Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccncc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc(-c2ccncc2)cc1
Yield: 40.1 %

Procedure:
A mixture of 4-benzyloxycarbonyl-1-(4-bromobenzyl)-2-piperazinone (807 mg), 4-pyridylboric acid (244 mg), tetrakis (triphenylphosphine)palladium (69 mg), 2M sodium carbonate solution (2 ml), toluene (8 ml) and ethanol (2 ml) was refluxed overnight. After the mixture was cooled, ethyl acetate was added to the reaction solution. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (283 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.N12CCCN=C1CCCCC2.Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[S:39][CH:40]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[S:39][CH:40]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.91 g (22.12 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 150 ml of DMF. 7.44 g (66.35 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.8 g (44.24 mmol) of 4-chloromethyl-2-(4-chlorophenyl)-1,3-thiazole are then added. The suspension is stirred at RT overnight, 50 g of silica gel are added and the mixture is concentrated under reduced pressure. The substance mixture on the silica gel is purified by chromatography on silica gel (mobile phase: toluene to toluene/ethyl acetate, 1:1 mixture). This gives 5.5 g (47% of theory) of product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH:7]1(B(O)O)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:7]1([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:9][CH2:8]1
Reactant: OB(O)C1CC1
Reactant: Ic1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: Ic1cnn(C2CC2)c1
Temperature: 50 °C
Yield: 42.8 %

Procedure:
In a flask were combined 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol), cyclopropylboronic acid (886 mg, 10.3 mmol) and sodium carbonate (1.09 g, 10.3 mmol) and the mixture suspended in 1,2-dichloroethane (20 mL). A suspension of copper (II) acetate (936 mg, 5.16 mmol) and 2,2-bipyridine (805 mg, 5.16 mmol) in 1,2-dichloroethane (40 mL) was warmed to 50° C. and added and the resulting mixture heated at 70° C. overnight. The mixture was then cooled and filtered and the solids rinsed with EtOAc. The combined filtrates were concentrated and the residue taken up in EtOAc and 50% saturated aqueous NH4Cl. The organic layer was washed with sat NH4Cl, sat NaHCO3 and sat NaCl and dried over MgSO4. The solution was concentrated and the residue purified by SiO2 chromatography (5-35% EtOAc/heptane) to afford 517 mg (43%) 1-cyclopropyl-4-iodo-1H-pyrazole as a colorless oil.
Reaction SMILES: C[O-].[Na+].C([O:6][CH2:7][CH3:8])=O.N#N.[CH2:11]([C:21]1[CH:30]=C2[C:24]([CH2:25][CH2:26][CH2:27][C:28]2=[O:31])=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1>[OH:31][CH:28]=[C:27]1[CH2:26][CH2:25][C:24]2[C:8](=[CH:30][C:21]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[C:7]1=[O:6]
Reactant: CCCCCCCCCCc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC=O
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1ccc2c(c1)C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.4 g, 40.5 mmoles), ethyl formate 7.4 g, 100 mmoles) and 100 mL dry toluene was cooled in an ice bath under inert atmosphere (N2 or Argon). A solution of 7-n-decyl-1-tetralone (11.5 g, 40 mmoles) in 100 mL dry toluene was added with rapid stirring. The ice bath was removed and the reaction was stirred at RT for 4 hours. The reaction was treated with 100 mL water and 100 l mL 6N HCl. The organic layer was separated and washed twice with 50 mL saturated NaCl, dried over anhydrous Na2SO4, filtered and evaporated to remove all the toluene. The oily residue was used for the next reaction without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][N:8]=1)(=O)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.[OH-].[Ba+2].[OH-].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][N:8]=1
Reactant: OB(O)c1ccccn1
Reactant: O=C(O)c1ccc(OS(=O)(=O)C(F)(F)F)nc1
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ccccn2)nc1

Procedure:
A mixture of 2-trifluoromethanesulfonyloxy-5-pyridine-carboxylic acid (0.442 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.086 mmol) is added, and the resultant solution is stirred at 80° C. for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[C:6]([C:13](Cl)=[O:14])[CH:5]=1>C(O)C.ClCCl>[CH3:1][N:2]([CH3:3])[C:13]([C:6]1[CH:5]=[N:4][N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=12)=[O:14]
Reactant: CNC
Reactant: O=C(Cl)c1cnn2ccccc12
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)c1cnn2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of dimethylamine in ethanol (35% w/v; 300 ml) was added to dichloromethane (1100 ml) and the resulting solution was stirred at 0° C. and treated slowly with a solution of pyrazolo[1,5-a]pyridine-3-carbonyl chloride (61.0 g) in dry dichloromethane (1100 ml). When the addition was complete, the mixture was allowed to warm up to room temperature and stand at room temperature overnight. The mixture was then washed twice with water and the organic solution was then dried over sodium sulphate and evaporated under reduced pressure. The resulting brown oil was recrystallised from cyclohexane, to give 3-(N,N-dimethylcarbamoyl)pyrazolo[1,5-a]pyridine (42.0 g), m.p. 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C1COCC1.C(OCC)(=O)C.O>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)(=[O:33])=[O:32])=[C:3]2[CH:16]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (390 mg, 1.24 mmol) in THF (12 mL) was added sodium tert-butoxide (297 mg, 3.09 mmol) and 3-chlorobenzenesulfonyl chloride (0.35 mL, 2.47 mmol). The reaction mixture was stirred at RT under nitrogen for ca. 3 h. The reaction mixture was diluted with ethyl acetate (ca. 30 mL) and water (ca. 50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (ca. 30 mL×2). The combined organic phase was dried over Na2SO4 and then concentrated in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in DCM, afforded the title compound (252 mg). LCMS (A) m/z: 490/492 [M+1]+, Rt 1.48 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:28]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3)c2)CC1
Reaction time: 0.08 h
Yield: 109.8 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (50 mg, 0.130 mmol) in tetrahydrofuran (1 mL) was allowed to stand for 5 min. 3-fluorobenzoyl chloride (28 μL, 0.229 mmol) and tetrahydrofuran (1 mL) were added to the reaction mixture. The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and allowed to stand for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43 mg (>100%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(O[N:23]1[N:31]=[N:30]C2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N-]=[N+]=[N-].[Na+].CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([N:30]=[N+:31]=[N-:23])=[O:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Agent: F[P-](F)(F)(F)(F)F
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 3-phenylisoxazole-5-carboxylic acid (1.0 g, 5 mmol, 1.0 equiv.) in DMF (20 mL) and THF (20 mL), was added HBTU (2.28 g, 6 mmol, 1.2 equiv.), followed by sodium azide (0.65 g, 10 mmol, 2.0 equiv.) and DIEA (2.6 mL, 15 mmol, 3.0 equiv.). The mixture was stirred at RT for 30 min, concentrated, followed by adding of H2O (40 mL). The precipitate was filtered, washed with H2O, and dried in vacuo to give 3-phenylisoxazole-5-carbonyl azide (0.65 g, 60%). LRMS (M−18+H+) m/z 187.1.
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[C:9]([CH2:19][OH:20])=[N:10][CH:11]=[C:12]([CH:14]2OCC[O:15]2)[CH:13]=1.CC(C)=O.[OH-].[Na+]>O>[Cl:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[N:10][C:9]=1[CH2:19][OH:20]
Reactant: OCc1ncc(C2OCCO2)cc1Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cnc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10 %

Procedure:
Oxalic acid (415 mg, 3.29 mmol) was added to a mixture of [3-chloro-5-(1,3-dioxolan-2-yl)-2-pyridinyl]methanol (142 mg, 0.659 mmol), acetone (7.5 ml), and water (7.5 ml) at room temperature and heated under reflux. After 2.5 h, HPLC showed full conversion. Cooled to rt, basified with 1M NaOH, extracted with TBME, dried (MgSO4), filtered and concentrated to give 139 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded impure product. Repurification by manual flash chromatography using a 1 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (11.3 mg, 10%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Nc1nc2cc(Cl)ccc2o1
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(Cl)ccc3o2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzooxazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]2[CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:9]=[C:10]([NH2:15])[N:11]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCC(F)(F)F)n1
Product: Nc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Br)ccc2OCC(F)(F)F)n1
Yield: 34 %

Procedure:
Following the method described in Example 26, 4-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-bromo-phenylamine provided the title compound (34% yield). 1H NMR (acetone-d6) δ 4.76 (q, 2H, J=8.5 Hz, CH2), 5.95 (bs, 2H, NH2), 6.72 (s, 1H, Ar), 7.21 (d, 1H, J=8.8 Hz, Ar), 7.44 (d, 2H, J=8.9 Hz, Ar), 7.58 (dd, 1H, J=8.8 Hz, J=2.4 Hz, Ar), 7.75-7.78 (m, 2H, Ar), 8.07 (d, 1H, J=2.4 Hz, Ar), 8.62 (br s, 1H, NH).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]1=[O:24])C.[OH-].[Na+]>C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:7]2=[O:24])=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
13.6 g of [3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] acetic acid ethyl ester and 1.52 g of NaOH are dissolved in 80 cc. of ethanol and the mixture is stirred at room temperature for 24 hours. The alcohol is distilled off in a vacuum and the residue is dissolved in water. The aqueous solution is shaken with ether, the aqueous phase is acidified with dilute hydrochloric acid and the precipitated acid is separated and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[CH:20]1[C:21]2[CH:9]([NH:8][C:6]3[C:5]([F:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)[N:7]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NC1c2ccccc2-c2ccccc21
Product: Oc1cccc(Nc2ncc(F)c(NC3c4ccccc4-c4ccccc43)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine and 3-aminophenol were reacted to produce N4-(fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.85 (d, 1H, J=2.9 Hz), 7.74 (d, 2H, J=7.6 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.41-7.28 (m, 6H), 7.14-7.05 (m, 2H), 6.56 (d, 1H, J=8.8 Hz), 5.28 (d, 1H, J=8.8 Hz); LCMS: ret. time: 23.27 min.; purity: 89%; MS (m/e): 385 (MH+).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=O)C1C=CC=CC=1.[ClH:40].[H][H]>C(OCC)(=O)C.CO.[Pd]>[ClH:40].[NH2:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Yield: 97.6 %

Procedure:
To a mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (16 g, 30.1 mmol) in ethyl acetate (300 mL) and methanol (150 mL) was added 1N HCl (31.6 mL, 31.6 mmol) followed by Pd/C (3.20 g, 3.01 mmol) and the mixture was stirred under balloon hydrogen atmosphere for 2 h. The mixture was then filtered through a pad of CELITE® and the pad was thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound (12.75 g, 98% yield),as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.11-8.16 (2 H, m), 7.62 (1 H, t, J=7.40 Hz), 7.48 (2 H, t, J=7.78 Hz), 4.19 (2 H, q, J=7.11 Hz), 4.13 (2 H, d, J=3.51 Hz), 2.71-2.83 (2 H, m), 2.53 (1 H, brs), 2.32-2.46 (2 H, m), 2.01-2.13 (2 H, m), 1.74-1.85 (2 H, m), 1.03 (3 H, t, J=7.03 Hz). LCMS (M+H)=398.10.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(Cl)Cl>C(Cl)CCl>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2,2,2-trifluoroethanol (5.0 g, 50.0 mmol) and triethylamine (10.5 ml, 7.6 g, 75.0 mmol) in 25 ml of ethylene chloride at -10° is added methanesulfonyl chloride (4.25 ml, 6.3 g, 55.0 mmol) over 20 min. maintaining the temperature at 0° to -10°. After addition is complete, the mixture is stirred at 0°-5° for 30 min. It is then poured into ice water and additional methylene chloride is added. The layers are separated, and the methylene chloride layer is washed with cold 10% HCl, with cold saturated sodium bicarbonate, with cold water until neutral, and with cold brine. The organic layer is dried over calcium sulfate with swirling and is filtered and the solvent is removed to give 2,2,2-trifluoroethyl methansulfonate.
Reaction SMILES: [C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[C:25](\[CH3:31])/[C:26]([O:28]CC)=[O:27])=[CH:20][C:19]=2[O:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[C:25](\[CH3:31])/[C:26]([OH:28])=[O:27])=[CH:20][C:19]=2[O:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNCC(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1cc(/C=C(\C)C(=O)O)ccc1-c1cccc(CNCC(=O)c2ccccc2)c1
Temperature: 52.5 °C
Yield: 65.6 %

Procedure:
265 mg (0.55 mmol) of ethyl (E)-3-{3′-[(benzoylmethylamino)methyl]-2-butoxybiphenyl-4-yl}-2-methylacrylate are placed in a solution of 109 mg (2.75 mmol) of sodium hydroxide in 5 mL of ethanol. After heating at 50-55° C. for 6 hours, the reaction medium is evaporated to dryness, taken up in water, acidified to pH 3 with aqueous 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from a 50/50 heptane/ethyl acetate mixture. 165 mg (66%) of (E)-3-{3′-[(benzoylmethylamino)methyl]-2-butoxybiphenyl-4-yl}-2-methylacrylic acid are obtained in the form of an off-white powder with a melting point of 166° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[OH:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:25]=2)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: ClCc1cccnc1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3cccnc3)c2)cc1O
Temperature: 40 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
3-Chloromethyl-pyridine hydrochloride (0.59 g 3.6 mmol) was added to a mixture of (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.39 g, 1.2 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in dry DMF (5 mL) at RT. After stirring at 40° C. for 5 hrs, the resulting mixture was poured into ice, and the resulting precipitate was filtered, washed with water and dried. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 2.5 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that, after neutralization, was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 50 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(pyridin-3-ylmethoxy)-phenyl]-acrylamide.