Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:12])=[N:3][C:4]=1[CH3:10]
Reactant: O=N[O-]
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(C)c1Br
Reaction time: 1 h
Yield: 90.9 %

Procedure:
2-amino-5-bromo-4,6-dimethylpyridine (15 g) was dissolved in a mixed solution of sulfuric acid (14.2 mL) and water (212 mL). A solution of sodium nitrite (6.18 g) in water (31 mL) was added to the solution at 0° C. The reaction mixture was stirred at mom temperature for one hour, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. MTBE was added to the residue to precipitate the solid, followed by filtration. The filtration residue was washed with MTBE to give the title compound (13.7 g).
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([O:11][C:12]([C:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][S:23][C:16]=2[C:15]=1Cl)=[O:13])[CH3:10].[N:25]1([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][S:23][C:16]=2[C:15]=1[N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:26][CH2:27]1)=[O:13])[CH3:10]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Temperature: 120 °C
Yield: 95.8 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (224 mg, 2 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (4) (240 mg, 1 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (215 mg, 1.1 mmol) in dry DMA. The solution was heated at 120° C. for 2 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (400 mg, 96%) as white solids. MP 252° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.31 (m, 4H), 3.77 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 6.97 (d, J=5.6 Hz, 1H), 7.15 (dd, J=3.6, 4.8 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 12.10 (s, 1H) ppm; MS m/z=418 amu (M++1).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1>[CH2:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(Cc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-trityl-imidazole-4-carboxaldehyde (5 g, 14.8 mmoles) in THF (40 mL) is added dropwise a solution of 1M phenylmagnesium bromide in THF (17.7 mL, 17.7 mmoles). The reaction mixture is stirred at room temperature for 3 h, then it is poured into a saturated solution of NH4Cl. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is dissolved in concentrated HI solution (75 mL) and the reaction mixture is heated at reflux overnight. After cooling at room temperature, the reaction mixture is extracted three times with Et2O. The aqueous phase is basified by adding solid Na2CO3 to pH 7, solid NaHSO3 is added until the red colour disappeared and the aqueous phase is extracted three times with Et2O. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure to give 4-benzyl-1H-imidazole.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:28])(=[O:27])[NH:11][C@H:12]([C:21](=[O:26])[N:22]([O:24][CH3:25])[CH3:23])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:29][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[S:10](=[O:27])(=[O:28])[NH:11][C@H:12]([C:21](=[O:26])[N:22]([O:24][CH3:25])[CH3:23])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]([OH:37])=[O:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 36.3 %

Procedure:
To a solution of 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid methyl ester (8.20 g, 15.3 mmol) in tetrahydrofuran (150 mL) at room temperature was added 1N lithium hydroxide (30.5 mL, 15.3 mmol). The reaction was stirred at room temperature for 3.5 h. The reaction was then diluted with ethyl acetate (300 mL) and acidified to pH 2 with 5% citric acid. The organic layer was then washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid as a white foam (2.9 g, 100%). MS(ACI) m/z 521.1 (M−H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13]C([O-])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[CH:13]/[C:12]([O:18][CH2:19][CH3:20])=[O:17])/[O:6]1)=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)/C=C1\OC(=O)c2ccccc21
Yield: 75 %

Procedure:
59.2 g (0.4 mol) of phthalic anhydride, 26.4 g (0.2 mol) of monoethyl malonate, and 15.8 g (0.2 mol) of pyridine are added to 200 ml of toluene, and the reaction mixture is heated under reflux for 4 hours. After terminating the reaction, 100 ml of water is added to the reaction mixture, and an organic layer is separated out. The organic layer is washed with 100 ml of 5%-aqueous acetic acid solution, and toluene is distilled off under a reduced pressure. The residue thus obtained is recrystallized from ethanol, to give 32.7 g (0.15 mol) of ethyl (Z)-3-phthalidylideneacetate. The yield is 75.0%.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O)[N:8]=1.[CH3:25][NH2:26]>CCO>[CH3:25][NH:26][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][S:13][C:9]1[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:23])[F:24])[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (0.18 g.) and a 33% w/v solution of methylamine in EtOH (5 ml.) was stirred at room temperature for 4 days and then evaporated to dryness. The residue was recrystallised from EtOAc to give N-methyl-4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.09 g.), m.p. 153°-155°.
Reaction SMILES: C([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12](I)[C:7]=2[CH:6]=[CH:5]1)(=O)C.[CH3:14][N:15](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:9]1[C:8]2[NH:4][CH:5]=[CH:6][C:7]=2[C:12]([C:14]#[N:15])=[N:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: CC(=O)n1ccc2c(I)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ncnc2[nH]ccc12
Yield: 80 %

Procedure:
A mixture of 7-acetyl-4-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.28 g, 4.46 mmol), zinc cyanide (427 mg, 2.45 mmol), tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.223 mmol) and N,N-dimethylformamide (10 mL) was tightly sealed in a vial, and the microwave was irradiated at 150° C. for 20 min. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) to give the title compound (520 mg, yield 80%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4](O)[O:3]2.[Br-].[C:14]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCC)[CH:19]=CC=C[CH:15]=1>>[CH3:1][C@@:2]1([OH:3])[CH2:8][CH2:7][C@@H:6]([CH2:5][CH:4]=[CH:15][CH2:14][CH3:19])[C:9]1([CH3:11])[CH3:10]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC12CCC(CC(O)O1)C2(C)C
Agent: [Br-]
Product: CCC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Yield: 69.4 %

Procedure:
Using the procedure of Example 7, 5 g of 1,8,8-trimethyl-2-oxa bicyclo [3,2,1] octan-3-ol and 15 g of triphenyl propyl phosphonium bromide were reacted and the product was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 4 g of (1R,S) 1,2,2-trimethyl-3-(2-pentenyl)-cyclopentanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:20]2[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[CH3:11])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:21][CH:20]([C:7]2[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]([CH3:11])=[C:5]([CH:6]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:23]1
Reactant: COC(=O)c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(N(C)C2CCOCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C2CNC2)cc(N(C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 121 %

Procedure:
To a stirred solution of tert-butyl 3-[3-(methoxycarbonyl)-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl]azetidine-1-carboxylate (400 mg, 0.96 mmol) in DCM (4 ml) was added TFA (1 ml) and the solution was stirred at room temperature for 45 min after which the solvent was evaporated to dryness and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with DCM (3×30 ml), washed with brine (30 ml), dried with MgSO4, filtered and evaporated to afford the title compound as an orange oil (370 mg, 95%). LC-MS 96%, m/z=319.1, 1H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J=1.4 Hz, 1H), 7.20 (d, J=1.3 Hz, 1H), 4.32-4.10 (m, 5H), 3.98 (d, J=11.0 Hz, 2H), 3.90 (d, J=8.4 Hz, 3H), 3.34 (t, J=10.8 Hz, 2H), 2.99 (ddd, J=14.7, 10.9, 3.8 Hz, 1H), 2.65 (d, J=8.3 Hz, 3H), 2.51-2.41 (m, 3H), 1.73 (ddd, J=15.7, 12.1, 4.3 Hz, 2H), 1.64 (d, J=11.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1)[C:10]([F:13])([F:12])[F:11].[CH2:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C@@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:24]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:22][C:17]1[N:18]=[C:19]([N:30]2[CH2:29][CH2:28][C:27]3([CH2:23][N:24]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[C@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26]3)[CH2:32][CH2:31]2)[CH:20]=[C:15]([O:14][C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Br:1])[C:10]([F:13])([F:12])[F:11])[N:16]=1
Reactant: Nc1nc(Cl)cc(O[C@H](c2ccc(Cl)cc2Br)C(F)(F)F)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol), and NaHCO3 (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCO3 (300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90° C. for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]2[C:22]([CH3:34])([CH3:33])[O:23][C:24](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:25]=2[C:26]#[N:27])=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:2]=[N-:3].O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[O:42]=[C:37]1[CH2:38][CH2:39][C:40](=[O:41])[N:36]1[O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]2[C:22]([CH3:34])([CH3:33])[O:23][C:24](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[C:25]=2[C:26]#[N:27])[CH:17]=[CH:18][C:4]=1[N:1]=[N+:2]=[N-:3]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N=[N+]=[N-])c(OCCCCCC(=O)O)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N=[N+]=[N-])c(OCCCCCC(=O)ON2C(=O)CCC2=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
The following procedure requires dark room conditions. To a cooled solution (5° C.) of 6-{2-Azido-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid (0.1 g, 0.21 mmol) in dichloromethane (20 ml) was added N-hydroxysuccinimide (0.027 g, 0.24 mmol) and DCC (0.052 g, 0.25 mmol). The resulting solution was allowed to stir at 5° C. for 2 hours and then at room temperature for 12 hours. The solvent was removed under reduced pressure and the resulting dark red solid was purified by column chromatography (70% EtOAc/30% Hexane) to give 6-{2-azido-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester as a dark red solid (0.084 g, 69%). 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, 1H, J=16.4 Hz), 7.24 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.09 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=8 Hz), 6.96 (d, 1H, J=16.4 Hz), 4.13 (t, 2H), 2.87 (s, br, 4H), 2.70 (t, 2H, J=7.2 Hz), 1.98 (m, 2H), 1.91 (m, 2H) 1.82 (s, 6H), 1.68 (m, 2H). 13C NMR (400 MHz, CDCl3) δ: 173.50, 169.25, 168.48, 152.61, 146.50, 133.66, 131.19, 123.40, 121.54, 114.10, 112.07, 111.62, 110.83, 110.29, 97.48, 69.18, 30.85, 29.71, 28.34, 26.55, 25.62, 25.22, 24.22. IR (neat): 3321, 2926, 2850, 2361, 2225, 2128, 2094, 1812, 1783, 1733, 1563, 1536, 1497, 1307, 1292, 1186, 1102, 1064, 1046, 849 cm−1.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:28])[C:22]=3[NH:21][CH2:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:10]([CH2:29][CH2:30][CH3:31])=[CH:11][C:12]([CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:28])[C:22]=3[NH:21][CH2:20]2)=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([OH:5])=[O:4]
Reactant: CCCc1cc(CN2CNc3c2ccnc3Cl)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(CN2CNc3c2ccnc3Cl)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 83.8 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (22 mg, 0.0410 mmol) in methanol (1mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2.5 h. The solvent was removed in vacuo then 5% citric acid solution added. The precipitate was filtered off, washed with water and dried in vacuo to give the titled carboxylic acid (18 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:34]=[O:35])=[CH:4][CH:5]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (11.13 g), 2-hydroxy-1-naphthaldehyde (5.96 g), anhydrous potassium carbonate (5.03 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (13.83 g, 89%) of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthaldehyde. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 141-142° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:29][C:30]1[CH:31]=[C:32]([C:8]2[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)c(F)c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (195 mg, crude) in dioxane (3 mL) was added 3,4-difluorophenylboronic acid (130 mg, 0.80 mmol), K3PO4 (180 mg, 0.8 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and water (5 drops) under a nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (86.0 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[F:12][C:13]1[CH:14]=[C:15]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[OH:36])[CH:16]=[CH:17][C:18]=1[C:19]([O:21]CC1C=CC=CC=1)=[O:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[O:36][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(OCc1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Reactant: BrCCCOC1CCCCO1
Product: O=C(O)c1ccc(-c2cc(F)ccc2OCCCOC2CCCCO2)cc1F

Procedure:
In accordance with the methods of Examples 11-2 and 1-5, 2-(3-bromopropoxy)tetrahydro-2H-pyran was used instead of the compound of Example 11-1, and the compound of Example 13-1 was used instead of the compound of Example 1-3 to afford 3,5′-difluoro-2′-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]biphenyl-4-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[S:9](=O)(=[O:18])([O:11]C1C=CC=CC=1)[NH2:10].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:7][O:6][C:4]([CH:3]([CH3:8])[CH2:2][O:1][S:9](=[O:18])(=[O:11])[NH2:10])=[O:5]
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: COC(=O)[C@@H](C)CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)COS(N)(=O)=O
Yield: 39.6 %

Procedure:
A mixture of 5.9 g (0.05 mole) of (S)-(+)methyl 3-hydroxy-2-methylpropionate, 9.5 g (0.055 mole) of phenyl sulfamate, 25 ml of toluene and 0.5 g of pyridine was heated at reflux for 2 hr. The reaction solution was concentrated under vacuum, and the residue was chromatographed, using silica gel and eluting with 2% methanol in methylene chloride. The desired fractions were concentrated under vacuum to give 3.9 g (40%) of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([CH2:15][CH2:16][NH2:17])=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([CH2:15][CH2:16][NH:17][CH2:20][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)c(CCN)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(CNCCc2nc(C)ccc2OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 675 mg (2.10 mmol) of 2-{3-[(4-bromobenzyl)oxy]-6-methyl-2-pyridinyl}ethylamine and 345 mg (2.10 mmol) of methyl 4-formylbenzoate in 5 ml of ethanol is heated at reflux for two hours. The solvent is then removed under reduced pressure and the resulting residue is dissolved in 5 ml of methanol. A total of 159 mg (4.21 mmol) of solid NaBH4 are added a little at a time. After two hours of stirring at room temperature, the mixture is poured into water and extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over Na2SO4. After filtration, the solvent is removed under reduced pressure and the resulting crude product is purified by preparative HPLC. This gives 351 mg (0.75 mmol, 35% yield) of a colorless oil.