Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
4-Bromoaniline (56.0 g., 0.33 Mol.), 2,5-hexanedione (37.6 g., 0.33 Mol), and acetic acid (5 ml) were placed into Toluene (500 ml) and heated under reflux for 8 hours employing a dean stark trap to remove the water from the reaction. The reaction was cooled to room temperature and concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate, washed one time each with 2N hydrochloric acid, 2N NaOH, and H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield a brown solid. Material was purified by silica gel flash chromatography eluting with hexane. Concentration of the appropriate fractions yielded 55.0 gm. of a light yellow solid. (68%) NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+ 249 m.p. 71°-73° C.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11]([Cl:25])=[O:12]
Reactant: C#CCOc1cc(F)c(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)c(C(=O)Cl)cc1F

Procedure:
To 20 ml of toluene were added 1.4 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid, 0.8 ml of thionyl chloride and 10 mg of DMF, and the mixture was heated to reflux for 2 hours. Then, the reaction mixture was concentrated under reduced pressure, and 1.5 g of 2,5-difluoro-4-(2-propynyloxy)benzoyl chloride was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:14][CH2:15][CH2:16][CH2:17]Cl)[C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]2[O:13][CH2:17][CH2:16][CH2:15][S:14][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(SCCCCl)c(O)c(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(N)=O)c1)OCCCS2
Temperature: 70 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
The 5-acetyl-3-(3-chloro-propylsulfanyl)-2-hydroxy-benzamide (2.87 g, 10 mmol) was dissolved in 8 mL dry DMF. Solid Cs2CO3 (4.93 g, 15.1 mmol) was added, followed by catalytic amounts of KI (0.1 g). The suspension was warmed to 70° C. under nitrogen and was stirred for 72 h. After cooling, it was diluted with ethyl acetate and enough 4 N HCl to make the pH about 2. The aqueous layer was extracted with more ethyl acetate. The combined organic layers were washed with water and brine. Drying over Na2SO4 and concentration yielded the product as a solid (1 g, 40%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH:15]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:15][C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:7]=2[F:14])([CH3:22])([CH3:21])[CH3:1]
Reactant: CCCC(=O)Nc1c(F)cc([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(F)c2[nH]1
Temperature: 120 °C
Yield: 84.7 %

Procedure:
To a solution of N-[2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol) at room temperature. The mixture was heated at 120° C. for 2 g before being cooled down to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 81%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 9.95 (brs, 1 H), 8.30 (d, J=2.1 Hz, 1 H), 7.74 (dd, J=1.8, 11.1 Hz, 1 H), 6.43 (dd, J=2.4, 3.3 Hz, 1 H), 1.43 (s, 9 H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26](OCC)=[O:27]>ClCCl>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:24][CH:26]=[O:27])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: Cc1ccc2c(c1)c1c(OCCN)cccc1n2Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(OCCNC=O)cccc1n2Cc1ccccc1
Temperature: 62 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylamine (0.2974 g, 0.90 mmol), dichloromethane (4 mL) and ethyl formate (4 mL) is heated at 62° C. Additional dichloromethane (6 mL) and ethyl formate (6 mL) are added. After 4 h, the mixture is concentrated to dryness and the residue is chromatographed on silica gel (100 mL) using methanol/dichloromethane (4/96). The resulting solids are recrystallized from ethyl acetate/dichloromethane/hexane to give 0.2716 g (84%) of the title compound; 1H NMR (CDCl3) δ2.55, 3.94, 4.36, 5.48, 6.11, 6.64, 6.99, 7.11, 7.24, 7.32, 8.06, 8.28.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1ccc(/C(C#N)=C/c2ccc3ccccc3n2)cc1OC
Yield: 62.7 %

Procedure:
2-Quinolinecarboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (225 mg) through Method A (production step 2), to thereby yield the target product (yield: 252 mg, 63%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46]1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[C:47]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)=[CH:46]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4coc5ccccc45)c3C2=O)c(OC)c1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (65 mg, 0.118 mmol), aqueous sodium carbonate (2 N, 0.237 mL, 0.474 mmol), 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (43 mg, 0.178 mmol) and bis(triphenylphosphine)palladium chloride (17 mg, 0.024 mmol) in DME (2 mL) was placed in a vial. The vial was purged with nitrogen, sealed, and the reaction mixture heated at 120° C. for 1 h. The mixture was filtered through a pad of Celite, which was rinsed with MeOH. The solvent was removed in vacuo and the residue diluted with MeOH, passed through a microfiltration frit, and purified via preparative HPLC. The fractions were collected and concentrated in vacuo to give the title compound as a tan oil (36.3 mg, 48%). [M+H] calc'd for C35H39FN4O6, 632. found, 632.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH2:7][CH:8]([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:3][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)CCOCCCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCOCCCCBr
Reaction time: 18 h

Procedure:
6.1 cc (0.0636 mol) of phosphoric tribromide are added dropwise at 0° over the course of 20 minutes and while stirring, to a solution of 27.5 g (0.172 mol) of 4-isopentyloxy-butanol (production: see Example 15) and 1.36 g (0.0172 mol) of pyridine in 150 cc of absolute chloroform. The cooling bath is removed, the mixture is then heated to 60° for 1 hour and stirred at this temperature for 18 hours. The reaction mixture is poured into ice-cold sodium bicarbonate solution, the chloroform phase is removed in a separating funnel, washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is filtered with hexane/ethyl acetate (98:2) on silica gel. The evaporated filtrate is fractionally distilled and pure 1-bromo-4-isopentyloxy-butane is obtained. B.P.: 96°-97°/12 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1>C(O)(=O)C>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]4[CH:32]=[CH:36][CH:35]=[CH:34]4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(-n2cccc2)c1
Yield: 67.8 %

Procedure:
A mixture of [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.04 g, 0.1 mmol) and 2,5-dimethoxytetrahydrofuran (0.08 g, 0.6 mmol) in 5 mL of acetic acid was heated at 80 for 1 h. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 30%) to give 30 mg (67%) of the title compound as an off-white solid. MS (ESI) m/z 443; HRMS: calcd for C27H17F3N2O, 442.1293; found (ESI, [M+H]+), 443.1373.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[Br:11]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: NC(=O)CCC(=O)NBr
Reactant: c1cnc2c(n1)CCCC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1CCCc2nccnc21
Temperature: 25 °C

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoxaline (Intermediate 19) (3.08 g, 23.0 mmol, commercially available) in CCl4 (200 mL) was added N-bromosuccinamide (4.09 g, 23.0 mmol) and a catalytic amount (56 mg) of benzoyl peroxide. The reaction mixture was heated at reflux for 17 hours. The reaction mixture was cooled to room temperature and filtered through Celite and concentrated in vacuo gave 5-bromo-5,6,7,8-tetrahydroquinoxaline, (Intermediate 20) (3.8 g, crude).
Reaction SMILES: [Li].[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:7][CH2:6][CH2:5][O:4]1.O1CCC[CH2:15]1.C[Li]>C(OCC)C>[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:15])[O:4][CH2:5][CH2:6][O:7]1
Reactant: CC1(CCCC(=O)O)OCCO1
Reactant: C1CCOC1
Agent: [Li]
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
348 Mg. of the lithium salt of the ketal acid, 4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml. anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml. of a 1.6 molar solution of methyllithium in diethylether was added dropwise over a period of one hour while stirring under a nitrogen atmosphere. The solution was allowed to rise approximately to 20° C. and kept at this temperature over a period of 2 hours. The reaction mixture was added to crushed ice and the organic solvents were removed in vacuo. The residue was extracted with ether, the extract was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated in vacuo to give crude 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:15]([C:25](=[O:43])[N:26]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[CH3:27])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1)[CH2:28][N:26]([CH3:27])[C:25]([C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=1)=[O:43]
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCC(C(=O)O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A mixture of 200 mg (0.33 mmol) 5′-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (Example 45), 10 ml 1N aqueous sodium hydroxide solution and 10 ml methanol was stirred at room temperature over night. After washing with 2 portions of ethyl acetate the aqueous layer was acidified to pH 4 with 1N aqueous hydrochloric acid solution. Extraction with dichloromethane, drying with sodium sulfate and flash column chromatography afforded 81 mg (42%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[C:47]([Cl:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1nc(Cl)ccc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light-yellow gum. MS(m/c): 442.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)c(Br)c1
Reaction time: 1 h

Procedure:
To 3-bromo-4-chloro-benzoic acid (9.4 g, 40 mmol) in dry DCM (100 mL), was added DMF (0.5 mL) followed by addition of oxalyl chloride (22.5 mL, 55 mmol, 2M in DCM) slowly. The mixture was stirred for 1 hr, then concentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1([CH3:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][C:6]1([O:5][CH2:4][CH2:3][CH:2]=[O:1])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(OCCCO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(OCCC=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of tert-butyl 4-(3-hydroxypropoxy)-4-methylpiperidine-1-carboxylate (6.4 g, 23.41 mmol) in CH2Cl2 (300 mL) was added Dess-Martin Periodinane (10.43 g, 24.58 mmol) and the resulting mixture was stirred at room temp for 3 h. Sat. NaHCO3 solution was then added and the mixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50% EtOAc/hexane) to afford tert-butyl 4-methyl-4-(3-oxopropoxy)piperidine-1-carboxylate (1.3 g, 4.79 mmol, 82% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 3.84-3.57 (m, 4H), 3.13-3.02 (m, 2H), 2.66 (td, J=6.0, 1.8 Hz, 2H), 1.74 (d, J=12.8 Hz, 3H), 1.47 (s, 9H), 1.46-1.38 (m, 2H), 1.20 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(c1)CCC(N)C(=O)N2
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: COc1ccc2c(c1)CCC(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N2

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step D by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.86 (m,1H), 2.4-3.0 (m,5H), 3.77 (s,3H), 4.49 (m,1H), 5.25 (br s,1H), 6.68 (d,8 Hz,1H), 6.70 (s,1H), 6.89 (d,8 Hz,1H), 7.55 (br s,1H). FAB-MS: calculated for C21H31N3O5 405; found 428 (M+Na,100%), 406 (M+H,23%).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Product: Fc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Yield: 4.3 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 4-fluorobenzyl bromide (0.12 ml, 0.99 mmol) as exemplified in Example 1. The crude product was triturated with hot methanol to give the title compound as a pale yellow solid mp 142°-144° C. (Found: C, 73.78; H, 5.57; N, 4.36. C20 H18FNS. 0.1H2O requires C, 73.86; H, 5.64; N, 4.30%). δH (CDCl3) 2.64 (2H, m, NH2CH2), 2.72 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 6.19 (1H, m, NCH2CH), 7.02 (2H, t, J 8.6Hz, ArH), 7.12 (1H, s, ArH), 7.30 (4H, m, ArH), 7.67 (1H, d of d, J 6.7Hz, ArH), 7.73 (1H, d of d, J 6.8Hz, ArH). m/z (ES+) 324 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccncc3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 4-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 203-205° C., Rf=0.2 (CH2Cl2/MeOH=15:1) is obtained. 1H-NMR (CDCl3): 1.0 (m, 9H), 3.55 (m, 2H), 5.2 (m, 2H), 5.8 (broad m, 1H), 7.05 (m, 1H), 7.4 (m, 2H), 7.55 (d, 1H), 7.85 (d, 1H), 8.65 (m, 2H).
Reaction SMILES: [Na].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8].[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:7]2[NH:9][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:8]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1cccc(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2cccc(Cl)c2)=N1

Procedure:
To a stirred solution of 56.4 g. of sodium metal in one liter of absolute ethanol there is added 156 g. of m-chlorobenzamidine hydrochloride followed by the dropwise addition of 144 g. of diethyl malonate over a fifteen minutes period. The reaction mixture is heated under reflux for three hours. The solution is filtered and the filter cake dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid separates which is removed by filtration. After washing this material several times with water the product (123 g., m.p. 254°-256°C.) is recrystallized from aqueous N,N-dimethylformamide to yield 2-(3-chlorophenyl)-4,6-(1H,5H)-pyrimidinedione, m.p. 256°-257°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[O:15])[C:10](OCC)=[O:11])=[C:4]([N+:22]([O-])=O)[CH:3]=1.Cl>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[O:15])[C:10](=[O:11])[NH:22]2
Reactant: CCOC(=O)CN(C(=O)C(=O)OCC)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
101.3 g (0.28 mol) of ethyl N-(4-chloro-2-nitrophenyl)-N-(ethoxycarbonylmethyl)oxamate were dissolved in 11 of acetic acid and heated to 80° C. Then 15.8 g (0.28 mol) of iron powder were added a little at a time. After 2 h, a further 15.8 g (0.28 mol) of iron powder were added. Half an hour later, the mixture was poured into ice-water and acidified with 4M hydrochloric acid. The precipitate was filtered off with suction to yield 75.7 g (95%) of the product.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.[CH3:37][NH2:38]>C1COCC1>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:38][CH3:37])=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Reactant: CN
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCNC

Procedure:
3-(4-(5-(2-Cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-N-methylpropan-1-amine (941 mg) is prepared in analogy to Example 29 starting from 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (700 mg, 1.36 mmol) and 2 M methyl amine solution in THF (20 mL); LC-MS: tR=0.96 min, [M+H]+=451.29.