Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:34]=[C:33]([C:32]2[CH:35]=[CH:36][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:30][CH:31]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCc1ccc(C#N)cc1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A mixture of 2.06 g of N-methyl-N-phenylsulfonyl-2-chlorobenzohydrazonoyl chloride, 1.30 g of 4-(6-methylhexyl) benzonitrile, 0.93 g of anhydrous aluminum chloride and 5 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide aqueous solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 1.52 g of the given compound (melting point: 64.0°-67.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([C@H:36]([CH2:41][OH:42])[CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32][CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:9])[NH:40][CH2:39][CH2:38][CH2:37][C@H:36]([N:31]([S:28]([C:25]1[CH:24]=[CH:23][C:22]([NH2:21])=[CH:27][CH:26]=1)(=[O:30])=[O:29])[CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:41][OH:42])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Product: COC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-methoxycarbonylamino-3-naphthalen-1-yl-propionic acid and amine intermediate VII. The final product was obtained in 76% yield. Rf=0.57, EtOAc 100%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][N:12]=1.B(Br)(Br)Br>ClCCCl>[S:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:11]([C:3]2[CH:4]=[CH:5][C:6]([OH:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:12]1
Reactant: COc1ccc(-c2nsc3ccccc23)c(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: Oc1ccc(-c2nsc3ccccc23)c(Cl)c1Cl
Temperature: 0 °C
Yield: 95.8 %

Procedure:
A mixture containing 8.2 g of 3-(2,3-dichloro-4-methoxyphenyl)benzisothiazole, 100 ml of 1,2-dichloroethane and 100 ml of BBr3 was refluxed for 30 minutes. Itwas then poured into ice/water and the organic solvent was removed under reduced pressure. The product was then filtered off, washed with hexane and dried to give 7.50 g (96%) of 4-(benzisothiazol-3-yl)-2,3-dichlorophenol.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.OO.[O-][Si]([O-])=O.[Mg+2].O1CCCC1.[F:22][C:23]1[C:31]([O:32][C:33]2[C:38]3=[C:39]([CH3:46])[C:40](C(O)(C)C)=[CH:41][N:37]3[N:36]=[CH:35][N:34]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:47])[NH:27]2>ClCCl>[F:22][C:23]1[C:31]([O:32][C:33]2[C:38]3=[C:39]([CH3:46])[C:40]([OH:7])=[CH:41][N:37]3[N:36]=[CH:35][N:34]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:47])[NH:27]2
Reactant: CCOCC
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Agent: FB(F)F
Agent: O=[Si]([O-])[O-]
Agent: OO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3ncnn4cc(O)c(C)c34)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of BF3•OEt2 (120 mL, 0.948 mol) in dichloromethane (200 mL) at 0° C. was added H2O2 (50% aqueous solution, 4.6 mL, 0.0790 mol). The reaction mixture was stirred at 0° C. for 30 min and then cooled to −20° C. In a separate flask, 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-propan-2-ol from previous step (20 g, 0.0564 mol) was dissolved in dichloromethane (400 mL) using indirect heat to achieve complete dissolution. This solution was then added rapidly via canula (addition time=20 min) to the peroxide solution. The reaction temperature during the addition was between −15° C. and −25° C. After the addition was complete, the reaction temperature was raised to −15° C. and maintained at that temperature for an additional 40 min. The reaction mixture was quenched by the addition of Na2SO3 (200 mL, 20% aqueous solution) and ethanolamine (33% aqueous solution, 300 mL). Both reagents were added at a rate so as to maintain the internal temperature below 0° C. The cooling bath was removed and the reaction mixture was stirred for 2 h and then poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with 5% aqueous citric acid (100 mL), 10% aqueous NaHCO3 (100 mL), water (2×100 mL), and brine (100 mL) and then dried, filtered and concentrated in vacuo to afford an orange foam. The crude material was loaded onto a Florisil® column using tetrahydrofuran as the loading solvent and the column was eluted with 30% ethyl acetate/heptane. The fractions containing the desired product were collected and concentrated in vacuo and then recrystallized from ethyl acetate/heptane. The solids were collected and washed with heptane to afford 9.1 g (52%) of the desired product as an off-white solid. The filtrate was concentrated in vacuo and purified on silica gel using 40% ethyl acetate/heptane as the eluent to afford and additional 2.5 g (14%) of the desired product. Total yield of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol was (11.6 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH2:23][CH:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: OCC1CCOC1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: Fc1cccc(OCC2CCOC2)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-ylmethoxy)-phenyl]-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and (Tetrahydro-furan-3-yl)-methanol in an analogous manner to Example 1273c. Title compound isolated as a white solid (270 mg, 83%). MP=115-116, purity=96%, LCMS 358.48 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.25-7.22 (m, 1H), 6.86-6.82 (m, 2H), 6.76 (d, J=8.4 Hz, 1H), 4.00-3.97 (m, 2H), 3.83-3.76 (m, 3H), 3.63-3.58 (m, 1H), 2.67-2.63 (m, 1H), 2.07-2.01 (m, 1H), 1.68-1.64 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=3)[CH:20]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22](=[CH2:25])[CH:21]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([O:9][CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:32][CH:33]=3)[CH:20]=2)[CH2:15][CH2:16]1
Reactant: Cc1cccnc1CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: C=C1C=CC(C(=O)NC2CC2)=CC1NC(=O)c1ccc(OCc2ncccc2C)cc1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in DCM (5 mL) was added thionyl chloride (200 μl) and the mixture stirred and heated at reflux for 4 h. The mixture was evaporated to dryness. To the residue was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) in acetonitrile (5 mL) and the resulting mixture heated at 80° C. for 16 h. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was concentrated under reduced pressure. Precipitation with DCM in diethyl ether gave the title compound as a solid (270 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.17 (d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82 (s, 1H), 7.97 (d, 2H), 8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: OB(O)c1cccs1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(-c4cccs4)nc23)CC1
Yield: 66.5 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (158 mg, 0.435 mmol) and 2-thiopheneboronic acid (83 mg, 0.653 mmol) were converted to 86 mg of the title compound by the procedure of Example 1 except that a wash with 3:1 chloroform:isopropanol was performed between the base and brine and the solvent system for chromatography was 0-5% methanol/dichloromethane. (67%). MS(FD) m/e 297.2 (M+). EA calculated for C17H19SN3: C, 68.69; H, 6.40; N, 14.14. Found: C, 69.02; H, 6.49; N, 14.23.
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:30])=[CH:28][CH:27]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)=NO
Reactant: O=C(OCc1ccccc1)c1ccc(F)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (3.79 g, 36.8 mmol) in anhydrous DMF (150 mL) under Ar was added tBuOK (4.09 g, 36.4 mmol) all at once. After 40 min benzyl-4-fluorobenzoate 17 (7.63 g, 17.9 mmol) was added and the reaction was stirred at room temperature. After 4 h the reaction was diluted with H2O (500 mL), extracted with EtOAc (4×100 mL), and the combined organics were washed with H2O (2×100 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 19 as a clear syrup (6.02 g, 58%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.0 Hz, 3H), 2.12 (s, 3H), 4.20 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 7.15-7.19 (m, 2H), 7.31-7.35 (m, 2H), 7.36-7.41 (m, 2H), 7.42-7.36 (m, 2H), 8.00-8.14 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.4, 63.1, 66.4, 113.4, 122.9, 128.1, 128.1, 128.6, 131.5, 136.3, 163.5, 166.3, 166.4; GC-MS 228 m/z [M-85]+, benzyl-4-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[C:6]1[CH3:30].O1CCCC1.[OH-].[Li+]>O>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}acetic acid methyl ester (0.21 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (1.2 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (25 mL), concentrated to low bulk under reduced pressure and the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate containing 0.1% formic acid (1:0 to 0:1 by volume), followed by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 by volume) to afford the title compound as a white solid (0.14 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9](Cl)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2].[SH:14][CH2:15][CH:16]([OH:18])[CH3:17]>>[N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9]([S:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2]
Reactant: CNc1cc(Cl)c(N)cc1[N+](=O)[O-]
Reactant: CC(O)CS
Product: CNc1cc(SCC(C)O)c(N)cc1[N+](=O)[O-]
Yield: 97.5 %

Procedure:
11.5 g (0.057 mol) of 2-nitro-4-amino-5-chloro-N-(methyl)aniline and 7.8 g (0.085 mol) of 1-mercaptopropan-2-ol were used as the starting materials to give dark brown crystals (14.3 g) melting at 152° C. (recrystallization from 96° ethanol) whose elemental analysis calculated for C10H15N3O3S was:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][CH:21]=1)=[O:18])(=[O:3])[CH3:2].[N+:30]([O-])([OH:32])=[O:31].O>C(O)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31])=[O:18])(=[O:3])[CH3:2]
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)cc2CCNC(C)=O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CCNC(C)=O)c(C(=O)Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC

Procedure:
To a solution of 200 g of 2-(2-acetamidoethyl)-4,4', 5,5'-tetramethoxydeoxybenzoin in 2000 ml of acetic acid was slowly added 60 ml of 70% nitric acid at 0° C. Immediately after the addition, the mixture was poured into water and extracted with methylene chloride. The extract was neutralized with a sodium hydrogencarbonate aqueous solution and washed with a saturated sodium chloride aqueous solution. The solvent was removed under reduced pressure, and the residue was recrystallized from ethanol to yield 196 g of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:37][CH2:36][NH:35][CH2:34][C:23]=3[N:24]=[C:25]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:37][CH2:36][N:35]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:34][C:23]=3[N:24]=[C:25]([CH2:27][N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCNC3)cc1
Agent: CCN(CC)C(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 30.4 %

Procedure:
A mixture of diisopropylethylamine (35 mg, 0.27 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine (70 mg, 0.18 mmol) and 2,3-dichloropyridine (54 mg, 0.36 mmol) in dioxane (2 mL) and N,N-diethylacetamide (0.2 mL) was heated via microwave in a sealed tube at 180° C. for 10 hr. Solvent was removed in vacuo and residue was purified by column chromatography, product was obtained as a light yellow foam (27 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:18]2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:31]1[CH2:32][CH:33]=[C:34]([C:2]2[C:3]([O:16][CH:17]3[CH2:20][N:19]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH2:18]3)=[N:4][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:35][CH2:36]1
Reactant: OCC1CCN(c2ncc(Br)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: OCC1CCN(c2ncc(C3=CCOCC3)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (1-(5-bromo-4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)methanol (see PREPARATION P7.1; 115 mg, 0.25 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52.5 mg, 0.25 mmol) and K3PO4 (100 mg, 0.5 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (15 mg, 0.02 mmol) then the reaction mixture was stirred at 110° C. under N2 atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2 (30 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give (1-(5-(3,6-dihydro-2H-pyran-4-yl)-4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)methanol (100 mg, 0.21 mmol, yield 84%). ESI-MS (M+1): 474 calc. for C27H31N5O3 473.
Reaction SMILES: Br.C(OC([NH:12][C@@H:13]([CH2:33][C:34](=[O:53])[NH:35]C(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[C:14]([NH:16][C@@H:17]([CH2:21][NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[C:18]([OH:20])=[O:19])=[O:15])=O)C1C=CC=CC=1.C(OCC)(=O)C>C(O)(=O)C>[NH2:12][C@@H:13]([CH2:33][C:34](=[O:53])[NH2:35])[C:14]([NH:16][C@@H:17]([CH2:21][NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[C:18]([OH:20])=[O:19])=[O:15]
Reactant: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CN[C@@H](Cc2c[nH]cn2)C(=O)O)C(=O)O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H](N)C(=O)N[C@@H](CN[C@@H](Cc1c[nH]cn1)C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 30% hydrogen bromide in acetic acid (4.0 ml) was added to (2S)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]propionic acid (772 mg) in an ice-water bath. The mixture was stirred for 15 minutes and then additional portion (4.0 ml) of a solution of hydrogen bromide in acetic acid was added thereto at ambient temperature. The mixture was stirred for 2.5 hours, and poured into a mixture of ice-water (25 ml) and ethyl acetate (25 ml). The aqueous layer was separated and then the remaining organic layer was extracted with water (30 ml). The aqueous layer were combined and subjected to a column of Dowex 50W x 8 (H30 , 20 ml) and the elution was carried out with water (200 ml) and 1.4% aqueous ammonia (250 ml). The fractions containing the object compound were combined and evaporated in vacuo. The residue was dissolved in water (30 ml) and filtered. The filtrate was lyophilized to give a white powder (315 mg) of (2S)-2-[[(2S)-2-amino-3-carbamoylpropionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]propionic acid.
Reaction SMILES: [CH:1]1([CH2:4]OC2C=C(CC3C(N)=NC(N)=NC=3)C=C(OCC)C=2C2C=CC(O)=CC=2)[CH2:3][CH2:2]1.Cl.ClCCN1CCOCC1.C1(CO[C:46]2[CH:51]=[C:50]([CH2:52][C:53]3[C:54]([NH2:60])=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[CH:49]=[C:48]([O:61][CH2:62][CH3:63])[C:47]=2[C:64]2[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[CH:66][CH:65]=2)CC1>>[CH:1]1([CH2:4][C:46]2[CH:51]=[C:50]([CH2:52][C:53]3[C:54]([NH2:60])=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[CH:49]=[C:48]([O:61][CH2:62][CH3:63])[C:47]=2[C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:71][CH2:72][N:73]3[CH2:74][CH2:75][O:76][CH2:77][CH2:78]3)=[CH:68][CH:69]=2)[CH2:3][CH2:2]1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(OCCN2CCOCC2)cc1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(O)cc1
Agent: Cl
Agent: ClCCN1CCOCC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(CC2CC2)c1-c1ccc(OCCN2CCOCC2)cc1

Procedure:
Starting from 2′-cyclopropylmethoxy-4′-(2,4-diamino-pyrimidin-5-ylmethyl)-6′ethoxy-biphenyl-4-ol (example 8h) (300 mg; 0.74 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (170 mg; 0.89 mmol), 129 mg (25%) 5-[2-cyclopropylmethoxy-6-ethoxy-4′-(2-morpholin-4-yl-ethoxy)-biphenyl-4-ylmethyl]-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CC(C)=O.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCCC[N+](CCCC)(CCCC)CCCC.[I-].O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCCCC1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCN1CCCCC1

Procedure:
To 2-tert-butyl-5-nitrophenol (1.01 g) and K2CO3 (1.72 g) was added acetone (35 ml) and H2O (10.5 mL), then 1-(2-chloroethyl)piperidine HCl (1.909 g) and TBAI (153 mg). The mixture was stirred at reflux overnight. Additional K2CO3 (850 mg) and 1-(2-chloroethyl)-piperidine HCl (950 mg) were added and the mixture was heated at reflux for 6 h. The mixture was concentrated in vacuo to an aqueous layer which was acidified with 2N HCl and extracted with EtOAc. The aqueous layer was basified with 6N NaOH and washed with CH2Cl2 (3×). The combined organic layers were washed with brine/1N NaOH and dried over Na2SO4. Washed the EtOAc layer with 2N NaOH/brine and dried over Na2SO4. The crude material was purified by silica gel column chromatography with 15% EtOAc/Hexanes to yield 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine as a light tan solid. (M+1)=307.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:19][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:14][C:13]([F:15])=[C:12]([NH2:16])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (1.306 g, 4.31 mmol) was dissolved in THF (108 ml) and MeOH (108 ml). Ammonium chloride (2.305 g, 43.1 mmol) was then added, followed by zinc dust (2.82 g, 43.1 mmol). The reaction mixture was stirred for 1 hour at RT. The solids were filtered over Celite® and the solution was concentrated under reduced pressure to yield 5-chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine as a brown solid which was used without purification assuming a 100% yield. MS (ESI) m/z: 273.0 (M+H+).