Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.NCC1C=CC=CN=1.[NH2:108][CH2:109][C:110]1[CH:111]=[C:112]([OH:116])[CH:113]=[CH:114][CH:115]=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:108][CH2:109][C:110]4[CH:115]=[CH:114][CH:113]=[C:112]([OH:116])[CH:111]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCc1cccc(O)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Agent: NCc1ccccn1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cccc(O)c6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethyl-amino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by 2-aminomethyl pyridine with 3-aminomethyl-phenol. MS (ES+) m/e 744.48 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cccc(OC)c3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.41 mmol, 1.00 equiv), 3-methoxyphenylboronic acid (188 mg, 1.23 mmol, 3.00 equiv), Pd(PPh3)4 (94 mg, 0.08 mmol, 0.20 equiv), K3PO4 (346 mg, 1.64 mmol, 4.00 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 50 mg (33%) of methyl 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[S:20][C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[S:20][C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCc1ccc(CN(C(=O)C2CCCc3ccccc32)c2ccc(C(C)C)cc2)s1
Yield: 10.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.7 g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as starting materials, N-[(5-ethylthiophen-2-yl) methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.S(Cl)([Cl:14])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([Cl:14])[CH2:6][CH2:5]2
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2cc(Br)ccc21
Solvent: ClCCl
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 47.2 (11.1 mmol) and thionyl chloride (44 mmol) in DCM (20 mL) was stirred at room temperature overnight. After evaporation of solvent, 47.3 was obtained and it was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:11])=O>>[ClH:11].[Cl:11][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCCC1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCCN1CCCC1
Yield: 49.5 %

Procedure:
2-pyrrolidin-1-ylethanol (6.24 g, 0.05 mol) was stirred while cautiously adding thionyl chloride (40 mL, 0.54 mol). The stirred mixture was refluxed for 1 hour under nitrogen atmosphere, then concentrated in vacuo. The residue was triturated with diethyl ether to give a solid, and the liquid decanted; this process was repeated several times, until the decantate was almost colorless. The flask containing solid was evaporated to give a free-flowing, cocoa-colored solid (4.21 g, 46%). 1H-NMR (CD2Cl2): δ 13.1 (br s, 1 H), 3.97 (t, 3 H), 3.7 (m, 2 H), 3.33 (dd, 2 H), 2.81 (m, 2 H), 2.14-1.95 (m, 3 H).
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3]([CH3:6])=[N:4][OH:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N([CH2:25][CH3:26])CC)C>O1CCOCC1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:5][N:4]=[C:3]([CH3:6])[C:2]([CH3:1])=[N:7][O:8][S:15]([C:12]2[CH:13]=[CH:14][C:25]([CH3:26])=[CH:10][CH:11]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(=NO)C(C)=NO
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Product: CC(=NOS(=O)(=O)c1ccc(C)cc1)C(C)=NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A mixture containing 70 ml of dioxane, 2.3 g (0.02 mole) of dimethylglyoxime, 3.8 g (0.02 mole) of p-toluenesulfonyl chloride and 2.0 g (0.02 mole) of triethylamine was stirred for several days at room temperature. Dioxane was then removed by evaporation under reduced pressure and the solid residue stirred in ice water. The slurry was filtered and the solid material (4.1 g) was dried in a vacuum oven. The solid had no definite melting point.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.Cl[C:30]1[NH:31][CH2:32][CH2:33][N:34]=1>CC(O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:30]4[NH:34][CH2:33][CH2:32][N:31]=4)=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 87.7 %

Procedure:
A mixture of 4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.28 g, 0.83 mmol) and 2-chloro-2-imidazoline sulfate (0.25 g, 1.25 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on neutral aluminum oxide, eluting with 1% methanol/dichloromethane, to give 2-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.29 g, 89%) as a foam. Analysis for C21H26N4O2S.5H2O: Calc.: C, 61.89; H, 6.68; N, 13.75; Found: C, 62.00; H, 6.52; N, 13.85.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:8]3([CH2:10][CH2:9]3)[S:7][C:6]=2[CH:13]=1.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:8]3([CH2:10][CH2:9]3)[S:7][C:6]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: Nc1ccc2c(c1)SC1(CC1)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)SC1(CC1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 2 ml of acetic acid and 2 ml of acetic anhydride was dissolved 9.5 mg of 6-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as obtained in Example 6, and the solution was stirred at room temperature for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of silica gel. Recrystallization of the resultant crude crystals from ethanol-water (1:2) yielded colorless needles of 6-acetylaminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting point: 195°-196.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: COCCN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: COCCN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10′ solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][OH:14].[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([O:14][CH2:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(CC2CCCCC2CO)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(CC2CCCCC2COC(C)=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-(3-methoxybenzyl)cyclohexyl]methanol (1.5 g) in pyridine (7.5 mL) was added acetic anhydride (4.1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at ambient temperature for 1 hour. The reaction mixture was added 1M HCl aqueous solution and was extracted with EtOAc. The organic layer was washed with 1M HCl aqueous solution and saturated NaHCO3 aqueous solution, and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford [2-(3-methoxybenzyl)cyclohexyl]methyl acetate (1.57 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]#[N:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC#N)c2cccc(N)c2)cc1OC
Yield: 38.8 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile (0.7 g, 2.3 mmol) in 40 mL of ethyl acetate was added 0.1 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 2.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 15% ethyl acetate/methylene chloride) to afford 0.25 g (56%) of a mixture of the E and Z isomers as a yellow solid: mp 100-101° C.; 1H NMR (CDCl3) δ 7.30-6.59 (m, 14 H); 5.63 (s, 1 H), 5.59 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) δ 163.1, 162.9, 151.1, 150.5, 148.8, 148.7, 146.5, 146.4, 140.4, 138.2, 131.5, 129.5, 129.5, 129.4, 123.2, 122.1, 119.9, 119.0, 118.4, 118.2, 116.8, 116.6, 115.9, 115.0, 112.7, 111.0, 110.7, 93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcd for C17H16N2O3. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.48; H, 6.05; N, 9.58.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[Cl:32][C:33]1[C:34]([OH:40])=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1.[Cl:41][C:42]1[CH:43]=[N:44][C:45]([N:48]2[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]2)=[N:46][CH:47]=1>CCCCCC.CCOCC.CN(C=O)C>[Cl:32][C:33]1[C:34]([O:40][CH:51]2[CH2:50][CH2:49][N:48]([C:45]3[N:46]=[CH:47][C:42]([Cl:41])=[CH:43][N:44]=3)[CH2:53][CH2:52]2)=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: OC1CCN(c2ncc(Cl)cn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=c1cc(OC2CCN(c3ncc(Cl)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a 200 mL recovery flask was added triphenylphosphine (7.34 g, 28.0 mmol) and DMF (40 mL) to produce a nearly complete solution with 2-3 minutes of stirring. To this mixture was added (E)-diethyl diazene-1,2-dicarboxylate (3.80 mL, 24.00 mmol). After stirring at room temperature for 5 minutes, 5-chloro-4-hydroxypyridin-2(1H)-one (Gimeracil) (5.82 g, 40.0 mmol) was added. After stirring at room temperature for 5 minutes, 1-(5-chloropyrimidin-2-yl)piperidin-4-ol (4.27 g, 20 mmol) was added. The reaction mixture was placed under a nitrogen line with a vent and placed in a 100° C. oil bath for 115 minutes. After cooling to room temperature, the clear brown reaction mixture was added to 1000 mL of ether with stirring which resulted in the formation of a tan-pink oily precipitate. To this mixture was added 500 mL of hexane. The mixture was stirred for 5 minutes and then allowed to settle for 10 minutes. The mixture was poured through a medium porosity funnel. The tan-pink solids that were retained were washed with 100 mL of ether/hexane (1/2 ratio) and dried in vacuo to provide 5.06 g of tan-pink solids. The clear, nearly colorless filtrate was concentrated to 54 g of a clear pale amber liquid. This material was dissolved in 500 mL of ethyl acetate and washed with 3×50 mL of water. The ethyl acetate solution was dried with magnesium sulfate, filtered, and concentrated to 20.3 g of tan solids. This was combined with the 5.06 g of tan-pink solids from above and purified on a 60 mm id×160 mm silica gel column eluting as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[PH2](=O)O.II>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 110 °C
Yield: 72.3 %

Procedure:
To a solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol (420 mg, 1.10 mmol) in acetic acid (20 mL) was added phosphinic acid (50% aqueous solution, 0.60 mL, 5.51 mmol) and iodine (700 mg, 2.76 mmol). The resulting solution was heated at 110° C. overnight. Solvents was then removed. The residue was diluted with water and pH was adjusted to 8-10 with 6N NaOH solution. The product was extracted by DCM and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 260 mg (72%) of the title compound. LCMS (method B): [MH]+=327, tR=2.52 min.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1)=O.[C:29](=O)(O)[O-:30].[Na+].C(Cl)Cl>C(O)(=O)C>[O:30]1[CH:29]=[CH:9][CH:10]=[C:11]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1-c1ccco1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1

Procedure:
A solution of 1.77 g of 3-amino-4-furanylpyrazole and 2.32 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide (Example 168) in 50 ml of glacial acetic acid was refluxed for 10 hours. Evaporation of the reaction mixture gave a solid which was treated with a saturated sodium bicarbonate solution and 200 ml of methylene chloride. The solid that precipitated was recovered by filtration and proved to be the desired product (2.57 g, mp 195°-196° C.). An additional quantity of product was isolated from the methylene chloride solution, mp 195°-196° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:4]=1[CH2:5][N:6]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:7]2.B(Br)(Br)[Br:22].CO>ClCCl>[BrH:22].[BrH:22].[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:4]=1[CH2:5][N:6]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:7]2
Reactant: COc1ccc(Cl)c2c1CN(Nc1ccncc1)C2
Reactant: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Oc1ccc(Cl)c2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
To a solution of 2,3-dihydro-4-chloro-7-methoxy-N-(4-pyridinyl)-1H-isoindol-2-amine hydrochloride (1.12 g) in dichloromethane (10 mL) was added boron tribromide (1.0 mL ) at 0° C. The solution was warmed to ambient temperature and stirred for 3 days. Methanol was added, and the mixture was filtered to give 1.2 g (79%) of product, mp>240° C. (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=[O:12].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[C:5]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1c[nH]c2ccc(Cl)cc12
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
110 ml of a solution containing 10 g of 5-chloro-1H-indole-3-carboxylic acid (commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in oil) in 400 ml of DMF at −10° C. After it returns to RT, it is stirred for 1 hour. The reaction mixture is cooled to −20° C. 4.86 ml of methyl bromoacetate is added dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours. The reaction mixture is added to 1 L of EtOAc/1N HCl mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, then dried over Na2SO4 and evaporated to dryness. 8.9 g of the expected compound is obtained in the form of a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][NH:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][N:20]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CNCC2
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc5c(c4)OCCO5)c3C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4 A molecular seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:14]([N:16]2[CH2:30][CH2:29][CH2:28][C@H:17]2[C:18]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])=[O:15])[CH3:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38]>O>[NH2:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39].[C:1]1([CH2:7][C:8]#[C:9][NH:11][C@H:12]([C:14]([N:16]2[CH2:30][CH2:29][CH2:28][C@H:17]2[C:18]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])=[O:15])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)CCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Product: C[C@H](NC#CCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 101.8 %

Procedure:
N-(3-phenylpropionyl)-L-alanyl-L-prolyl-L-proline (1.00 g, 2.41 m mole) was dissolved in a solution of L-arginine (0.42 g, 2.41 m mole) in water (30 ml), and the thus obtained solution was freeze-dried to give N-(3-phenylpropinyl)-L-alanyl-L-prolyl-L-proline L-arginine salt (1.40 g).