Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.O.O[N:14]1[C:18]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN>CN(C)C=O.ClCCl.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:14][CH3:18])=[O:11]
Reactant: O=C(O)Cc1ccccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)Cc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
(2-Hydroxyphenyl)acetic acid (9.89 g, 63.7 mmol) and 1-hydroxybenzotriazole hydrate (8.61 g, 63.7 mmol) were dissolved in N,N-dimethylformamide (50 ml) and dichloromethane (200 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8.67 g, 63.7 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. A 8.0 M solution of methyl amine (39 ml, 318 mmol) was added. The reaction mixture was stirred for 16 h, while it was slowly warming up to room temperature. It was diluted with ethyl acetate (600 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (2×300 ml). The combined aqueous phases were extracted with ethyl acetate. The combined organic layers were washed with saturated sodium hydrogen carbonate solution (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane (1:1) as eluent to give 4.90 g of 2-(2-hydroxyphenyl)-N-methylacetamide.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2nc(Br)sc2c1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Temperature: 140 °C
Yield: 96.3 %

Procedure:
A mixture of 2-bromo-1,3-benzothiazol-6-amine (53 mg, 0.23 mmol), 2-methoxy-5-pyridineboronic acid (50 mg, 0.327 mmol), Pd(dppf)Cl2*DCM (8 mg, 0.01 mmol) and sodium carbonate (0.1 g, 1 mmol) in THF/water (9:1, 3 mL) was heated at 140° C. for 10 minutes in a microwave reactor under argon atmosphere. The mixture was filtered and washed with THF/water (9:1). After having added DCM to the filtrate, the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography (20 to 70% ethyl acetate in heptane), to yield the title compound (57 mg) as an off-white solid. 1H NMR (CHLOROFORM-d) δ 8.68 (d, 1H) 8.16 (dd, 1H) 7.74 (d, 1H) 7.06 (d, 1H) 6.70-6.81 (m, 2H) 3.94 (s, 3H) 3.77 (s, 2H); MS m/z (M+H) 258.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][C:12](OCC)=[O:13])[C:8]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:29].[Li+].[BH4-].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][OH:13])[C:8]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:29]
Reactant: CCOC(=O)Cn1c2c(c3ccc(Cl)c(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3c(Cl)c(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 62.6 %

Procedure:
A solution of tert-butyl 7,8-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.0 g, 6.8 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH4 (0.74 g, 34 mmol) was added and the reaction was allowed to warm slowly to rt. Additional LiBH4 (0.30 g, 14 mmol) was added after 24 h. After another 7 h, the reaction was diluted with H2O (75 mL) followed by addition of 10% aqueous NaOH and extraction with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed by crystallization from EtOAc/heptane gave 1.7 g (64%) of a white solid: mp 149.0-149.5° C.; TR (diffuse reflectance) 3420, 2974, 1665, 1482, 1468, 1445, 1414, 1365, 1334, 1240, 1220, 1168, 1151, 1122, 900 cm−1; MS (EI) m/z 398 (M+), 398, 342, 298, 270, 268, 258, 256, 212, 57, 56; Anal. Calcd for C19H24Cl2N2O3: C, 57.15; H, 6.06; N, 7.01; found: C, 57.31; H, 6.10; N, 6.98.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1[CH:9]=[C:10]([C:17]#[C:18][C:19]2[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=2[CH3:25])[N:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[N:12]2.[CH3:27][N:28]([CH3:47])[CH2:29][CH2:30][S:31][C:32]1[NH:33][C:34]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:35]([C:37](O)=[O:38])[N:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:27][N:28]([CH3:47])[CH2:29][CH2:30][S:31][C:32]1[NH:33][C:34]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)=[C:35]([C:37]([NH:26][C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([C:18]#[C:17][C:10]3[N:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:16]4=[N:8][CH:9]=3)[CH:20]=2)=[O:38])[N:36]=1
Reactant: Cc1ccc(N)cc1C#Cc1cnc2cccnn12
Reactant: CN(C)CCSc1nc(C(=O)O)c(-c2ccc(F)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2nc(SCCN(C)C)[nH]c2-c2ccc(F)cc2)cc1C#Cc1cnc2cccnn12
Reaction time: 20 h
Yield: 80.7 %

Procedure:
3-Imidazo[1,2-b]pyridazin-3-ylethynyl-4-methyl-phenylamine TFA salt (450 mg, 1.24 mmol) was dissolved in DMF (10 mL) with 2-(2-Dimethylamino-ethylthio)-5-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid (575 mg, 1.86 mmol) at RT. HATU (700 mg, 1.86 mmol) was added, followed by DIEA (1.3 mL, 7.44 mmol). The mixture was stirred for 20 h. Water (80 mL) was added and the mixture was extracted with EtOAc (300 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 540 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 540.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1([CH3:17])[CH3:16].Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3([CH3:17])[CH3:16])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC1(C)NC(=O)c2ccccc2N1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC1(C)NC(=O)c2ccccc2N1CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 78 %

Procedure:
A mixture of 5.6 parts of 1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone, 4.9 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 6.6 parts (78%) of 1-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone; mp. 185.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]>C(O)C.N1CCCCC1>[C:13]([C:15](=[CH:7][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([Cl:1])[CH:9]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: N#CCC(=O)Nc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C(=O)Nc2ccccc2)cc(Cl)c1O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 5-chlorovanillin (728 mg, 3.9 mmol) and cyanoacetanilide (625 mg, 3.9 mmol) in ethanol (20 ml) were added 3 drops of piperidine, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the resulting solid was filtered and washed with ethanol: water (1: 1) to give the objective 2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenanilide (950 mg, 74% in yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:21](OCC)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCOCC.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][OH:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(OC)cc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A solution of compound 1 (9.1 g, 25.5 mM) in THF (50 ml) was added over 45 min to a stirred suspension of LiAlH4 (0.726 g, 19.1 mM) in THF (50 ml) at 0° C. and stirring continued for 1 hr. The suspension was diluted with Et2O (100 ml) and H2O (0.73 ml), 15% aq. NaOH (0.73 ml) and H2O (2.1 ml) were added in sequence. The mixture was stirred for 16 hr, MgSO4 added and the suspension stirred an additional hour, filtered and the solids washed with Et2O. The combined organic layer was concentrated in vacuo, the residue dissolved inhot EtOAc and crystallized by the addition of hexane to give pure 3 (7.43 g, 93%) as a white solid, mp 95°-97° C., MS, m/e 314 (M+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][O:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
20.00 g (85.38 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 17A were initially charged with 19.44 g (93.91 mmol) of 2,6-difluorobenzyl bromide and 61.20 g (187.83 mmol) of caesium carbonate in 1.18 l of DMF and stirred at 60° C. for 5 h. The flask content was poured 6.4 l of 10% strength aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed once with 854 ml of 10% strength aqueous sodium chloride solution, dried, evaporated and dried under high vacuum at RT overnight. This gave 28.2 g (92% of theory; purity about 90%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15]Br.[C-:17]#[N:18].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH2:15][C:17]#[N:18]
Reactant: Clc1cccc(Oc2ccccc2)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Cl)cccc1Oc1ccccc1
Yield: 63 %

Procedure:
A solution of 21.0 g (70.57 mmol) of (2-chloro-6-phenoxy-phenyl)-bromomethane in 16.5 ml of ethanol is added dropwise at 80° C. to a solution of 4.5 g (91.74 mmol) of sodium cyanide in 9.2 ml of water and 2.3 ml of ethanol and the reaction mixture is boiled under reflux for 4 hours. After cooling, the mixture is concentrated using a rotary evaporator, the residue is taken up in ethyl acetate and the organic phase is washed 2× with water and 1× with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel with ethyl acetate to yield 10.82 g (44.40 mmol)=63% of (2-chloro-6-phenoxyphenyl)-acetonitrile in the form of a brown oil; TLC (silica gel; ethyl acetate; UV): Rf =0.42; 1H-NMR (CDCl3, 200 MHz): 3.96 (s, 2H); 6.74-7.46 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)=[O:21]>>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:17]([NH:16][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:18]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Cc1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cc1N
Product: COc1cc(C(=O)Nc2cc(C(=O)NCc3ccc(Cl)c(Cl)c3)ccc2C)cc(OC)c1OC

Procedure:
Using an analogous procedure to that described in Example 2, 3,4,5-trimethoxybenzoyl chloride was reacted with 3-amino-N-(3,4-dichlorobenzyl)-4-methylbenzamide to give the title compound which was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent; NMR Spectrum: (CDCl3) 2.28 (s, 3H), 3.87 (m, 9H), 4.48 (d, 2H), 7.13 (m, 5H), 7.36 (m, 2H), 7.52 (d, 1H), 8.01 (s, 1H), 8.13 (s, 1H); Mass Spectrum: M−H−503.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][Cl:9].[OH:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Cs+]>CC(C)=O>[ClH:9].[OH:23][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: ClCc1ccccn1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCCC(O)c1cccc(OCc2ccccn2)c1
Yield: 65 %

Procedure:
A suspension of 3.3 g of picolyl chloride hydrochloride (Aldrich 16,270-1), 1-(3-hydroxyphenyl)-1-hexanol (3.9 g.), cesium carbonate (16.3 g.), cesium iodide (trace) and acetone was refluxed for 40 hours. The reaction was filtered through a pad of celite and silica gel and the solvent removed in vacuo. The remaining oil was dissolved in ethyl ether, filtered through celite and silica gel and treated with ethereal hydrochloric acid. The resulting white precipitate was filtered, washed (ethyl ether) and dried giving 4.2 g (66% yield) of solid, m.p. 164°-165° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH3:21][NH:22][CH3:23].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C(O)C.CCOCC>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:22]([CH3:23])[CH3:21])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CNC
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Yield: 92.8 %

Procedure:
75 mg (0.18 mmol) 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole in 2.5 ml DMA were treated with 98 μl (0.54 mmol, 3eq) 5.6 M N,N-dimethylamine in ethanol for 35 h at RT. The solution was diluted with ether and a saturated aqueous solution of NaHCO3. The inorganic phase was extracted with ether, the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 8:1 yielded 63 mg (92%) [2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-dimethyl-amine as colorless oil, MS: 377 (MH+, 1Br).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:31])([F:32])[F:30])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (177 mg, 0.326 mmol) in ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (4 mL) at room temperature. The mixture was stirred for 5 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (20 mL). The aqueous solution was washed with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 159 mg (92% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine as a white solid: mp 238-240° C. ES-HRMS m/e calcd for C24H19Cl2F3N2O4 (M+Na) 549.0567. found 549.0570.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:23])[CH:21]=[CH2:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li]OC(C)=O.O.[Li+].[Cl-].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41].C([O-])(O)=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:23])[CH2:21][CH2:22][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)C(C)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A degassed suspension of the product of Step 1 (15.0 g, 46.6 mmol), n-Bu4NCl (25.9 g, 93 mmol), LiOAc.H2O (7.7 g, 115 mmol), LiCl (1.98 g, 93 mmol), Pd(OAc)2 (0.315 g, 1.4 mmol), and methyl 2-(2-iodophenyl)propanoate in DMF (90 mL) was stirred for 2 hours at 100° C. The dark red solution was then cooled to 0° C. and poured into saturated NaHCO3 solution (500 mL). The product was extracted with EtOAc and the organic layer was washed with H2O followed by brine. The solvent was removed under vacuum and the residue was purified by flash chromatography (EtOAc:hexane 1:10, 1:5 and 3:10) to give a pale yellow foam (18.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl-].[NH4+].C(O)(C)C>O1CCCC1.C(OC(C)C)(C)C>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[N:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccnnc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(Cc1ccnnc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution under argon of 1.88 g (20.0 mmol) of 4-methylpyridazine and 3.36 g (20.0 mmol) of ethyl 4-fluorobenzoate in 50 ml of anhydrous tetrahydrofuran is cooled to 0° C. and then 20.0 ml (40.0 mmol) of a 2M solution of sodium hexamethyldisilazane in tetrahydrofuran (THF) are added dropwise. After the addition, the temperature is allowed to return to ambient temperature, while a gradual setting of the reaction medium is observed. After one hour, the mixture is poured into an aqueous solution of ammonium chloride and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orangey-red solid. The latter is triturated at reflux in 80 ml of diisopropyl ether containing a few ml of isopropyl alcohol and the solid is then isolated by filtration after cooling to 0° C. 3.35 g of a pale yellow powder are thus isolated after drying.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[Cl:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:29][CH2:28][CH2:27][Cl:26])=[O:4]
Reactant: OCCCl
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OCCCl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Chloroethyl perfluorooctanoate was prepared by adding 162 g (0.375 mol) of perfluorooctanoyl chloride to 32.2 g (0.40 mol) of 2-chloroethanol cooled at 0° C., stirring the resulting mixture at 0° for 2 h, and then stirring for about 2.5 days at 25°. Fractionation of the resulting solution gave 152.6 g (85% yield) of the chloroethyl ester, b.p. 84°-88° at 1.3 kPa (10 mm), 98% pure by GC. IR (CCl4): 2960 (sat'd CH), 1790 (C=O), 1300-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 4.59 (t, JHH 5.5 Hz, 2H, CH2) and 3.70 ppm (t, JHH 5.5 Hz, 2H, CH2); 19F -81.6 (t of t, JFF 10, 4 Hz, 3F, CF3), -119.0 (t of t, JFF 12, 6 Hz, 2, F, CF2C=O), -122.4 (m, 4F, CF2), -123.3 (m, 4F, CF2), and -126.8 ppm (m, 2F, CF2).
Reaction SMILES: O=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:17]([OH:19])=O.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([S:38][C:39]([F:42])([F:41])[F:40])[CH:33]=3)=[CH:30][C:29]([C:43]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[O:44])=[N:28]2)[CH:24]=[CH:25][CH:26]=1.ClC1C=C(N2C(C3C=CC=C(SC(F)(F)F)C=3)=CC(C(O)=O)=N2)C=CC=1.N1CCNCC1>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([S:38][C:39]([F:41])([F:42])[F:40])[CH:33]=3)=[CH:30][C:29]([C:43]([N:45]3[CH2:50][CH2:49][N:48]([CH:17]=[O:19])[CH2:47][CH2:46]3)=[O:44])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1cc(-c2cccc(SC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1)N1CCNCC1
Reactant: O=CO
Agent: C1CNCCN1
Agent: O=C(O)c1cc(-c2cccc(SC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=CN1CCN(C(=O)c2cc(-c3cccc(SC(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
Under exclusion of oxygen, 17.2 mg (0.09 mmol) of EDC and 11.7 mg (0.09 mmol) of HOBt and 8.3 mg (0.18 mmol) of formic acid are added to a solution of 35.0 mg (0.07 mmol) of 1-{[1-(3-chlorophenyl)-5-(3-trifluoromethylthiophenyl)-1H-pyrazol-3-yl]carbonyl}piperazine, prepared from the compound of example 8A and piperazine in analogy to example 1, in 1 ml DMF, and the mixture is stirred for 72 hours at room temperature. The reaction mixture is separated by preparative HPLC. 15.7 mg (42% yield of theory) of product are obtained.