Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12][CH:11]=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.C([OH:28])C>C(O)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[CH:11]=[N+:12]([O-:28])[C:13]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (0.5 gm, 1.09 mmol; see Example 8, Step 4) in glacial acetic acid (25 mL) at room temperature under nitrogen was added, with stirring, aqueous peroxide (30% by wt) (1.24 mL, 10.9 mmol). The reaction was warmed to 100° C. and stirred for 1.5 hours. The reaction was allowed to cool, ethanol (1 mL) was added and volatile components were removed under reduced pressure. The resulting oil was placed under high vacuum for 16 hours, then used as is. Alternatively, after cooling, water can be added and the volatile components removed under reduced pressure. The residue can be partitioned between CHCl3 and saturated Na2SO3. The organic extract can be dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([OH:18])=O)=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:24][O:23][C:4]1[CH:3]=[C:2]([CH3:1])[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:18])=[C:6]([CH3:21])[C:5]=1[CH3:22]
Reactant: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccncc2)c(C)c1C
Yield: 64.1 %

Procedure:
Reaction of acitretin (0.10 g, 0.31 mmol) with 4-aminopyridine (0.03 g, 0.31 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a yellow solid (0.08 g, 61%). EIMS m/z: 403 ([M]+), 401 ([M]−).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[Cl:23][C:24]1[N:25]=[C:26]([CH:35]=O)[NH:27][C:28]2[C:29]=1[O:30][CH2:31][C:32](=[O:34])[N:33]=2.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:23][C:24]1[N:25]=[C:26]([CH2:35][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[CH:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:6][CH2:7]2)[NH:27][C:28]2[C:29]=1[O:30][CH2:31][C:32](=[O:34])[N:33]=2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=CC1=NC(Cl)=C2OCC(=O)N=C2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: O=C1COC2=C(Cl)N=C(CNC3CCN(C[C@@H]4Cn5c(=O)ccc6ccc(=O)n4c65)CC3)NC2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.51 %

Procedure:
In a 10 mL round-bottomed flask were combined (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (for a preparation see Example 5A(j)) (60 mg, 0.178 mmol), 4-chloro-7-oxo-6,7-dihydro-1H-pyrimido[5,4-b][1,4]oxazine-2-carbaldehyde (for a synthesis see WO2008009700, Example 124 (g)) (38 mg, 0.178 mmol), and sodium bicarbonate (150 mg, 1.78 mmol) in DCM (5 ml) and methanol (1 ml) to give a brown solution. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction was allowed to stir at rt overnight. After 15 h sodium triacetoxyborohydride (113 mg, 0.533 mmol) was added and the reaction was allowed to stir at 25° C. under nitrogen for 4 h. The reaction mixture was adsorbed onto silica and purified using 0-20% MeOH/DCM (1% NH4OH) to give the title compound (4 mg orange solid, 4.51%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:21][OH:22])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O>[Cl:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[N:4]=[C:3]([CH2:2][Cl:1])[N+:21]([O-:22])=[C:12]2[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(O)cc1)c1cc(Cl)ccc1NC(CCl)=NO
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: [O-][n+]1c(CCl)nc2ccc(Cl)cc2c1-c1ccc(O)cc1
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A solution of 40.5 g (0.12 mole) 2,4'-dichloro-2'-(4-hydroxybenzoyl)-acetanilide oxime and 40.5 mg (0.329 mole) of boron trifluoride etherate was heated to reflux. After 5 hr, it was cooled and 200 ml of water was added. The dioxane was removed by distillation and the reaction mixture was made basic with a 5% sodium bicarbonate solution. The solid was collected, heated in methanol at reflux for a few minutes, cooled and collected to give, in two crops, 21.3 g (56%) of product. An analytical sample which was recrystallized from methanol melted at 226°-227° dec.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1)C.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].[OH-].[Na+].Cl>ClCCl.O>[C:40]([N:6]([CH2:5][C:4]([OH:3])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=2)=[CH:12][CH:13]=1)(=[O:42])[CH3:41]
Reactant: CCOC(=O)CNCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl{4-[5-(3,4-dichloro-benzoylamino)pyridin-2-yloxy]benzylamino}acetate (0.811 g, 1.59 mmol) in dichloromethane (5 mL) were added triethylamine (0.332 mL, 2.39 mmol) and acetyl chloride (0.136 mL, 1.91 mmol) at room temperature. The resulting solution was stirred for 1 hour at the same temperature. To the reaction solution was added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.785 g of residue. This residue was dissolved in ethanol (5 mL). To the resulting solution was added 5 M aqueous sodium hydroxide (0.350 mL, 1.75 mmol) at room temperature and stirred at the same temperature for 14 hours. To the resulting reaction solution were added 5 M hydrochloric acid (0.400 mL) and water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.776 g of the title compound.
Reaction SMILES: C[CH:2]([C@H:6]1[CH2:11][CH2:10][N:9]([C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@@H:8]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:7]1)[C:3]([O-:5])=[O:4]>CO>[I:24][C:21]1[CH:20]=[CH:19][C:18]([C@H:12]([N:9]2[CH2:10][CH2:11][C@@H:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][C@H:8]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:23][CH:22]=1
Reactant: CC(C)CC[C@@H](c1ccc(I)cc1)N1CC[C@H](C(C)C(=O)[O-])C[C@@H]1c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CC(C)CC[C@H](c1ccc(I)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
The ester from Step 1 (50 mg, 0.085 mmol) was stirred in MeOH (1 ml) at RT for 3 d. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM and 2M HCl. The DCM layer was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (silica, 3% MeOH in DCM) to give the title compound, 28 mg (57%). 1H NMR (500 MHz, CDCl3) δ (ppm) 0.58-0.66 (1H, m), 0.81-0.83 (6H, m), 0.86-0.95 (1H, m), 1.14 (1H, dq, J 3.8, 12.1), 1.34 (1H, q, J 12.1), 1.42 (1H, septet, J 6.5), 1.74-1.76 (3H, m), 1.84 (1H, br, d, J 12.7), 2.16-2.29 (2H, m), 2.33 (1H, dt, J 2.2, 12.1), 2.69 (1H, td, J 3.6, 12.1), 3.35 (1H, dd, J 5.1, 9.9), 3.72 (1H, dd, J 2.5, 10.9), 6.98 (2H, d, J 8.1), 7.54 (2H, br, d, J 7.45), 7.59-7.63 (4H, m); M/Z (ES+) 574 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[C:23]1([C:33](O)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:33]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:34])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3nccc4ccccc34)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and isoquinoline-1-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.33 (m, 1H), 1.47 (m, 1H), 1.56-1.74 (m, 2H), 1.81 (m, 1H), 1.93 (m, 1H), 3.00 (m, 1H), 3.21 (m, 1H), 4.26 (dd, 1H, J=10.1, 3.7 Hz), 4.82 (t, 1H, J=10.1 Hz,), 5.45 (m, 1H), 6.66 (d, 1H, J=8.0 Hz,), 6.95 (d, 1H, J=8.5 Hz), 7.50 (t, 1H, J=8.5 Hz,), 7.61 (m, 1H), 7.74-7.90 (m, 3H), 7.97 (br s, 1H), 8.02 (d, 1H, J=8.0 Hz), 8.28 (br s, 1H), 8.49 (d, 1H, J=5.8 Hz,), 10.94 (s, 1H). MS 466 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1>[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:14][CH:13]=[C:12]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C(C)(C)O[SiH2]C(C)(C)C)ccc2N)n1
Reactant: Brc1cncnc1
Agent: [Pd]
Product: Cc1csc(NC(=O)c2nc(C(C)(C)O[SiH2]C(C)(C)C)ccc2Nc2cncnc2)n1

Procedure:
Palladium catalysed arylation of 3-Amino-6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide with 5-Bromopyrimidine according to the general procedure described in example 4 step 4 yielded the title product as a light yellow solid, MS (ISP): m/e=457.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH3:25])([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:5]2[C:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([F:40])[F:39])=[C:27]([CH3:29])[N:28]=[C:4]2[CH:3]=1.[OH-].[Na+:42]>C1COCC1.CO>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH3:25])([C:20]([O-:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:5]2[C:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([F:40])[F:39])=[C:27]([CH3:29])[N:28]=[C:4]2[CH:3]=1.[Na+:42]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3Cl)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2cc(Cl)c(-c3cnc(N4CCC(C)(C(=O)[O-])CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 55 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a suspension of Example 297 (0.40 g, 0.71 mmol) in THF (4 mL) and methanol (4 mL) was added 1M aqueous sodium hydroxide solution (0.67 mL, 0.68 mmol), and the mixture was heated at 55° C. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove the organic solvents and the residue was treated with diethyl ether (50 mL). The ether was decanted and the aqueous layer was diluted with water, then freeze dried, to give the title compound (0.39 g, 97%) as an off-white solid. δH 1.07 (s, 3H), 1.22 (m, 2H), 2.02 (m, 2H), 2.28 (m, 2H), 2.35 (s, 3H), 4.29 (m, 4H), 6.99 (m, 1H), 7.14 (m, 2H), 7.24 (s, 1H), 7.30 (m, 2H), 7.49 (s, 1H), 7.75 (d, J 0.2 Hz, 1H), 8.30 (s, 1H), 8.36 (s, 2H). LCMS (pH 3): MH+ 540.0, RT 2.02 minutes. LCMS (pH 10): MH+ 540.0, RT 1.69 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)c(Br)cc1C
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2cc(C)c(C)cc2Nc2ccc(C)cc2)cc1
Yield: 90.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 54 ml (505 mmol) of p-toluidine. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 69 g (218 mmol) of a crystalline solid. The overall yield is 91%.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:27][C:28]([OH:30])=[O:29])[C:13]([NH:15][CH:16]([C:23]([O:25][CH3:26])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:27][C:28]([OH:30])=[O:29])[C:13]([NH:15][CH:16]([C:23]([O:25][CH3:26])=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: COC(=O)C(NC(=O)N(CCCNC(=O)OC(C)(C)C)CC(=O)O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(NC(=O)N(CCCN)CC(=O)O)c1ccccc1

Procedure:
2.3 g (5.4 mmol) of (1-(3-tert-butoxycarbonylaminopropyl)-3-(methoxycarbonylphenylmethyl)ureido)acetic acid are stirred at room temperature for 2 h together with 20 ml of 90% strength aqueous trifluoroacetic acid. After concentrating, the mixture is freeze dried.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH2:38][CH2:39][CH3:40].O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][CH2:38][CH2:39][CH3:40])=[N:3]2)=[CH:20][CH:19]=1
Reactant: CCCI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (710 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 72.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodopropane (0.33 g) was added to the reaction mixture, which was stirred at room temperature for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyloxy-1H-pyrazol-4-yl]propionic acid was obtained (0.59 g, yield. 81%). This was recrystallized from acetone-hexane. Melting point: 108–109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[CH:9][S:8]1)=[O:5])[CH3:2].[I:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([I:22])[S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=c1sccn1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N=c1sc(I)cn1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazoline (0.5 g) and N-iodosuccinimide (0.4 g) in chloroform (30 ml) was refluxed for 20 hours. After cooling, the reaction mixture was washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.1 of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-iodothiazoline (Compound No. 42).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[C:26]([CH3:28])([CH3:27])[C:25]2([CH3:30])[CH3:29])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[C:25]([CH3:30])([CH3:29])[C:26]4([CH3:28])[CH3:27])=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC1(C)C(C(=O)N2CCNCC2)C1(C)C
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: CC1(C)C(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)C1(C)C

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,2,3,3-tetramethylcyclopropyl)methanone, the title compound was obtained as a white solid (35% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 8.01, 7.01, 3.91-3.89, 3.81-3.65, 3.57, 1.21, 1.19, 0.79-0.072, 0.49-0.46, 0.11-0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1>O>[F:1][CH:2]([F:5])[CH2:3][NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([Cl:6])=[CH:8][CH:9]=1
Reactant: FC(F)CCl
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Product: FC(F)CNCc1ccc(Cl)cc1
Yield: 61 %

Procedure:
An amount of 22.4 g (207 mmol) of 2,2-difluoro-1-chloroethane and 10 g (69 mmol) of 4-chlorobenzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of water are added and the aqueous phase is separated. The aqueous phase is again extracted with 2,2-difluoro-1-chloroethane and the combined organic phases are distilled as described in Example 1.1. Here also, the 4-chlorobenzylamine hydrochloride which is present in the aqueous phase can be converted back into free 4-chlorobenzylamine by addition of sodium hydroxide solution. After distillation, 4.25 g of 2,2-difluoro-N-(4-chlorobenzyl)ethanamine are obtained, which corresponds to a yield of 61%, based on reacted 4-chlorobenzylamine
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Cl)=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:7]1[S:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1sc(C(=O)OC)cc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
A solution of 5-chloro-4-nitrothiophene-2-carboxylic acid methyl ester (6.03 g, 27.2 mmol), glycine ethyl ester hydrochloride (4.18 g, 29.9 mmol) and potassium carbonate (9.4 g, 68 mmol) in acetonitrile (200 mL) was stirred 4 h at 70° C. Quenched in ice/water. The resulting precipitation was collected by filtration, washed with water and dried to give methyl 5-(2-ethoxy-2-oxoethylamino)-4-nitrothiophene-2-carboxylate 19 (7.02 g, 89%). NMR (400 MHz, CDCl3) 1.35 (t, J=7.0 Hz, 3H), 3.87 (s, 3H), 4.11 (d, J=5.5 Hz, 2H), 4.33 (q, J=14.0 and 7.0 Hz, 2H), 8.04 (s, 1H), 8.75 (br s, 1H). (m/z)=289 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[C:15]([CH3:26])[CH:14]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.C1([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=2B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:26][C:15]1[CH:14]=[C:13]([O:12][CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:34]3[CH:33]=[CH:38][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=3)[N:7]=2)[CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 21.8 %

Procedure:
A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)butyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.12 mmol) in DME (0.5 mL) was treated with phenyl 4-(triflouromethyl)benzeneboronic acid (23 mg, 0.12 mmol) followed by Pd(PPh3)4 (14 mg, 0.01 mmol) and a solution of Na2CO3 (38 mg, 0.36 mmol) in water (0.5 mL), and the resulting mixture was heated at 70° C. for 18 hours under nitrogen. The solvent was then removed under vacuum and the resulting mixture acidified with aqueous HCl (2M) and then partitioned between water and EtOAc, the layers separated and the organic layer reduced to an oil. Purification by mass directed auto-prep HPLC afforded the title compound (12 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13]>O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:13][CH2:12][C:11]#[N:14])[CH3:3]
Reactant: C=CC#N
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CNCCC#N
Yield: 42 %

Procedure:
139.6 g (1 mole) of glycine ethyl ester hydrochloride was dissolved in 80 ml of distilled water and to this solution was added 230 ml of an aqueous solution of 67.3 g (1.2 mole eq.) of potassium hydroxide. Then, 106.2 g (2 mole eq.) of acrylonitrile was added to the reaction solution while heating and stirring at 50° to 60° C. The reaction mixture was stirred for 5 hours with heating and then the organic layer was separated. The aqueous layer was extracted with ethyl ether and the extract was combined with the organic layer as separated above. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was distilled under reduced pressure (100° to 150° C./10.25 torr) to obtain 65.6 g (Yield: 48%) of the title compound.