Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.[CH2:4]([C:6]1[CH:60]=[CH:59][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C@@H:20]3[CH2:25][C@H:24]([CH2:26][O:27]CC4C=CC=CC=4)[C@@H:23]([O:35]CC4C=CC=CC=4)[C@H:22]([O:43]CC4C=CC=CC=4)[C@H:21]3[O:51]CC3C=CC=CC=3)=[CH:12]2)=[CH:8][CH:7]=1)[CH3:5].O>C(Cl)Cl>[CH2:4]([C:6]1[CH:60]=[CH:59][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C@@H:20]3[CH2:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:35])[C@H:22]([OH:43])[C@H:21]3[OH:51])=[CH:12]2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(Cn2cc([C@@H]3C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3ccccc32)cc1
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CCc1ccc(Cn2cc([C@@H]3C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 5 %

Procedure:
In a nitrogen stream, dimethylsulfide (0.72 mL) and a boron trifluoride-diethyl ether complex (0.36 mL, 2.8 mmol) were added to a solution of 1-(4-ethylbenzyl)-3-[(1S,2S,3R, 4R,5R)-2,3,4-tris-benzyloxy-5-(benzyloxymethyl)cyclohexyl]-1H-indole (213 mg, 2.28 mmol) in methylene chloride (4.7 mL) under cooling with ice. The mixture solution was stirred at room temperature for 64 hours, and then water was added thereto under cooling with ice and the resulting solution was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate) and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (50:1)] to obtain the title compound (45 mg, 41%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]([NH:5][C:6]2[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=2[S:12][CH3:13])=[O:4])[CH2:22][CH2:21]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (6.41 g, 0.02 mol) in acetonitrile (120 ml) was added 1-(2-hydroxyethyl)piperazine(3.53 g, 0.027 mol), and then added potassium carbonate (3.75 g, 0.027 mol) with ice-cooling and the mixture was stirred at room temperature for 23 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was recrystallized from ethanol-ether to provide 7.19 g (yield 97%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:23][CH:24]=1)=[O:43]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.644 g, 5.1 mmol) was added, and dissolved in 30 mL dichloromethane. Triethylamine (2.13 mL, 15.3 mmol) was added, and in an ice bath a dichloromethane solution dissolving 2-naphthoyl chloride (1.067 g, 5.6 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 1 h, and stirred at room temperature overnight. It was filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 0.53 g, at a yield of 21.8%.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:39])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH2:36][O:37][CH3:38])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]2=[O:39])=[C:28]([CH2:36][O:37][CH3:38])[CH:29]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
25 g (48 mmol) of the compound from Example 31A are dissolved in 500 ml of ethyl acetate and 500 ml of ethanol. 18 g (286 mmol) of ammonium formate and 1 g of palladium on carbon are added, and the mixture is heated at reflux for 45 min. The reaction solution is then allowed to cool and filtered through silica gel. The filtrate is concentrated to dryness under reduced pressure. This gives 25 g (100% of theory) of the desired product.
Reaction SMILES: [OH:1][CH:2]([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:27]([C:24]1[S:25][CH:26]=[C:22]([C:20]([N:16]2[CH2:15][C:14]3([CH2:30][CH2:31][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:32])[CH2:12][CH2:13]3)[O:19][CH2:18][CH2:17]2)=[O:21])[N:23]=1)([CH3:29])[CH3:28]
Reactant: CC(O)CCCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reaction time: 0.08 h

Procedure:
To a solution of (9-(9-hydroxydecyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 280, step b) (287 mg) in DCM (10 mL) at 0° C. under nitrogen was added trifluoroacetic acid (0.048 mL). The mixture was stirred for 5 minutes then Dess-Martin periodinane (392 mg) was added. The reaction mixture was stirred at room temperature for 5 hours then a further amount of Dess-Martin periodinane (392 mg) was added at 0° C. then stirred at room temperature for 1.75 h. Saturated sodium thiosulfate solution (20 mL), saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate were added and the mixture stirred then the phases separated. The aqueous layer was extracted with ethyl acetate (×2) and the combined organics were washed with saturated aqueous sodium bicarbonate solution. Acetic acid (0.053 mL) was added then the organics were dried over sodium sulfate, filtered and evaporated to afford the titled compound as a yellow gum. Yield 0.338 g.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (400 mg,1.70 mmol) in dichloromethane (15 ml) was treated with morpholinomethyl-polystyrene HL resin (1.00 g, 3.4 mmol/g loading) followed by 4-bromo-3-fluorobenzenesulfonyl chloride (0.50 ml, 930 mg, 3.40 mmol). The resulting solution was stirred at room temperature for overnight (20 hours). The reaction mixture and was then filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was applied to an SCX column eluting first with methanol and then 2M ammonia in methanol. The fractions containing product were collected, combined and evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster with an eluting gradient of 0 to 5% methanol in dichloromethane over 40 mins. Fractions containing product were combined and evaporated in vacuo to afford the title compound (E105). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C1COCCN1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To dichloromethane solution (2 ml) of 3-bromo-4-methylbenzoic acid (50 mg, 0.23 mmol), WSCI (67 mg, 0.348 mmol), morpholine (24 μl, 0.278 mmol) and N,N-dimethylaminopyridine (28 mg, 0.232 mmol) were added, followed by stirring at room temperature for 16 hours. To the reaction mixture, saturated aqueous ammonium chloride solution was added, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), whereby (3-bromo-4-methyl-phenyl)-morpholin-4-yl-methanone was obtained as a yellow brown solid (68 mg, 100%).
Reaction SMILES: ClC(Cl)(Cl)CO.ClC([NH:13][C:14](=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17])C(Cl)(Cl)Cl.Cl>C1(C)C=CC=CC=1>[C:14]([NH2:13])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Agent: Cl
Agent: OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1ccccc1O
Temperature: 25 °C
Yield: 272.5 %

Procedure:
A solution composed of 2,2,2-trichloroethanol (30 g), N-(1,2,2,2-tetrachloroethyl) salicylamide (30 g) and toluene (200 ml) is refluxed until the generation of hydrogen chloride ceases (for about 5 to 8 hours). The reaction mixture is cooled to room temperature. The toluene layer is washed with water and dehydrated, and toluene is evaporated under reduced pressure to give the desired N-8 2,2,2-trichloro-1-(2,2,2-trichloroethoxy)-ethyl]salicylamide (37 g) represented by the foregoing formula as colorless crystals. mp. 111°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccccc2Cl)cc1
Yield: 62 %

Procedure:
A solution of 17.8 gm (59 millimols) of methyl 4-(2'-chloro-4-biphenylyl)-4-oxo-butyrate in 150 ml of anhydrous acetic acid was admixed with 4 ml of perchloric acid of 70% and hydrogenated in the presence of 4 gm of palladium/barium sulfate (5%) at 5 atmospheres and at room temperature for 8 hours. The catalyst was vacuum-filtered off and the solvent was removed in vacuo; the residue was taken up in water and ethylene chloride. The carboxylic acid obtained from the separated organic phase was extracted with potassium carbonate and precipitated by acidifying. The free acid was extracted with ether, the ethereal solution was dried and distilled in a high vacuum (b.p. 186°-190° C. at 0.08 mm Hg). Yield: 62% of theory; m.p. 61.5°-63° C. (from cyclohexane/benzene). Melting point of the cyclohexylamine salt: 140° C. (from isopropanol).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:15].[NH4+].[Ce].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [Ce]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C=O)cc1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A methanol solution of 24.6 g of cerium(III) nitrate is placed into an anode chamber, and a methanol solution of 2 g of ammonium nitrate is placed into a cathode chamber. The cerium salt is electrolyzed with a constant current of 50 mA to pass electricity across the electrodes in a quantity of 1.2 F/mole. A 1.22 g quantity of p-methyl anisole is added to the solution withdrawn from the anode chamber after the electrolysis, and the mixture is stirred for 30 minutes. The same procedure as in Example 1 is thereafter repeated, giving 1.312 g of anisaldehyde. Yield: 96.5%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[Cl:15][CH:16]([C:20]1[O:25][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:34])([F:33])[F:32])[C:22]=2[N:21]=1)[CH:17]([CH3:19])[CH3:18]>CCCCCC.O1CCCC1>[Cl:15][CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](=[O:26])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:25]
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F

Procedure:
10.6 g of N-(2-thiazolyl)-acetamide, 325 ml of tetrahydrofuran and 106 ml of n-butyllithium in hexane titrating 1.4 M and 11.4 g of 2-(1-chloro-2-methylpropyl)-8-(trifluoromethyl)-4H-3, benzoxazin-4-one of Step A in solution in 80 ml of tetrahydrofuran were reacted by the procedure of Step A of Example 6 of Belgian Patent No. 896,941 to obtain 13.8 g of 2-[(2-chloro-1-oxo-3-methylbutyl)-amino]-β-oxo-N-(2-thiazolyl)-3-(trifluoromethyl)-benzene propanamide melting at 186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][NH:31]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:34].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][N:31]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:34]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1Cl
Reaction time: 16 h

Procedure:
3-Fluorobenzenesulphonyl chloride (0.027 g, 0.137 mmol, 1.05 equiv.) was added to a mixture of 2-chloro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid methyl ester (0.045 g, 0.130 mmol) and pyridine (0.1 ml) in dichloromethane (2 ml) and the mixture shaken for 16 hours. The solution was washed with saturated sodium hydrogen carbonate (2 ml) and 1M aqueous HCl (2 ml) then dried over magnesium sulphate. The solution was evaporated to afford the crude 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, 0.097 g, as a red oil. This material was taken onto the next step without further purification. LC @215 nm; Rt 1.64: 100%, m/z (ES+): 502 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][CH2:10][CH2:11][NH:12][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:12]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH2:9][CH2:10][CH2:11]3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cn1ncc2c(c1=O)CCCN2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c1=O)CCCN2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
In DMF (5 ml) was dissolved 6-methyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one (116 mg) followed by addition of sodium hydride (60%) (56 mg), and the mixture was stirred at room temperature for 30 minutes. Then, 4-(4-chlorobenzoyl)benzyl bromide (341 mg) was added and the mixture was further stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with ethyl acetate-THF. The organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to provide 165 mg of the title compound as yellow amorphous solid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CO[Si](OC)(OC)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C)(C)(C)C>[Pd](Br)Br.O1CCCC1>[C:12]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO[Si](OC)(OC)c1ccccc1
Reactant: CCCCCCCBr
Agent: Br[Pd]Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCCc1ccccc1
Yield: 85.1 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.358 g (2 mmol) of n-heptyl bromide, 0.476 g (2.4 mmol) of trimethoxyphenylsilane, 0.021 g (0.08 mmol) of palladium (II) bromide, 4.8 ml (4.8 mmol) of 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride and 4.8 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.096 g (0.2 mmol) of di-tert-butylmethylphosphonium tetraphenylborate obtained in Example B-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 21 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.300 g of 1-phenylheptane (yield: 85 mol % based on n-heptyl bromide). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:43]Br)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:33]2([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:35][CH2:34]2)[N:27]=3)=[C:20]([F:42])[CH:19]=1>CN(C=O)C>[F:42][C:20]1[CH:19]=[C:18]([CH2:17][CH:16]2[CH2:43][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]2)[CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2
Reactant: Fc1cc(CC(CBr)CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
To a slurry of sodium hydride (0.206 g, 5.14 mmol) in 7 mL DMF was added diethyl malonate (0.690 mL, 4.57 mmol) dropwise via syringe (bubbling). After 3 min, the reaction mixture was clear, and solid 2-(4-(3-bromo-2-(bromomethyl)propyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.640 g, 1.14 mmol) was added, the reaction mixture was sealed, and heated to 100° C. After 1 h, the reaction mixture was partitioned between sat'd aq. NH4Cl and EtOAc. The org layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, EA/hexanes gradient, to give diethyl 3-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)cyclobutane-1,1-dicarboxylate as a white solid. MS (ESI) m/z: calculated: 558.2; Observed: 559.1 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH3:23])=[C:15]([CH3:22])[C:16]=1[C:17](OCC)=[O:18]>>[CH3:23][C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[C:15]=1[CH3:22]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Product: Cc1sc2nc3ccc(C(N)=O)cn3c(=O)c2c1C

Procedure:
From 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.0 g (0.040 mol) of 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966), following the procedure of Example 22, there is obtained 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide; mp 361°-363° C. after recrystallization from pyridine.
Reaction SMILES: O=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14](O)=O)[CH2:3]1.C[N:18]1[CH2:23][CH2:22]O[CH2:20][CH2:19]1.ClC(OCC)=O.C(NCC)C.C(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.O1CCCC1>[CH2:19]([N:18]([CH2:23][CH3:22])[CH2:14][CH:4]1[CH2:3][CH2:2][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5]1)[CH3:20]
Reactant: CN1CCOCC1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: CCOC(=O)Cl
Agent: O=C=O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CC1CCN(Cc2ccccc2)C1
Temperature: -25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of 32.9 g (0.15 mole) 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid [J. Org. Chem., 26, 1519 (1961)] and 300 mL of dichloromethane was added 15.2 g (0.15 mole) of N-methylmorpholine. After 15 minutes the solution was cooled to -25° C. and 16.3 g (0.15 mole) of ethyl chloroformate was added. After an additional ten minutes, a solution of 13.5 g (0.18 mole) of diethylamine and 18 mL dichloromethane was added to the reaction. Carbon dioxide was evolved and after 1.5 h another 10 g (0.13 mole) of diethylamine in 10 mL of dichlormethane was added. The reaction was stirred four hours, washed with 1N sodium hydroxide, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was added to a suspension of 17.4 g (0.46 mole) of lithium aluminum hydride and 210 mL anhydrous tetrahydrofuran. The reaction was refluxed overnight then cooled to room temperature. The cooled solution was quenched by the successive addition of 17.4 mL water, 17.4 mL 15% sodium hydroxide, and 52.2 mL water. The resulting precipitate was filtered and washed with ethyl alcohol. The filtrate was concentrated under reduced pressure, taken up in dichloromethane and dried over magnesium sulfate. The solvent was removed under vacuum giving 25.8 g (69%) of N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as a yellow oil. This material was used in the next step without purification.