Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C=O.[C:12]([BH3-])#N.[Na+].O>C1COCC1>[CH3:12][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: [BH3-]C#N
Reactant: OCCN1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCO)CC1
Temperature: 50 °C

Procedure:
In THF (30 ml) were added N-(2-hydroxyethyl)piperazine (500 mg, 3.84 mmol), a solution of formaldehyde (3117 mg, 38.41 mmol) and sodium cyanoborohydride (1207 mg, 19.20 mmol). The mixture was heated up to 50° C. overnight under stirring. After cooling some water was added and the mixture was extracted with DCM (3×). The organic layers were dried over MgSO4 and evaporated. The residue was purified over a silica plug with DCM/MeOH 9:1 as eluant to afford an oil (370 mg, Y=67%). 1H NMR (DMSO-d6) δ 4.45 (t, J=5.3 Hz, 1H), 3.51-3.45 (m, 2H), 3.02-2.84 (m, 4H), 2.71-2.64 (m, 2H), 2.61 (s, 3H), 2.58-2.53 (m, 2H), 2.47-2.43 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(C#N)[CH2:66][O:67][CH2:68][CH:69]([C:72]#[N:73])CCl.C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:66][O:67][CH2:68][CH2:69][C:72]#[N:73])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CC(CCl)COCC(C#N)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethylether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)guanosine (384 mg; yield 48%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[C:29]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:28][CH:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[C:29]([O:30][CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[N:28][CH:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1nccnc1OC1CCOCC1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4OC4CCOCC4)C3)nc2c1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
A mixture of cesium carbonate (0.63 g, 1.94 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.14 g, 0.49 mmol), and 2-chloro-3-(tetrahydro-2H-pyran-4-yloxy)pyrazine (0.10 g, 0.49 mmol) in DMA (1 mL) was heated to 100° C. for 16 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.16 g, 0.40 mmol, 83% yield) as a white solid. [M+1] 386. IC50 (uM) 0.9004.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(C)(C)C.[CH2:25]([N:27]([CH2:30][C:31]1[S:35][C:34]([C:36](O)=O)=[CH:33][C:32]=1[CH3:39])[CH2:28][CH3:29])[CH3:26]>Cl.O1CCOCC1.O>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:23]=[C:36]([C:34]3[S:35][C:31]([CH2:30][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[C:32]([CH3:39])[CH:33]=3)[O:22][N:21]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(C(=N)NO)cc1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCCN)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.5 %

Procedure:
Crude (2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzenesulfonylamino}-ethyl)-carbamic acid tert-butyl ester (156 mg) is obtained starting from {2-[4-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-ethyl}-carbamic acid tert-butyl ester (277 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol) according to Method A; LC-MS: tR=0.61 min; [M+1]+=550.16. This material (156 mg, 0.284 mmol) is dissolved in 4 M HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The mixture is diluted with water and washed with EA. The organic washing is extracted with water. The combined aq. extracts are neutralised by adding sat. aq. NaHCO3 solution and extracted twice with EA. These organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge, eluting with a gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (11 mg) as a pale yellow oil; LC-MS: tR=0.42 min; [M+1]+=449.64.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine (0.40 g, 0.90 mmol) was dissolved in dichloromethane (8 mL) and propane-1-sulfonyl chloride (0.169 g, 1.18 mmol) and N,N-dimethylpyridin-4-amine (0.152 g, 1.24 mmol) were added. The reaction mixture was stirred at room temperature over night. Water was added and the aqueous phase was extracted several time with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=99:1). Yield: 0.35 g (0.68 mmol, 76%, colorless oil).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C(O[K])(C)(C)C.[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][NH:20]C>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CNCCN(C)C
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1cc(F)cc(Br)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 1,3-dibromo-5-fluorobenzene (LXXIV) (4 g, 15.75 mmol) in toluene (50 mL) was added tBuOK (5.3 g, 47.25 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (2.778 mL, 31.5 mmol). The reaction was stirred at 110° C. overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→5:95 MeOH:CHCl3) to produce N1-(3-bromo-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXXV) as a brown viscous oil (1.02 g, 3.91 mmol, 24.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.17 (s, 6H), 2.40 (t, J=3.5 Hz, 2H), 3.01-3.09 (m, 2H), 6.10 (t, J=5 Hz, 1H), 6.38 (dt, J=12 Hz, J=2 Hz, 1H), 6.51 (dt, J=8.5 Hz, J=2 Hz, 1H), 6.60 (s, 1H); ESIMS found C12H16BrFN2 m/z 261 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:56]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][Br:56])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A 200 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (3.03 g, 6.18 mmol), anhydrous THF (75 mL), and then triphenylphosphine (3.24 g, 12.4 mmol) and CBr4 (4.10 g, 12.4 mmol). The yellow mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was concentrated. The residue was diluted with EtOAc (500 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a solid. The crude product was purified using a Biotage medium pressure chromatography system (EtOAc:hexanes 10:90) to give a yellow oil (2.95 g, 86%), MS (ES) m/e 572 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 4-fluorophenylisocyanate (0.137 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol. The resulting pale yellow precipitate (identified as the bis-adduct) was isolated by filtration. The filtrate was concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)urea as a white solid, m.p. 145-150° C. Mass spec M+1=469.2. Analysis: C27H25FN6O: %C, 69.21; %H, 5.37; %N, 17.94; Found: %C, 66.70; %H, 5.33; %N, 17.03.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)O)[OH:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:17][C:16]3[CH:18]=[CH:20][CH:21]=[CH:22][C:23]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CCNCC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Brc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 87.3 %

Procedure:
A mixture of (4-bromophenyl)-piperidin-4-yl-methanone (536 mg, 2.00 mmol), catechol (880 mg, 8.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux with a Dean-Stark apparatus to remove water for 68 hours. Standard work-up and purification gave 4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidine (629 mg, 87%) as a yellow foam.
Reaction SMILES: [F:1][C:2]([F:73])([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:72])([F:71])[F:70])=[CH:61][CH:60]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH:16]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][C:48]=2[N+:56]([O-])=O)[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:45])([F:44])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:73])([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:72])([F:71])[F:70])=[CH:61][CH:60]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH:16]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:48]=2[NH2:56])[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:44])([F:45])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:41])([F:42])[F:43])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 89.2 %

Procedure:
8.70 g (8.38 mmol) of 2-(2,4-dinitrophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate is dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.32 g of 2-(2,4-diaminophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([O:20][C@H:21]([CH3:25])[C@H:22]([OH:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[Cl-].[Na+]>C(OCC)C.C(#N)C>[CH2:13]([O:20][C@H:21]([CH3:25])[C@@H:22]([CH3:23])[O:24][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.00 g (23.0 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 5.40 g (30.0 mmol) of (2R,3R)-3-benzyloxybutan-2-ol in 60 ml of diethyl ether and 65 ml of acetonitrile were admixed at 0° C. with 1.21 g (27.7 mmol) of sodium hydride (55% strength), divided into 3 portions, and then stirred for 90 minutes at 15° C. The mixture was admixed with dilute sodium chloride solution and extracted (3×) with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 95:5). This gave 1.60 g (4.4 mmol; yield: 19%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.BrN1C(=[O:16])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)(Cl)Cl.O>[OH:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
The compound of Example 4A (13 g, 110 mmol) is dissolved in 400 ml tetrachloro-methane, and 29.4 g (165 mmol) N-bromosuccinimide and 0.4 g (1.6 mmol) dibenzoylperoxide are added. The reaction mixture is refluxed for three hours, cooled down to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is dissolved in 200 ml dioxane and 200 ml water, calciumcarbonate (44 g, 440 mmol) is added, and the mixture is stirred at reflux for 2 hours. After cooling down to room temperature, the mixture is filtered, and dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent cyclohexane/ethyl acetate 2:1).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C(N)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C(=O)OC)c2ccccc2)c([N+](=O)[O-])c1
Yield: 89.6 %

Procedure:
A solution of methyl 2-amino-2-phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4-fluoro-3-nitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DIEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30° C. in a 100-mL round-bottom flask. The reaction was then quenched by the addition of 200 mL of water, and the solids were collected by filtration. Purification via silica gel column (petroleum ether/EtOAc (50:1)) yielded 3.82 g (90%) of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56](O)=[O:57])([CH3:50])[CH3:49]>CN(C=O)C.O>[CH:48]([C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]([CH3:59])[C:56]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:57])([CH3:49])[CH3:50]
Reactant: CC(Oc1cccc(C(C)C)c1)C(=O)O
Reactant: CC#CC(CC(=O)OCC)c1ccc(N)cc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Reaction time: 72 h

Procedure:
To a solution of 200 mg (0.75 mmol) of ethyl 3-(4-aminophenyl)hex-4-ynoate, 258 mg (2.24 mmol) of N-ethylmorpholine, 126 mg (0.82 mmol) of HOBt hydrate and 128 mg (0.82 mmol) of EDAC in 3 ml of DMF was added a solution of 202 mg (0.74 mmol) of 2-(3-isopropylphenoxy)propionic acid in 2.5 ml of DMF. After 72 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. This gave 156 mg of ethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[CH3:7][O:8][SiH:9]([O:12][CH3:13])[O:10][CH3:11]>[Pt]>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][Si:9]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:7]
Reactant: CO[SiH](OC)OC
Reactant: C=COCCCl
Agent: [Pt]
Product: CO[Si](CCOCCCl)(OC)OC
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A 50 ml two-necked recovery flask equipped with a thermometer and a calcium chloride tube was charged with 4.26 g (40 mmol) of 2-chloroethylvinyl ether (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and 0.2 g of a platinum catalyst (“BY 24-835” manufactured by Toray-Dow Corning Co.). Then, 4.89 g (40 mmol) of trimethoxysilane (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was slowly added with stiffing while controlling the temperature at 50° C. or less. After then, more 0.2 g of the platinum catalyst was added and the mixture was stirred at room temperature (20° C.) for 6 hours. The reaction mixture was distilled under reduced pressure to obtain 7.32 g of the target 2-(2-chloroethoxy)ethyltrimethoxysilane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[C:14]([O:16]C)=O)=[O:7])([CH3:4])(C)C.[BH4-].[Na+].[C:20](O)(=O)[CH3:21].[BH4-]>O1CCCC1.O>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[CH2:14][OH:16])=[O:7])[CH2:4][CH2:20][CH3:21]
Reactant: COC(=O)C1NC(=O)C1NC(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A solution of 2.0 g (8.2 mmole) of methyl 3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate in 20 ml of tetrahydrofuran is cooled in ice and a solution of 0.75 g (20 mmole) of sodium borohydride in 10 ml of water is added. The mixture is stirred 20 min at 0° and then 1.5 hr at room temperature. Acetic acid is added dropwise to decompose the excess borohydride and the mixture is concentrated in vacuum. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCO3 ; dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128°-131°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1ccc(F)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)ccc1F

Procedure:
To a solution of 2-fluoro-5-methylbenzoic acid (20.0 g, 0.13 mol) in MeOH (100 mL) is added thionyl chloride (1.9 mL, 26.0 mmol) dropwise, via syringe, and the solution is refluxed overnight. After cooling, the solvent is evaporated, and the residue is taken up in ethyl acetate (200 mL), extracted with sat'd aq. NaHCO3 (50 mL), brine (50 mL), water (50 mL), dried (MgSO4), and chromatographed (silica, 5% EtOAc/hexane) to yield methyl 2-fluoro-5-methylbenzoate, as a clear oil.