Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55][CH3:56].[OH-].[Na+]>C1COCC1.CCO>[CH3:56][O:55][C:5]1[CH:6]=[C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:57])=[O:2]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.352 g, 0.44 mmol, 1 eq) in THF/EtOH (3/2) (10 mL) was added 1M NaOH (4 mL) and the reaction was stirred at rt overnight. It was then concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane+1% Formic acid) to afford the title compound (0.342 g, 865) as a white foam. 1H NMR (DMSO-d6)δ 12.50 (bs, 1H); 8.59 (t, 1H); 7.99–7.92 (m, 6H); 7.80–7.68 (m, 4H); 7.37 (d, 1H); 7.26–7.10 (m, 5H); 6.38 (s, 1H); 6.30 (d, 1H); 4.21 (s, 2H); 3.58 (s, 3H); 3.26 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3350, 2950, 2850, 1720, 1640, 1620, 1550, 1495, 1475, 1415, 1320, 1160, 1150, 1120, 1095, 1080, 1030 cm−1; mass spectrum [(+)APCI], m/z 778 (M+H)+; Anal. Calcd. for C44H41F6NO5: C, 67.95; H, 5.31; N, 1.80. Found: C, 67.22; H, 5.22; N, 1.74.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH2:11].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (184 mg, 1.00 mmol, 1.00 equiv) in CH3CN/H2O (1/1, 33 ml) was cooled to 0° C. Methylamine (40 w % in H2O) (0.252 ml, 3.25 mmol, 1.00 equiv) was added. The reaction mixture was adjusted to a pH of about 9-10 using 1 N NaOH. After being stirred at 0° for 10 min, the reaction was complete. The resulting suspension was used in the next step without workup or purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=S)=[N:14]1.O.[NH2:37][NH2:38]>C1COCC1.O.C(OCC)(=O)C.[Hg]Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[N:18]=[C:19]2[NH:37][NH2:38])=[N:14]1
Reactant: NN
Reactant: Cn1cc(C#N)cc1-c1c2c(=S)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Agent: Cl[Hg]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C#N)cc1-c1c2c(NN)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reaction time: 4 h

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.24 g) in THF (5 mL) were added hydrazine hydrate (0.30 mL) and mercury chloride (0.30 g). After 4 h, a second addition of hydrazine hydrate (0.20 mL) and mercury chloride (0.30 g) was done. After stirring overnight, the mixture was diluted with water and ethyl acetate. The mixture was then filtered through a celite bed. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using a FlashMaster™ yielding 0.18 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]#[C:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1>CO.C([O-])=O.[NH4+].[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[N:20]=3)[CH2:14][CH2:15]2)=[O:9])[N:5]=[C:4]([C:33]([F:36])([F:34])[F:35])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C#Cc3cccc4ccccc34)cs2)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(CCc3cccc4ccccc34)cs2)CC1
Yield: 54.3 %

Procedure:
2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(naphthalen-1-ylethynyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (I-50, 157 mg) is dissolved in methanol (1.5 ml) and, at 60° C., reacted with ammonium formiate (195 mg) and 20% Pd(OH)2/C (4 mg) as catalyst. The catalyst is filtered off and the solvent is removed under reduced pressure, giving 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[2-(naphthalen-1-yl)ethyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (86 mg) as a colourless oil.
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:30][C:24]3[C:25](=[O:29])[NH:26][CH:27]=[CH:28][C:23]=3[CH:22]=2)=[CH:17][CH:16]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>ClCCl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:26]2[CH:27]=[CH:28][C:23]3[CH:22]=[C:21]([C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=4)[S:30][C:24]=3[C:25]2=[O:29])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.1 %

Procedure:
Add pyridine (0.62 mL, 7.64 mmol) and triethylamine (0.53 mL, 3.82 mmol) to a mixture of 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (0.5 g, 1.91 mmol), 4-bromobenzeneboronic acid (1.15 g, 5.73 mmol), cupric acetate (1.05 g, 5.73 mmol), and 4A molecular sieves (0.4 g) in dichloromethane (38 mL). Stir the mixture at RT for 2 days. Dilute the mixture with CH2Cl2, wash twice with a solution of 5% NH4OH/H2O, and H2O. Dry the organics over Na2SO4, filter, wash with Et2O, and concentrate. Purify the crude material by flash chromatography eluting with 10-15% EtOAc/CH2Cl2 to give 0.2 g (25%) of the title compound. LC-ES/MS m/z (81Br, 35Cl) 417.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:20])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](C#Cc1ccc(Cc2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.6 g (5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}-methanol and 4.1 ml triethylsilane in 50 ml dichloromethane is cooled in the ice bath. Then 4.7 ml trifluoroacetic acid are slowly added dropwise, and the solution is stirred for 4 h at ambient temperature. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulphate the solvent is removed and the residue is purified using silica gel (cyclohexane).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:27][CH2:26][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17](=[O:18])[C:8]=2[CH2:7]1)=[O:5])C.[OH-].[K+].C(O)C.Cl>O>[C:4]([CH:6]1[CH2:27][CH2:26][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17](=[O:18])[C:8]=2[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCc2c(c(=O)c3cccnc3n2-c2cccc(Cl)c2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2c(c(=O)c3cccnc3n2-c2cccc(Cl)c2)C1
Reaction time: 21 h

Procedure:
Saponify 7-ethoxycarbonyl-10-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-5(10H)-one (7.1 g) with potassium hydroxide (1.10 g) in a solvent of ethanol and water (142 ml, 9:1 by volume). After 21 hours at 25° C., add water (200 ml), cool the resulting solution in ice, and acidify (pH 2) the solution with concentrated hydrochloric acid. Collect the resulting precipitate on a filter, and crystallize it from ethanol to provide 7-carboxy-10-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo [b][1,8]naphthyridin-5(10H)-one, m.p. 279°-280.5° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C.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].C(Cl)Cl>[CH3:3][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:1]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nccs2)cc1C#N
Temperature: 120 °C
Yield: 53.9 %

Procedure:
To a suspension of 2-[(1-methylethyl)oxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (D39) (109 mg), 2-bromo-1,3-thiazole (93 mg) and cesium carbonate (148 mg) in acetonitrile (3 mL)/water (0.750 mL) stirred under nitrogen was added PdCl2(dppf)-CH2Cl2 adduct (31.0 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 1 h. After cooling the reaction, the reaction mixture was diluted with ethyl acetate, filtered through celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product, which was purified by column chromatography to afford 2-[(1-methylethyl)oxy]-5-(1,3-thiazol-2-yl)benzonitrile (D64) (50 mg). MS (ES): C13H12N2OS requires 244. found 245.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[N+:16]([C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:26]([C@@H:24]([NH:25][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 61 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-nitro-L-phenylalanine to provide the title compound in 61% yield as yellow needles (recrystallization from MeOH/water).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>O1CCOCC1.CCOCC.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCCC2=O)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 70 °C
Yield: 67.1 %

Procedure:
Stir a solution of 500 mg (1 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate, 0.1 mL (1.1 mmol) of 2-pyrrolidinone and 450 mg (1.4 mmol) of caesium carbonate in 10 mL of anhydrous 1,4-dioxan for 10 minutes while bubbling with argon, then add 9 mg (0.01 mmol) of Pd2(dba)3 and 17 mg (0.03 mmol) of Xantphos and heat the reaction mixture for 6 h at 70° C. while stirring. Then distribute the mixture in 100 mL of ether/EtOAc 1:1 mixture and 50 mL of a saturated aqueous solution of NH4Cl. After extraction, wash the organic phase with 2×50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 293 mg of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]1([CH2:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:18]([NH:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in DMF (6 mL) were added phenylmethanamine (268 mg, 2.5 mmol) and TEA (345 mg, 3.4 mmol). The reaction mixture was stirred at 120° C. for 30 min under microwave. The reaction solution was diluted with water (40 mL), and the resulting precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was used in next step without further purification. LCMS (m/z): 307.1/308.1 [M+H]+/[M+2H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=4)=[C:4]2[CH:3]=1.[CH2:32]([NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH:33]=[CH2:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(NC2CCCCC2)CCCCC1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13](/[CH:34]=[CH:33]/[CH2:32][NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH:14]=4)=[C:4]2[CH:3]=1
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(OS(=O)(=O)C(F)(F)F)cc1c23
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(/C=C/CNC(=O)C(F)(F)F)cc1c23
Yield: 60 %

Procedure:
(Method P) Under an atmosphere of nitrogen, trifluoromethanesulphonic acid 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl ester, 38 (30 mg, 0.075 mmol), allyltrifluoroacetamide (17 mg, 1.5 eq), palladium (II) acetate (2 mg, 10 mol %), triphenyl phosphine (4 mg, 20 mol %), dicyclohexylamine (0.032 mL, 2 eq), and dioxane were mixed in a sealed tube and heated reflux in a sealed tube for 18 hrs. On cooling, the products were dissolved in dichloromethane and adsorbed onto silica. Separation of the more polar product by column chromatography (85:15 hexane:ethyl acetate) gave the title compound (22 mg, 0.045 mmol, 60%).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([CH3:69])=[CH:65][CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:78]([OH:85])(=[O:84])/[CH:79]=[CH:80]/[C:81]([OH:83])=[O:82]>C(O)CCC>[C:78]([OH:85])(=[O:84])/[CH:79]=[CH:80]/[C:81]([OH:83])=[O:82].[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][C:66]([CH3:69])=[CH:67][CH:68]=3)[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc(OCCCCl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 56 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of α,α-bis (p-fluorophenyl)-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(4-methylphenoxy) propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 100 g of Florisil®. Fractions eluted with 10% acetone in benzene were combined and concentrated to give a gum. This gum was converted to the fumaric acid salt and the solid was recrystallized from absolute ethanol to yield 3.2 g (56%) of title compound as a white solid, mp 193°-194° C. with decomposition. pe f 49495948.hsc
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 71.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.25 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.17 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.C[Si]([C:16]#[N:17])(C)C.O=P(Cl)(Cl)Cl.Cl>C1C=CC=CC=1.[I-].[Zn+2].[I-].ClCCl.N1C=CC=CC=1>[C:16]([C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:1][CH2:2][CH:3]=1)#[N:17]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCSc2ccccc21
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CCSc2ccccc21
Temperature: 25 °C

Procedure:
80 mg of zinc iodide are added to 1.7 g 1-thiochroman-4-one in benzene followed by, dropwise, with stirring at room temperature, 2.4 g of trimethylsilylcyanide. After 8 hours reaction 2.8 ml of POCl3 and 16 ml of pyridine are added and the mixture refluxed for 8 hours. After cooling the mixture is poured onto ice/conc. HCl and, after addition of dichloromethane, separated. The organic phase is dried over MgSO4, concentrated by evaporation and purified by chromatography on kieselgel (eluant hexane/ethyl acetate; 4/1).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.CC(C)([O-])C.[Na+].Cl[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)[CH:12]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: COC(=O)c1cccc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(Cl)cn2)c1
Yield: 60 %

Procedure:
To a toluene (10.0 mL) solution of 3-amino-benzoic acid methyl ester (330 mg, 2.2 mmol) was added palladium acetate (200 μL of 0.001 mmol stock solution), BINAP (200 μL of 0.001 mmol stock colution), sodium t-butoxide (2.2 mmol) and 2,5-dichloro-pyridine (296 mg, 2.0 mmol). The reaction mixture was refluxed for 10 h. Collected crude reaction mass was added to water, extracted with ethyl acetate. Solvent was evaporated and the crude mass was purified by flash column chromatography using 20% ethyl acetate in hexanes on a prepacked silica column to give 3-(5-chloro-pyridin-2-ylamino)-benzoic acid methyl ester (315 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH:12](O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:12]=[N:10][C:5]=2[C:4]=1[CH3:11]
Reactant: O=CO
Reactant: COc1ccc(N)c(N)c1C
Product: COc1ccc2[nH]cnc2c1C
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 4-methoxy-3-methyl-1,2-benzenediamine (2.8 g, 18.4 mmol) and formic acid (30 mL) was heated at 60° C. for 30 minutes. The formic acid was removed under pressure and the product was partitioned between chloroform and water containing sufficient sodium hydroxide to basify the solution. After evaporation of the solvent the crude product was chromatographed (methanol:chloroform) to give 2.55 g (84%) of 5-methoxy-4-methyl-1H-benzimidazole.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccncc3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(bromomethyl)pyridine to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 347.1 (M+1).