0.88 ml (6.3 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 20 ml of ethyl acetate. 120 mg of 10% palladium/carbon was added to the obtained solution and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction solution was filtered through Celite. The solvent was evaporated and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH-].[K+].[S:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5][CH2:4]1.[CH3:14][C:15]1[N:19]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:17][C:16]=1[CH:39]=O>CO>[CH3:14][C:15]1[N:19]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[N:17][C:16]=1/[CH:39]=[C:5]1/[CH2:4][S:3][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]/1=[O:13]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCSc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C2/CSc3ccccc3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3.5 h
Yield: 74.4 %

Procedure:
A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was added to a solution of thiochroman-4-one (0.93 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2 g) in methanol (25 ml), and the resulting solution was stirred at 50° for 3.5 h. The resultant precipitate was filtered off, washed with methanol (20 ml) and dried to give the title compound (2.1 g), m.p. 225°-226°.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32](O)[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH:10]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:24])[N:7]=4)[N:18]=3)[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH3:33]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(O)cc2OCC3)n(C(C)C)n1
Reactant: CC(O)c1ccncc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4ccncc4F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.92 mmol), 1-(3-fluoropyridin-4-yl)ethanol (195 mg, 1.38 mmol) and PPh3 (411 mg, 1.57 mmol) in dioxane (5 mL) was added DIAD (325 μL, 1.57 mmol) and the resulting yellow solution stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and 1M NaOH, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) then triturated with TBME affording 167 (220 mg, 53%). LCMS: RT 4.36 min [M+H]+ 449.3. 1H NMR (DMSO, 400 MHz): δ 8.47 (1H, d, J=1.61 Hz), 8.39-8.36 (2H, m), 7.56 (1H, s), 7.39-7.34 (1H, m), 6.69 (1H, dd, J=8.99, 2.60 Hz), 6.46 (1H, d, J=2.57 Hz), 5.91-5.83 (1H, m), 5.66 (1H, q, J=6.47 Hz), 4.44-4.43 (2H, m), 4.39-4.35 (2H, m), 2.40 (3H, s), 1.68 (3H, d, J=6.45 Hz), 1.55 (6H, d, J=6.65 Hz)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=1.[CH:18](=O)[CH2:19]C.CCCCCCC>C1(C)C=CC=CC=1>[N:1]1([CH:18]([NH:10][C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=2)[CH3:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCC=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(NC(C)n2nnc3ccccc32)n(C)n1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
Benzotriazole (2.14 g, 18 mmol) and dry toluene (24 mL) were charged to a flask under an argon atmosphere. A solution of 5-amino-1,3-dimethylpyrazole (2 g, 18 mmol) in toluene (10 mL) was added to the benzotriazole solution over approximately 0.5 min, followed by the drop-wise addition of propionaldehyde (1.14 g, 19.8 mmol). After this reaction mixture was stirred for 24 hours, n-heptane (30 mL) was added and slurry was stirred for an additional 1 hour, after which time the n-heptane was decanted off, and the pasty residue was dried under vacuum to afford the title compound (4.04 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH2:41]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[CH3:42]>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[C:2]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([CH2:41][CH3:42])[CH:44]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1cccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)c1
Yield: 97.7 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid (145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][C:12](Cl)=[O:13].[CH2:15]([N:19]=[C:20]=[S:21])[CH2:16][CH2:17][CH3:18]>>[CH2:15](/[N:19]=[C:20]1\[S:21][CH2:11][C:12](=[O:13])[N:4]\1[C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cccc(N)c1C
Reactant: CCCCN=C=S
Reactant: O=C(Cl)CCl
Product: CCCC/N=C1\SCC(=O)N1c1cccc(C)c1C

Procedure:
2-[(Z)-n-butylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is prepared following Method B and starting from 2,3-dimethylaniline, chloroacetyl chloride and n-butylisothiocyanate. LC-MS: tR=0.80 min, [M+1]+=277, 1H NMR (CDCl3): δ 7.23-7.16 (m, 2H), 6.99-6.94 (m, 1H), 4.01 (s, 2H), 3.38-3.23 (m, 2H), 2.33 (s, 3H), 2.05 (s, 3H), 1.59-1.49 (m, 2H), 1.38-1.25 (m, 2H), 0.91 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: O=C(O)CC1CCNC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C(O)CC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-acetic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and pyrrolidin-3-yl-acetic acid following General Procedure B.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2F)n1
Product: Nc1nnc(-c2cccc(Cl)c2)c(-c2ccc(F)cc2F)n1
Yield: 18 %

Procedure:
6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (23 mg, 15%) was prepared from 6-bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 0.40 mmol) and 3-chlorophenylboronic acid (0.07 g, 0.40 mmol) according to the general procedure of Example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (13.4 g), methyl 5-hydroxypyridine-3-carboxylate (9.84 g), anhydrous potassium carbonate (8.90 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (12.42 g, 59%) of methyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl([O-])=[O:13].[Na+].O1CCOCC1.S(=O)(=O)(O)N>O>[F:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[C:10]([OH:13])=[O:11]
Reactant: COc1ncc(F)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
In a round bottom flask, 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.500 g, 3.22 mmol) was combined with sodium chlorite (0.6734 g, 5.957 mmol), 30 mL of 1,4-dioxane, 10 mL of water, and sulfamic acid (2.39 g, 24.6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then poured into 100 mL of water and extracted with 100 mL of ethyl acetate. The organic layer was washed with water, brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (150, 512 mg), used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:30]3[S:29][CH:28]=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1csc(-c2ccc(N(c3ccc(-c4cccs4)cc3)c3ccc(-c4cccs4)cc3)cc2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
First, 1 g (2 mmol) of tris(4-bromophenyl)amine (Aldrich) was dissolved in 100 ml of toluene, and then 2.9 ml (4.5 eq.) of 2-tributylstannylthiophene and 27 mg (1.1%) of Pd(PPh3)4 were added thereto. The mixture was refluxed under a nitrogen atmosphere for 12 hours. The reaction mixture was allowed to cool to room temperature, washed with brine twice, and dried over MgSO4. After the solvent was evaporated, the obtained residue was washed with petroleum ether (PE), and dried, affording 0.87 g (yield: 85%) of tris[4-(2-thienyl)phenyl]amine as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH:8]=[CH:9][C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH:14]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>O>[C:25]([O:1][CH2:2][C:3]1[S:7][C:6]([CH:8]=[CH:9][C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH:14]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: OCc1ccc(C=Cc2csc3ccccc23)s1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1ccc(C=Cc2csc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred solution of 3-[2-(5-hydroxymethyl-2-thienyl)ethenyl]-benzo[b]thiophene (5.35 g) and pyridine (50 ml) was added over 5 mins acetyl chloride (1.54 g). The mixture was stirred at ambient temperature overnight and was poured into water (500 ml). The mixture was extracted with dichlormethane, and the combined organic phase was washed with 5% aqueous hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, sample loaded in dichloromethane, eluted with 15% ethyl acetate in hexane.) The appropriate fractions were combined and concentrated. The residue was recrystallized from cyclohexane to afford 3.15 g (51%) of product, mp 66°-68° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.ClC([CH2:33][CH:34]=[O:35])C([O-])=O.CO.C(=O)([O-])[O-:39].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[OH:39][CH2:33][C:34]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)=[O:35]
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: O=C([O-])[O-]
Reactant: O=CCC(Cl)C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)CO)cn3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.417 mmol) in N,N-dimethylacetamide (5 mL) was added 2-chloro-2-oxoethylacetate (45.0 μL, 0.419 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane→2% methanol-ethyl acetate) to give the title compound (70.1 mg, 40%) as a pale-yellow solid.
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:23]1([CH2:29][C:30](N)=[NH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N>C(O)C.CCOCC>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:30](=[NH:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CC(CNC(=N)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (6.0 g.) was added to a suspension of phenylacetamidine p-toluenesulphonate (12.4 g.) in absolute ethanol (20 ml.). The mixture was heated to reflux for 4 hours by which time the initially vigorous evolution of ammonia had practically ceased. The resulting solution was cooled somewhat and diluted with ether to give an oil which rapidly crystallised on scratching. The solid was filtered and recrystallised from a mixture of ethanol and water to give N-(2-phenoxypropyl)phenylacetamidine p-toluenesulphonate, m.p. 127°-129°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N[C:15]1C=C(C)C=CC=1C(O)=O>>[NH2:1][C:2]1[CH:11]=[C:10]([CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(OC)ccc1N
Reactant: Cc1ccc(C(=O)O)c(N)c1
Product: COC(=O)c1ccc(C)cc1N

Procedure:
In a manner similar to that described above for methyl 2-amino-5-methoxybenzoate, 1.90 g of 2-amino-4-methylbenzoic acid was converted to i-g (94%): MS m/z=166 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:27](O)(=O)[CH3:28].C(=O)([O-])O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23][CH2:27][CH3:28])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)cc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-[(4-{2-[(4-Chlorophenyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.03 g) synthesized in Example 286-2 and heptylaldehyde (0.34 g) were dissolved in dichloroethane (15 mL), acetic acid (171 μL) and hydrogenated tri(acetoxy)boric acid (0.79 g) were successively added thereto, and the mixture was stirred at room temperature for 2.5 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (1.07 g) as a colorless oil.