Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.O>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
5-Hydrox-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (550 mg, 1.3 mmol), 550 mg (4 mmol) of K2CO3 and 0.2 mL of methyl acrylate in 40 mL of acetone was heated to maintain reflux for 100 hours (additional methyl acrylate was added at various times). After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2SO4). After concentrating, the residue was chromatographed on silica (eluted with CH2Cl2→1% MeOH/CH2Cl2) and crystallized from CH2Cl2/ether to give 375 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]-propanic acid methyl ester, mp, 113-115° C.
Reaction SMILES: C1([C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:12][CH:7]=2)=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: c1ccc(-c2ccccc2-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: -5 °C
Yield: 119 %

Procedure:
After a mixture of 172 g of terphenyl, 860 ml of benzene, and 353 g of acetyl chloride was cooled to -5° C., it was added with a total of 200 g of anhydrous aluminium chloride in few instalments, and subjected to reaction at -5° C. for 1 hour and further at 10° C. for 1 hour. The solid materials thus formed were separated by filtration, washed with a total of 4 liter of methanol in few instalments, and then recrystallized from chloroform to obtain 121 g of 4-acetyl-p-terphenyl, 2. The yield was 59%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:24](Br)[CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:24][CH2:25][OH:26]
Reactant: OCCBr
Reactant: Cc1c(SCCCN)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(SCCCNCCO)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(3-aminopropylthio)-2-pyridyl)methylthio)1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (20 ml) and thereto were added ethylene bromohydrin (0.83 g) and potassium carbonate (1.25 g). The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The residue was subjected to column chromatography and extracted with chloroform-methanol to give 2-((3-methyl-4-(3-(2-hydroxyethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=1[Si](C)(C)C.F>C1COCC1.O>[CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: CCOC(=O)Cn1nnc(C)c1[Si](C)(C)C
Agent: F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc(C)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a solution of 0.77 g (3.2 mmol) of ethyl [4-methyl-5-(trimethylsilyl)-1H-1,2,3-triazole-1-yl]acetate from step A above in 2 mL of THF was added 1.3 mL (32 mmol) of a solution of 50% hydrofluoric acid in water. The resulting mixture was stirred at room temperature for 3 h and then evaporated to dryness in vacuo. Next, 5 mL of a 2.0 N ammonia in methanol solution was added and then the mixture was again evaporated to dryness in vacuo. The mixture was dissolved in dichloromethane, filtered and then evaporated in vacuo to afford the title compound as a clear gum (0.51 g. 93%). 1HNMR (500 MHz, CDCl3) δ: 7.5 (s, 1H), 5.05 (s, 2H), 4.23 (m, 2H), 2.30 (s, 3H), 1.30 (m, 3H).
Reaction SMILES: C([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])(C)C.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44](Cl)=[O:45]>ClCCl>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44]([NH:29][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([OH:28])=[C:17]([N:18]=[N:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:8]([S:5]([OH:4])(=[O:7])=[O:6])=[CH:9]2)=[CH:14][CH:13]=1)=[O:45]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N=Nc2c(S(=O)(=O)O)cc3cc(NC(=O)c4ccc(OC)c(OC)c4)ccc3c2O)cc1
Reaction time: 16 h

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo-napthalene-2-sulfonic acid isopropyl ester (Example 6, 100 mg, 0.24 mmol ) was dissolved in dichloromethane (15 mL) and diisopropylethylamine (84 μL, 62 mg, 0.48 mmol). 3,4-Dimethoxybenzoyl chloride (56 mg, 0.28 mmol) was added under nitrogen and the reaction mixture was allowed to stir for 16 h. The solution was washed with water, 1N HCl, and saturated sodium bicarbonate solution. The organic layer was dried with MgSO4 and concentrated. This concentrate was purified by chromatography (silica gel, eluent: 50% ethyl acetate/hexane) to provide the sulfonic acid, isopropyl ester (27 mg, 0.047 mmole, 17%). This ester (16 mg, 0.028 mmole) was suspended in 2-butanone (0.5 mL) and sodium iodide (6 mg, 0.041 mmole) was added. The resulting suspension was heated with stirring to 60° C. for 72 h. The solvent was removed under a stream of nitrogen. The remaining solid was suspended in acetone and filtered to provide the title compound (9 mg, 0.016 mmole, 67%, calculated from the isopropyl ester) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.39 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.68 (d, J=9 Hz, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.10 (m, 3H), 3.95 (m, 9H): Analytical HPLC: 82% pure: MS (ES-NEG): [M−H] 536.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([O:35][CH3:36])[C:29](N(OC)C)=[O:30])=[CH:24][CH:23]=2)[CH:21]=[N:20][CH:19]=[N:18]1>>[N:17]1([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([O:35][CH3:36])[C:29]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:30])=[CH:26][CH:27]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cncn2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4cncn4)cc3)o2)cc(OC)c1Br
Yield: 11 %

Procedure:
2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) followed by another purification (40% acetone-hexanes) gave 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a pale yellow solid (0.078 g, 11% yield). MS: ink 498.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[C:5]([CH3:10])([CH3:9])[NH:4][C:3]1=[O:11].C([Li])CCC.CCCCCC.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26].P([O-])([O-])([O-])=O>O1CCCC1>[Br:23][CH:24]([CH3:28])[C:25]([N:4]1[C:5]([CH3:9])([CH3:10])[C:6]([CH3:8])([CH3:7])[N:2]([CH3:1])[C:3]1=[O:11])=[O:26]
Reactant: CC(Br)C(=O)Br
Reactant: CN1C(=O)NC(C)(C)C1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Br)C(=O)N1C(=O)N(C)C(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 1,4,4,5,5-pentamethylimidazolidin-2-one (14 mg; 0.091 mmol) in dry tetrahydrofuran (0.2 ml), a 1.57 N solution of n-butyl lithium in hexane (0.06 ml; 0.1 mmol) was added at 0° C. After 5 minutes, a solution of 2-bromopropionyl bromide (24 mg; 0.11 mmol) in dry tetrahydrofuran (0.1 ml) was added thereto at the same temperature and followed by stirring for 10 minutes. A phosphate buffer (pH 7.0) was added to decompose the excess reaction agent. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were successively washed with a 5% aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (benzene:ethyl acetate=5:1) to give 3-(2'-bromopropionyl)-1,4,4,5,5-pentamethylimidazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13]([C:12]1[C:11]([CH3:18])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:14])[CH3:17]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxobutanoate as a yellow solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH3:5][N:6]([C@@H:8]1[C:26](=[O:27])[C:25]([C:28]([NH2:30])=[O:29])=[C:24]([OH:31])[C@:23]2([OH:32])[C@H:9]1[CH2:10][C@H:11]1[C:20]([C:21]2=[O:22])=[C:19]([OH:33])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][C:17]=2[OH:34])[CH2:12]1)[CH3:7].[CH2:36]1[CH2:40]OC[CH2:37]1>>[CH:37]1([C:14]2[CH:15]=[CH:16][C:17]([OH:34])=[C:18]3[C:13]=2[CH2:12][C@@H:11]2[C:20]([C:19]3=[O:33])=[C:21]([OH:22])[C@@:23]3([OH:32])[C@H:9]([C@H:8]([N:6]([CH3:7])[CH3:5])[C:26]([OH:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]3=[O:31])[CH2:10]2)[CH2:36][CH2:40]1
Reactant: C1CCOC1
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Agent: [Cl-]
Agent: [In+3]
Product: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(C5CC5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1000 mL 2 or 3 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After the flask cooled to ambient temperature and was flushed with argon, anhydrous THF (240 mL) was added. The solution was cooled to −78° C. and c-PrMgBr (244 mL, 122 mmol) as a 0.5 M solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form a clear heterogeneous solution. To the reaction flask was added 7-iodosancycline (19.4 g, 36.0 mmol) and Pd(t-Bu3)2 (0.920 g, 1.80 mmol). The solution was heated to reflux under argon until complete (approximately 1 hour). After cooling to ambient temperature, the solution was quenched with MeOH (1 mL) and poured into a stirring cold solution of 1M HCl (3 L). After 1 hour, the solution was filtered through a pad of Celite, while rinsing with water. The water solution was loaded onto a DVB column for solid phase extraction and the product was isolated by eluting with 1% TFA/CH3CN. The crude product was further purified by preparatory HPLC (C18, linear gradient 20-60% acetonitrile in water with 0.1% TFA, to afford 11.8 g in 72% yield as a yellow solid. 1H NMR (CD3OD) δ 7.18 (d, J=7.4 Hz, 1 H), 6.61 (d, J=7.4 Hz, 1 H), 3.99 (s, 1 H), 3.34 (dd, J=9.1, 2.8 Hz, 1 H), 3.05-2.84 (m, 10 H), 2.32-2.09 (m, 2 H), 0.86-0.75 (m, 2 H), 0.51-0.37 (m, 2 H). LC/MS (MH+) 455.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl.O1CCO[CH2:20]1>>[ClH:1].[CH3:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:20]1
Reactant: Cc1ccccc1CNCCc1cccs1
Reactant: C1COCO1
Agent: Cl
Product: Cc1ccccc1CN1CCc2sccc2C1
Temperature: 10 °C
Yield: 62.7 %

Procedure:
N-[(2-methylbenzyl)]-2-(2-thienyl)ethylamine HCl (26.8 g, 0.1 moles) is suspended in 75 ml of 1,3-dioxolane. 0.25 ml of 37% hydrochloride acid is added. The reaction mixture is refluxed for 24 hours. Thereafter, the mixture is cooled to 10° C. and the crystalline precipitate is filtered and washed twice with 5 ml of isopropanol. The product is dried at 60° C. under vacuum to yield 17.4 g (62.7%) of 5-(2-methylbenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine HCl having a m.p. of 207-210° C.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][C:15]([CH3:22])([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:16])[C:11](Cl)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][C:15]([CH3:16])([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:22])[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Reactant: ON=C1CSCCS1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1CSCCS1

Procedure:
Prepared as in Example 1 by reacting 8.0 g (0.053 m) of 2-oximino-1,4-dithiane, 15.2 g (0.058 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 5.42 g (0.053 m) of triethylamine in 100 ml of dioxane. The product crystallized from isopropyl ether-ethyl acetate to yield 4.3 g of a white solid, (m.p. 80°-82° C.) Recrystallization raised the melting point to 85°-86° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(N2CCN(Cc3ccccn3)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of pyridine-2-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 8.52 (d, J=6.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.50-7.19 (m, 4H), 6.84 (dd, J=3.6 Hz, 1.0 Hz, 1H), 4.09-4.06 (m, 4H), 3.89 (br s, 2H), 2.51-2.41 (m, 4H) ppm. MS: m/z: 378 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH2:14].[N:15]([O-])=O.[Na+].[ClH:19]>O>[ClH:19].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:14][NH2:15]
Reactant: O=N[O-]
Reactant: Nc1cc(-c2ccccc2)ccc1Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(-c2ccccc2)ccc1Br
Temperature: 0 °C

Procedure:
To 4 g of 4-bromo-[1,1'-biphenyl]-3-amine were added 25 ml of water and 50 ml of concentrated HCl with stirring. The solution was cooled to 0° C. A solution of 1.1 g of sodium nitrite in 6 ml of water was then added dropwise while maintaining a temperature of 0° C. After this addition, the mixture was stirred at 0° C. for one hour. A solution of 20 g of stannous chloride in 20 ml of concentrated HCl cooled to -20 C. was added to the reaction mixture and again the mixture was stirred for one hour.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][N:6]=1)([O:3][CH3:4])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:9]([C:8]2[CH:12]=[CH:13][C:5]([C:1]([O:3][CH3:4])=[O:2])=[N:6][CH:7]=2)=[O:10])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Reactant: C1COCCN1
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)cn1

Procedure:
In step b, the acid chloride 11 is amidated with morpholine 12 by techniques and procedures well known and appreciated by one of ordinary skill in the art to give the corresponding 5-(morpholine-4-carbonyl)-2-pyridinecarboxylic acid, methyl ester 13.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:23]2[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccn2)c1C
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)c2ccccn2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 97.1 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-2-yl-methanone (550 mg, 2.22 mmol), (R)-2-methyl-piperazine (320 mg, 3.20 mmol) are added into a microwave vial followed by NMP (6 mL) and triethylamine (0.92 mL, 6.66 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 1 h. The crude material is directly purified via flash chromatography on silica gel (20-70% methanol in CH2Cl2) to afford the title compound (671 mg, 97%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[F:26])[C:20](O)=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36])[CH3:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][N:35]([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([F:26])=[C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[O:27][CH3:28])=[CH:14][CH:13]=2)[CH:18]=1)[CH3:36])[CH3:31]
Reactant: CCOC(=O)CNC
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cc(C(=O)O)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1ccc(F)c(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of 3-(4′,5′-difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid (0.3 g, 0.77 mmol) and N-methyl-glycine ethyl ester hydrochloride (0.7 g, 4.5 mmol) in methylene chloride (40 mL) was added HOAT (0.2 g, 1.46 mmol), EDCI (0.3 g, 1.56 mmol) and triethylamine (1.4 mL, 10 mmol). The mixture was stirred at room temperature for 3 hrs and extracted with methylene chloride and dilute hydrochloric acid. The organic layer was dried and concentrated. The residue was purified through flash column chromatography (80 g silica gel, 5% to 60% ethyl acetate in hexanes over 25 minutes) to give amorphous material as {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoyl]-methyl-amino}-acetic acid ethyl ester (0.29 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].CCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: -15 °C

Procedure:
A mixture of 25 g (0.11 mol) N-(2′-chloro-6′-fluorophenyl)-4-methylaniline and 40 ml (0.5 mol) of chloroacetylchloride is heated under a nitrogen atmosphere for 15 minutes at 60°. The solvent is evaporated under reduced pressure to give an oil which is dissolved in 25 ml of ethyl acetate. Pentane (250 ml) is added dropwise over 15 minutes to precipitate the product. The mixture is cooled to −15° C. and the solid is filtered and washed with pentane to give N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline, m.p. 80-83°.