Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH:20]=O.C(O)(=O)C.Cl>CO>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28])[CH2:20][NH:15][C:13]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (200 mg, 819 μmol) in MeOH (3.5 ml) was added 3-chloro-4-(trifluoromethyl)benzaldehyde (94.0 mg, 451 μmol) followed by acetic acid (36.7 mg, 35.0 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (52.6 mg, 492 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml). The resulting suspension was filtered to collect the solid. Purification by flash chromatography (silica gel, 24 g, 2% to 4% MeOH in DCM) afforded a white solid as desired product (121.4 mg, 68% yield). MS +m/z: 436 (M+H)+
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:17]([O:21][C:22](=[O:38])[CH2:23]OC1C=NC(C2C=CC=CC=2F)=CC=1)([CH3:20])([CH3:19])[CH3:18].C(OC(=O)CBr)(C)(C)C>CN(C=O)C>[C:17]([O:21][C:22](=[O:38])[CH2:23][O:16][C:13]1[CH:14]=[N:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1ccc(-c2ccc(F)cc2)nc1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nc1
Agent: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
119 mg (2.72 mmol) of sodium hydride (55% in mineral oil) were added to 430 mg (2.27 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ol (prepared analogously as described in Example 76(a) to (d)) in 10 ml of DMF, and the mixture was stirred at room temperature for 60 min. Then 532 mg (2.72 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 3 h. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried, and evaporated. Yield: 433 mg.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH2:33][CH2:34][CH2:35][CH3:36])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH2:30][CH2:31][CH3:32])=[O:19])=[CH:7]2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:39][N:38]=[N:37][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH2:33][CH2:34][CH2:35][CH3:36])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH2:30][CH2:31][CH3:32])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(CCCC)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)N(CCCC)Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-butyl-amide (0.285 g, 0.52 mmol), prepared in the previous step, sodium azide (0.101 g, 1.56 mmol) and ammonium chloride (0.083 g, 1.56 mmol) in 10 mL of anhydrous DMF was stirred at 100° C. under nitrogen for 5 h. By TLC starting material remained. Additional amounts of sodium azide (0.101 g, 1.56 mmol) and ammonium chloride (0.083 g, 1.56 mmol) were added and the reaction stirred at 100° C. under nitrogen for 3 h. The reaction was diluted with water, made basic with 1N NaOH and extracted five times with ethyl acetate. The organic layer was separated and acidified with 1N HCl. The solvent was removed under reduced pressure and the residue diluted with 10 mL of water. A solid foam formed, which was collected by filtration and dried under reduced pressure to give the title compound (0.2765 g, 90%) as a tan foam, MS m/z: 588 [M−H]−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH:15]=1
Reactant: c1ccc2sc(-c3ccncc3)nc2c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(c2nc3ccccc3s2)CCN(Cc2ccccc2)C1
Yield: 66.9 %

Procedure:
4-(Benzothiazol-2-yl)pyridine (4.5 g, 0.02 mol) was suspended in DMF (10 ml) and benzyl bromide (3.8 ml, 0.03 mol) added and the reaction mixture stirred at reflux for 1 hour. On cooling, the solid was filtered and washed with ether (20 ml). The solid was then suspended in ethanol (100 ml), sodium borohydride (1.05 g, 0.026 mol) added and the reaction stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue diluted with water (50 ml) and the product extracted into dichloromethane (3×50 ml). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give a solid. Recrystallisation from ethyl acetate afforded the title compound as a white solid (4.1 g, 67%); (Found: C, 74.31; H, 5.87; N, 9.07. C19H18N2S requires C, 74.47; H, 5.92; N, 9.14%). δH (CDCl3), 2.76 (2H, m, NCH2 CH2), 2.83 (2H, m, NCH2CH2), 3.23 (2H, m, NCH2 CH2), 3.67 (2H, s, NCH2Ph), 6.67 (1H, m, NCH2CH), 7.35 (7H, m, ArH), 7.81 (1H, d, J 7.9Hz, ArH), 7.97 (1H, d, J 8.1Hz, ArH). m/z (ES+) 307 (M+1)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([N:17]2[C:21](=[O:22])[C@H:20]3[CH2:23][C@@H:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=4)[CH2:25][N:19]3[C:18]2=[O:35])[CH:13]=[C:14]([Cl:16])[CH:15]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>C1COCC1.O.CCOC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][C@:20]12[CH2:23][C@@H:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH2:25][N:19]1[C:18](=[O:35])[N:17]([C:12]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=1)[C:21]2=[O:22]
Reactant: COC(=O)CBr
Reactant: O=C1[C@H]2C[C@@H](OCc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@]12C[C@@H](OCc3ccc(Br)cc3)CN1C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O
Temperature: -65 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
The compound of formula (Io), wherein Z is methoxycarbonylmethyl and the bonds depicted as wavy bonds define the 7aS,6R stereoisomer, was prepared as follows. 1.65 mL of a solution of LDA (1 M) in THF (1.5 eq.) was added to a solution of (7aR,6R)-2-(3,5-dichloro-phenyl)-6-(4-bromobenzyloxy)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (500 mg) (1.1 mmol) (Ex. 6) in 5 mL of dry THF cooled to −65° C. under nitrogen. The reaction mixture was stirred for 1 h then treated with a solution of methyl bromoacetate (340 mg) (2 eq.) in 3 mL of THF. After 1 h at −65° C., the reaction mixture was allowed to warm to −20° C., stirred for 2 h, and then poured in a mixture of water/EtOAc (1:1, 20 mL). The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting oily residue was purified over SiO2 column (25 g) (eluent: EtOAc/cyclohexane 3/7) to afford the above-titled compound (28.8 mg) as a foam. NMR (CDCl3, 200 MHz): 7.43 (2H, d), 7.35 (1H, m), 7.15-7.0 (4H, m), 4.4-4.2 (3H, dd+m), 4.15 (1H, m), 3.7 (3H, s), 3.2-3.0 (2H, dd+d), 2.75 (1H, d), 2.52 (1H, dd), 2.05 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]1.C(CN)O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Reactant: O=C(O)C1CCNCC1
Solvent: NCCO
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCC(C(=O)O)CC4)=NC3=O)cc12

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid following General Procedure C. The compound was then prepared as an ethanolamine salt.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:27])[C:13]2[C:18]([NH2:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([O:22][CH:23]([F:25])[F:24])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Cl>O1CCCC1>[NH2:19][C:18]1[C:17]([F:20])=[C:16]([F:21])[C:15]([O:22][CH:23]([F:25])[F:24])=[C:14]2[C:13]=1[C:12](=[O:27])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(N)c(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c(N)c2c1=O
Reaction time: 0.5 h

Procedure:
The whole of the ethyl 3-cyclopropylamino-2-(6-amino-3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate prepared as described above was dissolved in 340 ml of tetrahydrofuran, and 3.82 g (0.096 mole) of a 60% w/w dispersion of sodium hydride in mineral oil were added slowly to the resulting solution, whilst ice-cooling. The mixture was then stirred at the same temperature for 30 minutes, and then at room temperature for a further 1 hour. At the end of this time, the reaction mixture was acidified by the addition of 96 ml of 1N aqueous hydrochloric acid, whilst stirring vigorously. The resulting precipitate was collected by filtration and washed with water and with ethanol, in that order, to give 18.76 g of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII) R1 =--OCHF2, R17 =C2H5, X=F] as a colorless powder, melting at 295°-296° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[NH2:22][C:23]1[C:28]([F:29])=[C:27](Cl)[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[Cl:35].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:23]1[C:28]([F:29])=[C:27]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[Cl:35]
Reactant: CC1(C)OB(c2cc(F)c([Si](C)(C)C)cc2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 43.5 %

Procedure:
In a microwave vessel, a suspension of (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (see, e.g., WO 2013003740 A1) (0.6 g, 1.922 mmol), methyl 4-amino-3,6-dichloro-5-fluoropicolinate (Head B) (0.383 g, 1.601 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.112 g, 0.160 mmol) and sodium carbonate (0.204 g, 1.922 mmol) in a 3:1 mixture of acetonitrile (4.00 mL) and water (1.334 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (0.271 g, 0.697 mmol, 43.5%): 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=7.8, 5.1 Hz, 1H), 7.13 (dd, J=9.3, 4.0 Hz, 1H), 4.95 (s, 2H), 3.98 (s, 3H), 0.33 (d, J=0.8 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −106.81, −106.87, −121.20, −121.25, −121.29, −121.35, −137.32, −137.41; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C.Cl>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
(R)-(-)-3,4-Dihydro-2-(4-methoxybenzyl)-2H-benzopyran (812 mg, 3.2 mmol), and lithium iodide (750 mg, 5.6 mmol) were dissolved in 2,4,6-collidine (2 ml) and heated to reflux for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate (20 ml) and 10% HCl (20 ml), and stirred for 10 minutes. The layers were separated and the aqueous portion was extracted with ethyl acetate (50 ml). The combined organics were washed with water (20 ml), brine (20 ml), and were dried MgSO4). The solvent was removed in vacuo and the residue purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford 730 mg of a colorless oil which crystallized upon standing, mp 60°-62° C.; [α]D -110.2° (c 1.0, MeOH); 1H NMR (300 MHz, CDCl3) δ1.7 (m, 1H), 2.0 (m, 1H), 2.7-2.8 (m, 3H), 3.1 (dd, 1H), 4.2 (m, 1H), 6.8 (m, 3H), 7.0-7.2 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.F[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([S:10][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[CH:14]=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: Sc1cccc(Cl)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
A 2.5 mol/L sodium hydroxide aqueous solution (1.2 mL, 3.1 mmol) and tetrabutylammonium bromide (0.012 g, 0.031 mmol) were added to 3-chlorobenzenethiol (0.11 g, 0.73 mmol), followed by stirring at 25° C. for 10 minutes. A toluene (1.2 mL) solution of 2-fluoro-5-nitrobenzaldehyde (0.12 g, 0.73 mmol) was added to the reaction liquid, followed by stirring at 110° C. for 1.5 hours. After the conventional post-reaction treatment, the residue was purified by silica gel chromatography (eluted by chloroform) to give 2-[(3-chlorophenyl)thio]-5-nitrobenzaldehyde (72 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[NH2:24].N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:21]([O:20][CH3:19])[CH:22]=3)[N:7]=2)[CH:10]=1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Reactant: COc1cc(N)cc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc(OC)c1
Temperature: 100 °C

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (70 mg 0.272 mmol) and 3,5-dimethoxyaniline (42 mg, 0.274 mmol) was suspended in a sealed tube with 0.3 mL of a solution of DMSO containing Et3N-TFA (50 mg). The resulting mixture was heated at 100° C. for 3 h, cooled to RT, diluted with 0.4 mL DMSO and purified via preparative HPLC to give N4-quinolin-3-yl-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine as a yellow solid. M+H—374. Calc'd for C21H19N5O2: 373.414.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:25]=O>>[CH3:31][O:30][C:28]1[CH:27]=[C:24](/[CH:25]=[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=2)\[C:18]#[N:19])[CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(/C=C(\C#N)c2ccc(OCCCCCCCCO)cc2)cc(OC)c1
Yield: 68 %

Procedure:
(2Z)-3-(3,5-dimethoxyphenyl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and the commercial 3,5-dimethoxybenzaldehyde according the same procedure following for example 1 in 68% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[NH:33][C:32](=[O:36])[CH:31]=[N:30]2)=[CH:25][C:21]=1[C:22](Cl)=[O:23].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClC(Cl)C.C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[NH:33][C:32](=[O:36])[CH:31]=[N:30]2)=[CH:25][C:21]=1[C:22]([NH:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:23]
Reactant: O=C(Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reactant: CCCCC(CC)CN
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCCCC(CC)CNC(=O)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reaction time: 16 h

Procedure:
To a solution of 2-ethylhexylamine (15 mg, 0.125 mmol) in dichloroethane (1 ml) was added diisopropylethylamine resin (60 mg, 0.225 mmol) followed by a solution of 2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoyl chloride (21 mg, 0.075 mmol) in a 3:1 mixture of dichloroethane and THF (15 ml). The reaction mixture was shaken for 16 hours and filtered. The filtrate was treated with MP-carbonate resin (75 mg, 0.225 mmol) and the resulting mixture was shaken for 3 hours. The mixture was filtered and the resin washed with dichloromethane followed by 9:1 methanol/acetic acid. The combined filtrates were concentrated under reduced pressure to give the title compound as an amorphous solid. Mass spec [M−1] 3:1 ratio of 377.2 and 379.2; 1H nmr (500 MHz, CDCl3) δ 0.92 (t, 3H), 0.96 (t, 3H), 1.26–1.66 (m, 9H), 3.46 (m, 2H), 6.26 (broad s, 1H), 7.51 (d, 1H), 7.59–7.62 (m, 2H), 7.94 (s, 1H), 8.72 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.CN1CCCC1=O.COP([O-])OC.[OH-].[Na+]>O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: COP([O-])OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccncc1
Product: Clc1cccc(C(Cl)Cl)n1
Yield: 81.4 %

Procedure:
In a stirred reaction vessel was placed 2.31 grams (0.010 mole) of 2-chloro-6-(trichloromethyl)pyridine, 20 ml of N-methylpyrrolidone and 1.35 grams (0.011 mole) of dimethylphosphite. The mixture was heated for about 21/2 hours. During this period, 50 percent aqueous sodium hydroxide was slowly added to maintain the pH slightly basic. At the end of the reaction period, there was 1% of the pyridine starting material remaining. Additionally, it was found that 0.0225 mole of the aqueous sodium hydroxide had been added. The reaction mixture was poured into water, extracted with methylene chloride, dried and the methylene chloride removed by evaporation, to yield 1.6 grams (80% of theoretical) of crude 2-chloro-6-(dichloromethyl)pyridine.
Reaction SMILES: C(NC1C=C(C(=O)C=CN(C)C)C=CC=1)(=O)C.NC1C(C#N)=CNN=1.[C:26]([C:28]1[CH:29]=[N:30][N:31]2[C:36]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=3)=[CH:35][CH:34]=[N:33][C:32]=12)#[N:27].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:26]([C:28]1[CH:29]=[N:30][N:31]2[C:36]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=3)=[CH:35][CH2:34][NH:33][C:32]=12)#[N:27]
Reactant: CC(=O)Nc1cccc(-c2ccnc3c(C#N)cnn23)c1
Agent: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: N#Cc1c[nH]nc1N
Agent: [BH3-]C#N
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C2=CCNc3c(C#N)cnn32)c1

Procedure:
A mixture of 7.0 g of 3'-actamido-3-(N,N-dimethylamino)acrylophenone and 3.3 g. of 3-amino-4-cyanopyrazole in 100 ml of acetic acid was heated at reflux for 8 hours. Crystals that formed on cooling were filtered and dried to give 7.4 g. of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide, m.p. 254°-256° C. This was reacted with 14.8 g of sodium cyanoborohydride in 50 ml of acetic acid to give 3.0 g of N-[3-(3-cyano-4,5-dihydropyrazolo[1,5-a]-pyrimidin-7-yl)phenyl]acetamide, m.p. 251°-254° C. This is reacted with chloroacetic anhydride and sodium carbonate in toluene as in Example 3 to give the title compound.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[C:12](=[O:14])=O.CC(C)=O.CN(CCN(C)C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[Cl:35].CN(C=O)C>C1COCC1.CCOCC>[F:34][C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([Cl:35])[C:30]=1[CH:12]=[O:14]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1Cl
Temperature: -45 °C

Procedure:
A solution of 1.3M s-butyl lithium in cyclohexane (244 mL, 317 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (34 g, 293 mmol) in THF (250 mL), maintaining the internal reaction temperature <-70° C. The resulting reaction mixture is cooled and maintained at ≤-90° C. with an ether/liquid nitrogen bath while a solution of 1,2-dichloro-4-fluorobenzene (40 g, 244 mmol) in THF (100 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (89.1 g, 1.22 mol) in THF (125 mL). The resulting mixture is warmed to -45° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated to afford 44.38 g of 2-fluoro-5,6-dichlorobenzaldehyde as an oil.