Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[CH2:8](N)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N.[OH-].[Na+]>>[CH2:19]([NH:7][C:5](=[O:6])[CH:4]=[CH2:3])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCN
Reactant: COCCC(N)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCCCCCCCCCCC

Procedure:
103.1 g (1.0 mole) of 3-methoxypropionamide are heated with 194.6 g (1.05 mole) of dodecylamine in a temperature range of 130°-170° C. until the evolution of ammonia is complete. The mixture is allowed to cool, 1.5 g of sodium hydroxide is added and the mixture is heated in a high vacuum at 90° to 110° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 172.4 g (0.72 mole=72% of the theoretical yield) of N-dodecylacrylamide having a Bp0.1 of 165°-170° C., which solidifies into crystalline form in the receiver, are distilled off.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@@H:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Clc1ccc(Nc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
Sodium hydride (0.36 g, 60% in oil) was added to 20 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 2.0 g of 3,4-dichlorophenyl-phenylamine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 1.5 g of 3(R)-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution, and the reaction solution was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.13 g of light brown amorphous solid 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[Li]CCCC.Br[C:15]1[S:19][C:18]([C:20]2[N:24]3[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]3=[N:22][C:21]=2[CH3:35])=[C:17]([Cl:36])[CH:16]=1>[Cl-].[Cl-].[Zn+2].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].C1COCC1>[Cl:36][C:17]1[CH:16]=[C:15]([C:4]2[N:3]([N:2]([CH3:8])[CH3:1])[CH:7]=[CH:6][CH:5]=2)[S:19][C:18]=1[C:20]1[N:24]2[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[C:23]2=[N:22][C:21]=1[CH3:35]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Reactant: CN(C)n1cccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccn4N(C)C)cc3Cl)c(C)nc12
Yield: 46.3 %

Procedure:
Using a procedure analogous to Example 27, 1-(dimethylamino)-pyrrole (0.20 mL, 1.65 mmol), THF (4 mL), 1.6 M n-BuLi (1.10 mL, 1.73 mmol), 0.5 M ZnCl2 (3.46 mL, 1.73 mmol), 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.34 g, 0.82 mmol) and PdCl2(dppf) (0.030 g, 0.041 mmol), furnish the title compound (0.17 g, 0.38 mmol, 46%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.52 (s, 6H), 2.84 (s, 6H), 3.28-3.39 (m, 1H), 6.21 (dd, J=4.1, 3.2 Hz, 1H), 6.38 (dd, J=4.1, 1.8 Hz, 1H), 6.68 (s, 1H), 7.02 (dd, J=3.2, 1.8 Hz, 1H), 7.29 (s, 1H). LC/MS (m/z): calcd. for C23H28ClN5S (M+H)+: 442.2; found: 442.3.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:22]([O:24][CH2:25]Cl)[CH3:23]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:22]([O:24][CH2:25][N:6]1[CH:7]=[C:2]([I:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])[CH3:23]
Reactant: CCOCCl
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Product: CCOCn1cc(I)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
In 50 ml of dichloromethane, 4.76 g (20 mmol) of 5-iodouracil was suspended and added with 11 ml (45 mmol) of bistrimethylsilylacetamide and stirred for 15 minutes at room temperature to form a homogeneous solution. This solution was added with 2.04 ml (22 mmol) of chloromethyl ethyl ether and 60 mg of tetra-n-butylammonium iodide and heated under reflux for 3 hours. After the solvent was evaporated under reduced pressure, the residue was added with water to produce crystals, which were taken by filtration. The crystals were washed by suspending them in hot methanol and recovering them by cooling and filtration to obtain 5.43 g of 1-(ethoxy-methyl)-5-iodouracil.
Reaction SMILES: O.NN.[C:4]([N:7]1[C:13]([CH3:14])=[CH:12][C:11]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:10]=2[C:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[N:8]1)(=[O:6])[CH3:5]>[Ni].CO>[C:4]([N:7]1[C:13]([CH3:14])=[CH:12][C:11]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:10]=2[C:9]([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[N:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C=C1C)OCO3
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2C=C1C)OCO3
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
0.1 g of Raney nickel and 0.25 ml (4.93 mmol) of 98% hydrazine hydrate are added to a suspension of 0.6 g (1.64 mmol) of 7-acetyl-5-(4-nitrophenyl)-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine in 40 ml of methanol. The mixture is stirred for 0.5 hour. The starting material is dissolved within a few minutes. After the reaction is completed, catalyst is filtered out. The filtrate is concentrated by evaporation in a vacuum. The residue is absorptively precipitated in water, suctioned off and rewashed with water. 0.49 g of 7-acetyl-5-(4-aminophenyl)-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine with a melting point of 175°-180° C. is obtained. Recrystallization of this crude product from 50% aqueous ethanol yields 0.46 g (79%) of 7-acetyl-5-(4-amino-phenyl)-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine with a melting point of 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14]#[N:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[OH-:23].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14](=[O:23])[NH2:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: [OH-]
Reactant: CN1C(=CC#N)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=CC(N)=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
15.2 g of the 7-chloro-1-methyl-2-cyanomethylene-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine obtained in Example 1 A are subsequently portion-wise introduced into 80 ml of concentrated sulfuric acid under stirring, and the resulting suspension is slowly heated up to a temperature of 50° C. until a clear solution is formed. Subsequently, the solution is maintained at a temperature of 50° C. for 1 hour. After cooling, the solution is worked-up by pouring it on ice, neutralizing the sulfuric acid with diluted potassium hydroxide solution and extracting the raw product with methylenechloride. The organic phase is separated, washed with water until neutral reaction of the washing-water, and dried over sodium sulfate. After filtration and evaporation of the solvent a residue is obtained which is re-crystallized from ethanol. 11 g of 7-chloro-1-methyl-2-carbamoylmethylene-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine, having a melting point of 179° to 181° C., are obtained.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]([NH2:10])=O)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.CN1CCOCC1.S(Cl)(Cl)=O>CN(C)C=O>[C:4]1(=[O:21])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]#[N:10])[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: COc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC
Solvent: O=S(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(CC#N)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To an ice bath cooled stirred suspension of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide (1.77 g, 5.00 mmol) and 4-methylmorpholine (1.3 mL, 12 mmol) in dimethyformamide (17 mL) under nitrogen, was added thionyl chloride (0.7 mL, 9.6 mmol) dropwise via a syringe. There was a slight exotherm and after 30 minutes, the cooling bath was removed and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a mixture of sodium bicarbonate (17 g) and 75 mL of ice water and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The wet solid was dissolved in methylene chloride (50 mL) and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford an orange solid. The solid was purified by flash column chromatography (silica gel, 5/95 ethyl acetate/methylene chloride, 50 mm id column) to afford 1.32 g (79%) of the product as a white solid: 1H NMR (CDCl3) δ7.9–7.6 (m, 4H), 7.10 (m, 2H), 6.83 (m, 1H), 5.64 (dd, J=6.5, 10.2 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (dd, 1H), 3.30 (dd, J=6.5, 16.8 Hz, 1 H); 13C NMR (CDCl3) δ167.7, 149.5, 149.2, 134.4, 131.5, 129.1, 123.6, 120.1, 116.9, 111.1, 110.7, 56.0, 55.9, 51.1, 21.1. Anal. Calcd for C19H16N2O4 0.18 H2O. Theoretical: C, 76.2. H, 4.85; N, 8.25. Found: C, 67.23; H, 4.79; N, 8.27.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCOC(=O)CCc1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (760 mg), 1 N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for two hours. The reaction mixture was poured into water, which was acidified with 1 N hydrochloric acid, and precipitated crystals were collected by filtration. This was recrystallized from methanol-ethyl acetate, and 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (550 mg, yield: 77%). Melting point: 170–171° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25]
Reactant: O=c1c(Cc2ccccc2)nc2c(n1CCO)CCCC2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=c1c(Cc2ccccc2)nc2c(n1CCCl)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml), and stirred at room temperature for 2 hours. Dilute aqueous K2CO3 was added to the reaction mixture, which mixture was then extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain compound 644 (7.55 g, yield: 78.0%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[O:19][C:18]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[N+:29]([O-])([OH:31])=[O:30]>>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[O:19][C:18]3[C:20]([Cl:24])=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1O2
Temperature: 5 °C
Reaction time: 0.42 h

Procedure:
Concentrated sulfuric acid (240 mL, 4.2 mol) was added to a solution of compound of Example 1i (37 g, 0.105 mol) in concentrated nitric acid (1100 mL, 17.34 mol) at 5° C. The reaction mixture was stirred at 5° C. for 25 min, and then at 40° C. for 4.5 h. Reaction mixture was quenched into ice water (2500 mL), the solid precipitated was filtered, washed with water till filtrate was neutral to pH and dried to obtain the title compound. Yield: 38 g (90.91%); 1H NMR (CDCl3, 300 MHz): δ 2.7 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.79 (s, 2H, CH2), 8.10 (s, 1H, Ar), 8.22 (s, 1H, Ar), 8.38 (s, 1H, Ar), 8.48 (s, 1H, Ar); MS: m/e (ES−) 396 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2=CC=CC=C2C1=O.[ClH:22]>O>[ClH:22].[ClH:22].[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: Cn1ncc(CCCN2C(=O)c3ccccc3C2=O)c1N
Agent: Cl
Solvent: O
Product: Cn1ncc(CCCN)c1N

Procedure:
5-Amino-1-methyl-4-(3-phthalimidopropyl)pyrazole (1.42 g, 5 mmol) was added to concentrated hydrochloric acid (10 ml) at room temperature, and the mixture was stirred under reflux for 23 hours. To the reaction mixture was added water (50 ml), and most of insoluble materials were removed by filtration. The filtrate was washed with ethyl acetate, and the aqueous layer was concentrated in vacuo. The residue was triturated with 2-propanol and dried in vacuo to give 3-(5-amino-1-methylpyrazol-4-yl)propylamine dihydrochloride (700 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5](/[CH:6]=[C:7]2/[C:8](=[O:24])[C:9]3[C:14]([CH2:15]/2)=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:11]([O:22][CH3:23])[CH:10]=3)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(Cl)c(C(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
The 88 (65 mg, 0.148 mmol) was dissolved in ethyl acetate 50 mL, Pd/C 15 mg added, and the reaction stirred under hydrogen balloon for 6 h, then filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 89. The crude was purified by flash chromatography using 100-200 mesh silica gel. The compound 89 was eluted at 25% ethyl acetate in hexane as half white coloured solid compound 2-(4-chloro-3-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 89. 1HNMR (400 MHz, CDCl3) δ ppm 7.55 (d, 1H), 7.41 (d, 1H), 7.34 (dd, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 3.87 (m, 7H), 3.33 (dd, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.93 (m, 1H), 2.66 (m, 2H); MS (ESI) m/z 439.9 (M+H).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[OH-:24].[K+].Cl>O.C1COCC1>[C:11]1([C:9]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:7][NH:6][C:5](=[O:24])[N:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(-c2nnc(S(C)(=O)=O)nc2-c2ccccc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2n[nH]c(=O)nc2-c2ccccc2)cc1
Yield: 92.1 %

Procedure:
To a solution of 3-(methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine (98.9 mg, 0.304 mmol) in a 1:1 mixture of H2O/THF (6.0 mL) was added potassium hydroxide (109.1 mg, 1.945 mmol). The mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature and neutralized with 1 M HCl, then extracted with CH2Cl2. The combined organic phases were washed with H2O and brine, dried over MgSO4, and concentrated to give the title compound as a yellow solid (73.7 mg). LCMS m/z=264.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([OH:16])=O)[CH:4]=1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([NH:51][C:48]2[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2c1OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2ccn(C)n2)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (24 g, 0.11 mol) in CH2Cl2 (500 mL) were added EDCI (31.6 g, 1.08 mol), NMM (54.5 g, 0.54 mol), HOBt (22 g, 0.16 mol) and 1-methyl-1H-pyrazol-3-ylamine (11 g, 0.11 mol) sequentially. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. The mixture was washed with water (250 mL), sat. aq. citric acid (250 mL×2), sat. NaHCO3 (250 mL) and brine (250 mL) sequentially. The organic phase was dried over Na2SO4 and concentrated to give a white solid. The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/10˜1/1) to give the title compound (9.6 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 7.49 (s, 1H), 7.44 (s, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.96 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCCCC1)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (119 mg, 0.3 mmol) and triethylamine (0.125 mL, 0.90 mmol) in methylene chloride was added to a vial charged with cyclohexanecarbonyl chloride (88 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added until the solution was basic and the layers were separated. The aqueous layer was washed with methylene chloride. The organic layers were combined and evaporated under a stream of nitrogen to give the title compound of Step A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:20]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Yield: 92 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (12.43 g, 0.04620 mol) in MeOH (200 mL) was added H2SO4 (8 mL). The reaction mixture was heated at reflux overnight and then concentrated to small volume. The residue was extracted with EtOAc and washed with water, brine, aq. sat. NaHCO3, and brine. The organic solution was concentrated to give methyl 3-bromo-5-(trifluoromethyl)benzoate (12.7 g, 92%). 1H NMR (300 MHz, CDCl3) δ: 8.36 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), and 3.97 (s, 3H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C\COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C=C\COC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-pyran (100 g) was dissolved in 2000 ml of dry tetrahydrofuran/600 ml of dry N,N-dimethylformamide. To the solution was added 100 g of diethyl malonate, and then 25 g of 60% sodium hydride with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 65.5 g of the objective compound as oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 49 (step 1), 410 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-methylphenyl)ethoxy]thiophene-2-carboxamide, 0.15 ml of methanesulfonyl chloride, and 0.28 ml triethylamine in 15 ml dichloromethane give (1-{5-carbamoyl-4-[1-(2-methylphenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.