Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:17][OH:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].[CH2:21](I)[CH3:22]>C(COC)OC>[CH2:21]([O:18][N:17]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:22]
Reactant: ON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone oxime in 25 ml of dimethoxyethane is treated portionwise with 0.51 g of sodium hydride dispersion (55% in oil) and the mixture is stirred for 30 minutes at room temperature. Thereupon, 2.0 g of ethyl iodide are added and the mixture is heated at reflux temperature. After 4 hours, the mixture is poured onto ice and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel to yield 2',4'-dichloro-2-(3-pyridyl)-acetophenone O-ethyl oxime as a yellowish oil.
Reaction SMILES: [C:1]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:28][N:29]([CH:31]=[C:23]1[CH2:24][N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][C:22]1=[O:25])[CH3:30]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 80 °C

Procedure:
A suspension of 1-tritylpyrrolidin-3-one (4.9 g) from Step A in anhydrous DMF (36.0 mL) was dissolved by heating at 80° C. under nitrogen for 10 min. The clear solution was treated with N,N-dimethylformamide dimethyl acetal (18.0 mL) and heated at 80° C. for 12 h. The resulting dark brown solution was evaporated under reduced pressure. The residue was chromatographed on a Biotage® system (silica gel, gradient from 50% to 100% ethyl acetate in hexanes) to yield the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:37])([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][N:31]=[N:30]1)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:37][C@@:9]([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][N:31]=[N:30]1)=[O:19])=[O:15])([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:8]
Reactant: CC(C)C[C@](C)(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@](C)(N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Reaction time: 1 h

Procedure:
Each diastereomer of N-(tert-butoxycarbonyl)-2-methylleucyl-N-[5-chloro-2(1H-tetraazol-1-yl)benzyl]-L-prolinamide (A: 86 mg, 0.161 mmol; B: 84 mg, 0.158 mmol) was dissolved in a 2:1 solution of CH2Cl2/TFA (3 mL) and stirred for 1 h. Both reactions were then concentrated to oils. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded each diastereomer as a clear oil. Diastereomer A: 1H NMR (300 MHz, CDCl3): δ0 9.32 (s, 1 H), 8.08 (br s, 2 H), 7.78 (t, J=5.1 Hz, 1 H), 7.64 (d, J=2.4Hz, 1 H), 7.44 (dd, J=2.1, 8.7 Hz, 1 H), 7.29 (d, J=8.7 Hz, 1 H), 4.44–4.41 (m, 1 H), 4.23 (m, 2 H), 3.67–3.63 (m, 2 H), 2.28–2.24 (m, 1 H), 2.08–1.85 (m, 5 H), 1.78–1.71 (m, 1 H), 1.68 (s, 3 H), 0.86 (d, J=6.3 Hz, 3 H), 0.78 (d, J=6.6 Hz, 3 H). LCMS (M+H): 434.0. Diastereomer B: 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1 H), 8.30 (br s, 2 H), 8.08–8.04 (m, 1 H), 7.55 (d, J=2.1 Hz, 1 H), 7.44 (dd, J=2.1, 8.7 Hz, 1 H), 7.30 (d, J=8.7 Hz, 1 H), 4.49–4.45 (m, 1 H), 4.26–4.21 (m, 2 H), 3.77–3.66 (m, 2 H), 2.16–1.80 (m, 6 H), 1.77 (s, 3 H), 1.72–1.66 (m, 1 H), 0.92 (d, J=6.6 Hz, 3 H), 0.79 (d, J=6.3 Hz, 3 H). LCMS (M+H): 434.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:29][C:30]([C@@H:32](OS(C(F)(F)F)(=O)=O)[CH3:33])=[O:31]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][N:20]([CH:21]([CH3:23])[CH3:22])[C@@H:32]([C:30]([OH:29])=[O:31])[CH3:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)C
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C(C)C)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine (prepared as described in Example 56) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 6H); 1.31 (d, 3H); 3.10 (m, 1H); 3.63 (q, 1H); 3.98 (s, 3H); 4.02 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.59 (m, 1H); 8.42 (s, 2H); 9.68 (brs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8]([NH:10][NH2:11])=[O:9])[CH3:5].C(=O)([O-])O.[Na+].CN(C=O)C>O>[NH2:1][C:2]1[O:9][C:8]([C:7]2[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([CH3:16])[C:6]=2[CH2:4][CH3:5])=[N:10][N:11]=1
Reactant: CCc1c(C(=O)NN)ccc(O)c1C
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2nnc(N)o2)ccc(O)c1C
Yield: 11.8 %

Procedure:
196 mg of cyanogen bromide are added dropwise to a solution of 300 mg of 2-ethyl-4-hydroxy-3-methylbenzohydrazide in 50 ml of water, 130 mg of sodium hydrogencarbonate and 4 ml of DMF. A gas forms and a precipitate deposits. The latter is filtered off with suction and purified by column chromatography on silica gel, giving 40 mg of 4-(5-amino-1,3,4-oxadiazol-2-yl)-3-ethyl-2-methylphenol as colourless powder; MS-FAB (M+H+)=220; Rf (polar method): 1.43 min;
Reaction SMILES: [C:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[CH2:11][CH2:12][N:6]1[CH2:7][CH2:8]2)([OH:3])=[O:2].[ClH:13].[CH2:14](O)[CH3:15]>>[ClH:13].[CH2:14]([O:2][C:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[CH2:8][CH2:7][N:6]1[CH2:12][CH2:11]2)=[O:3])[CH3:15]
Reactant: CCO
Reactant: O=C(O)CC1CC2CCN1CC2
Agent: Cl
Product: CCOC(=O)CC1CC2CCN1CC2

Procedure:
28 g of 2-carboxymethyl-quinuclidine were esterified by treatment with a solution of anhydrous hydrogen chloride in absolute ethanol for 48 hours at room temperature. 25 g of 2-ethoxycarbonylmethyl-quinuclidine hydrochloride were obtained.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[S:26])[CH:21]=[CH:22][CH:23]=1>C1C=CC=CC=1.CCCCCC>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCC(=N)N
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCC(=N)NC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
Following a procedure similar to that described in Example 42 and using 3.4 g. sodium in 350 ml. dry acetone, 24.7 g. heptanamidine hydrochloride, and 30.4 g. 3-(trifluoromethyl)phenyl isothiocyanate [b.p. 50°-52°C./0.05-0.08 mm.; prepared from 3-(trifluoromethyl)aniline] in 150 ml. dry acetone there was obtained 1-[3-(trifluoromethyl)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 105°-107°C. (from benzene-n-hexane); hydrochloride (34.4 g.), m.p. 154°-155°C. (from acetonitrile).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1>[CH3:6][C:7]1[C:12]([B:22]([OH:23])[OH:21])=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: Cc1cc(C)cc(-c2ccccc2)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
t-Butyllithium (1.7 M solution in hexane, 36.2 ml, 61.6 mmol) is added dropwise to a solution of 3,5-dimethylbiphenyl (7.27 g, 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. under an atmosphere of nitrogen. The reaction mixture is stirred at −78° C. for 30 minutes, then trimethylborate (9.54 ml, 84 mmol) is added. The resulting mixture is stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture is acidified with 10% aqueous hydrochloric acid solution and extracted with diethyl ether. The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness to give a yellow solid. The crude product is triturated with isohexane and filtered to give 3,5-dimethylbiphen-4-ylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:36])[C:7]([CH2:18][NH:19][C:20](=[O:35])[NH:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:36])[C:7]([CH2:18][NH:19][C:20]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:35])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL flask, tert-butyl 4-(3-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)ureido)piperidine-1-carboxylate (1.6 g, 3.13 mmol) and HCl gas were combined with dioxane (30 mL). The reaction mixture was stirred overnight at room temperature. After this time, LC/MS showed the reaction to be complete. The product 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-ylmethyl)-3-piperidin-4-yl-urea hydro-chloride salt (1.4 g, 100%) was used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22](OC4C=CC([N+]([O-])=O)=CC=4)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([Cl:34])[CH:12]=3)=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:22]([C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:34])[CH:12]=3)[N:7]([CH2:6][C:5]3[CH:35]=[CH:36][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1)=[O:23]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccc(F)cc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 169.5 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-fluoro benzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (170 mg, 0.4276 mmoles) in dry DMF (6 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (69.7 mg, 0.1116 mmoles) was added followed by sodium hydride (60% suspension, 37.0 mg, 0.8553 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 100 mg of the title compound as an off white solid, m. p: 249-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(N3CCCCC3)ccc21
Yield: 20.8 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (200 mg, 0.6 mmol), piperidine (195 mg, 2.3 mmol) and NMP (2 ml) gave title compound (50 mg, 21%) after purification by column chromatography using DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][CH3:16])[C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>>[Cl:19][C:11]1[N:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][C:10]=1[CH2:15][CH3:16]
Reactant: CCc1cc(-c2cccc(Cl)c2)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2cccc(Cl)c2)nnc1Cl
Temperature: 110 °C

Procedure:
A RBF was charged with 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one (1.50 g, 6.4 mmol) and phosphorus oxychloride (6.0 ml, 64 mmol). Hunig's base (1.2 ml, 7.0 mmol) was added to the mixture dropwise (slightly exothermic). The flask was fitted with a reflux condenser and a nitrogen inlet and the mixture was heated at 110° C. for 3 h. Upon cooling the reaction mixture was poured onto ice. 6N NaOH was added dropwise until pH 9 while keeping the mixture cold by gradual addition of ice. The solids were filtered, washed with water and dried to provide 3-chloro-6-(3-chlorophenyl)-4-ethylpyridazine as a peach colored solid. MS m/z=253 [M]+. Calc'd for C12H10Cl2N2: 253.13.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[C:7]#[CH:8].Cl[C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[NH:16][C:15]2[CH:25]=[CH:26][CH:27]=[N:28][C:14]1=2)=[O:12]>CCCCCC.O1CCCC1>[CH2:6]([O:9][C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[NH:16][C:15]2[CH:25]=[CH:26][CH:27]=[N:28][C:14]1=2)=[O:12])[C:7]#[CH:8]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C#CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCOC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 15° to 20° C., 3.08 g (0.048 mol) of n-butyl-lithium in 30 ml of n-hexane are added dropwise to a solution of 2.24 g (0.04 mol) of propargyl alcohol in 120 ml of tetrahydrofuran. After it has all been added, the mixture is stirred for a further 30 minutes at ambient temperature and then mixed with a suspension of 10.9 g (0.04 mol) of 11-chlorocarbonyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 250 ml of tetrahydrofuran. In order to complete the reaction the mixture is stirred for a further hour. It is evaporated to dryness in vacuo and the residue is crystallised by stirring in water. After recrystallisation from ethyl acetate, 7.5 g (64% of theory) of the desired product are obtained, m.p. 213° C.
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([N:6]([CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[NH:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)[CH3:5].Cl.[C:33](=[NH:38])(OCC)[CH3:34].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:33]([N:17]1[CH2:16][CH2:15][CH:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]([CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[NH:27])[CH2:4][CH3:5])=[CH:8][CH:9]=2)[CH2:19][CH2:18]1)(=[NH:38])[CH3:34]
Reactant: CCOC(C)=N
Reactant: CCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 189.1 %

Procedure:
To a solution of 3-[3-[N-ethyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (420 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (319 mg) and triethylamine (0.72 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 20% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (287 mg, yield 63%) as a colorless amorphous solid.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+:16]>CO>[K+:16].[CH3:14][O:13][C:11]([C:2]1[N:1]=[C:6]([C:7]([O-:9])=[O:8])[CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(C(=O)[O-])n1
Reaction time: 0.05 h
Yield: 79 %

Procedure:
To a suspension of dimethyl 2,6-pyridinedicarboxylate (95.22 g, 488 mmol) in a 2 L round-bottom flask under nitrogen in methanol (1,200 mL; ˜12.5 volumes) was added powdered potassium hydroxide (27.4 g, 488 mmol). The mixture was stirred and after 3 min was almost all in solution. After 20 min lab HPLC showed a 33:62 ratio of starting material to product. Solvent was evaporated and the resulting solid was stirred well with 1000 mL ethyl acetate, then filtered under vacuum, then dried at 40° C. under high vacuum to give 84.5 g (79%) of a white solid that lab HPLC showed to be 98.2% pure (ret time 1.41 min). LC-MS m/z 182 (M+H)+, 0.57 min (ret time).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cnn(CC)c4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cn1
Yield: 89.4 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (350 mg), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (20 mL) and ethanol (20 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was acidified by adding 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from tetrahydrofuran-hexane gave {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (300 mg, yield 89%). melting point: 146-147° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:6])C)[CH3:3].[ClH:7].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]CC>>[ClH:7].[CH3:1][NH+:2]([CH2:4][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]
Reactant: CCCCCCC
Reactant: CC(C)N(C)C
Agent: Cl
Product: C[NH+](C)Cc1ccccc1

Procedure:
6 g of N,N-dimethylisopropylamine and 300 ml of heptane were placed under argon in a 500 ml three-necked flask fitted with internal thermometer and gas inlet stopcock. HCl gas from a gas generation apparatus was passed into this reaction mixture for 1 hour. The N,N-dimethylbenzylammonium hydrochloride formed was separated off via a G4 frit, washed with 100 ml of heptane and dried in an oil pump vacuum. 7.4 g (87%) of the desired product were isolated.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[CH2:35]Br>CN(C=O)C.C(OCC)(=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:41])([F:42])[F:43])[CH2:35][N:15]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][N:6]2[C:2]=1[CH3:1])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1c(NS(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(N(Cc2ccc(C(F)(F)F)c(F)c2)S(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of compound 10-G (0.023 g, 0.048 mmol) in DMF (1 mL) was added Na2CO3 (0.015 g, 0.14 mmol) and 3-fluoro-4-trifluoromethylbenzyl bromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 100 as a yellow solid (0.017 g, 66%); MS m/z (M+H+) 532.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33].CCCCCC.C(OCC)(=O)C>C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][O:25][C:26]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:32])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: Clc1cccc(Cl)c1OCCBr
Solvent: CCCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCOc3c(Cl)cccc3Cl)CC2)cc1

Procedure:
A mixture of 6.13 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 5.38 g (0.03 mole) of 2-(2-bromoethoxy)-1,3-dichlorobenzene was heated overnight at gentle reflux in 200 ml of 1-butanol. The reaction mixture was filtered and stripped to dryness. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide solution. The oil which was obtained was chromotagraphed on 300 g of silica gel using hexane-ethyl acetate (50/50 v/v) as eluant. The fractions containing product were combined and solvent removed to furnish an oil. The oil was dried overnight in vacuo at 80° C. This furnished 5.99 g (59%) of product oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:22][C:19]1[C:18]([F:23])=[CH:17][C:13]([C:14]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:12]([F:11])[C:20]=1[OH:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: N
Product: Oc1c(F)c(F)cc(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluoro-3-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.63-7.76 (m, 2H), 8.44 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.25 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 294 (M+H)+.