Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)cc4F)c32)[nH]1
Yield: 60 %

Procedure:
4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[CH:38]=[CH:37][C:31]2[C:32](=[O:36])[O:33][C:34](=O)[C:30]=2[CH:29]=1>>[CH3:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][CH:38]=1)[C:32](=[O:36])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:34]2=[O:33]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c1)C2=O

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-methyl-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:31]2OCC[O:32]2)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].II>CC(C)=O>[C:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:31]=[O:32])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCNC(=O)OC(C)(C)C)c1OC
Agent: II
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OCCOCCOCCOCCNC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.00 g (3.99 mmol) N-Boc-2-(3-{2-[2-(2-{2-aminoethoxy}ethoxy)ethoxy]ethoxy}-4,5-dimethoxyphenyl)-1,3-dioxolane 13 in 50 ml of acetone was treated with iodine (100 mg, 10% n/n) and stirred at room temperature for 60 minutes. Acetone was removed and replaced by ethyl acetate. The organic phase was washed with diluted sodium thiosulfate solution, water and brine and dried over magnesium sulfate. After removal of the solvent 1.17 g (3.74 mmol, 94%) of a slightly yellow oil remains. 1H-NMR (CDCl3) δ=9.85 (s, 1H), 7.16 (d, 1H, J=1.8 Hz), 7.13 (d, 1H, J=1.8 Hz), 5.00 (br, 1H), 4.25 (m, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.89 (m, 2H), 3.74 (m, 2H), 3.70-3.59 (m, 6H), 3.53 (t, 2H, J=5.0 Hz), 3.30 (t, 2H, J=5.0 Hz), 1.44 (s, 9H) ppm. 13C-NMR δ=144.3, 131.6, 109.1, 106.6, 79.1, 70.8, 70.6, 70.5, 70.2, 70.1, 69.6, 69.0, 60.9, 56.2, 40.5, 28.3 ppm. MS: m/z=480 [M+Na]+, 358 [M-(COOtBuH2)]+. HRMS: Calcd. for C22H35NO9Na+480.2204, found 480.2203.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(NCCN2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-N-(2-morpholinoethyl)-4-nitroaniline (3.50 g, 12.25 mmol) in EtOAc (60 mL) was added catalyst Pd/C (0.73 g). The reaction was stirred at rt under H2 overnight, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])(O)=[O:18].[Na+].[Na+].P([O-])([O-])(O)=O.[K+].[K+].O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: O=P([O-])([O-])O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1C=O
Temperature: 80 °C
Yield: 35.9 %

Procedure:
A mixture of (E)-methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (10.0 g, 90% pure), sodium hydrogen orthophosphate dibasic (Na2HPO4, 5.74 g) and potassium hydrogen monophosphate monobasic (KH2PO4.0.55 g) in DMSO (20 ml) was heated at 80° C. for 1 hour and then at 110° C. for a further hour (compare J H Babler, M J Coghlan, M Feng and P Fries, J.Org.Chem., 1979, 44, 1716). After cooling, the reaction mixture was poured into water and extracted with ether. The extracts were washed with brine, dried, concentrated and chromatographed using ether as eluant to give (E)-methyl 2-(2-formylphenyl)-3-methoxypropenoate (2.77 g, 40% yield) as a white crystalline solid, m.p. 67°-69° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:38](=[O:39])[CH:37]=[C:12]2[N:13]([CH:34]3[CH2:36][CH2:35]3)[C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)[C:17]([F:33])=[CH:16][C:15]=3[N:11]2[C:10]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([O:8][N:9]1[C:38](=[O:39])[CH:37]=[C:12]2[N:13]([CH:34]3[CH2:35][CH2:36]3)[C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:17]([F:33])=[CH:16][C:15]=3[N:11]2[C:10]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc2n(C3CC3)c3cc(N4CCNCC4)c(F)cc3n2c(=O)n1OCc1ccccc1
Yield: 88.4 %

Procedure:
tert-Butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate (580 mg, 1.05 mmol) is treated with 33 percent hydrobromic acid in glacial acetic acid (5 ml). After 18 hours at room temperature the separated crystals are filtered off, washed with glacial acetic acid and recrystallized from methanol. The crystals are then dissolved in a water/ethanol mixture (2:1, 50 ml). The pH is adjusted to 8 using 1N sodium hydroxide solution, whereby white crystals separate. The crystals are filtered off, washed with water and dried in a high vacuum. There are obtained 417 mg (88%) of 2-(benzyloxy)-5-cyclopropyl-8-fluoro-7-(1-piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.
Reaction SMILES: I[C:2]1[C:3]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:19][C:20]1[N:25]=[C:24]([S:26][CH3:27])[N:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:2]([C:22]2[N:21]=[C:20]([CH3:19])[N:25]=[C:24]([S:26][CH3:27])[N:23]=2)=[CH:7][N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Reactant: COc1ccc(Nc2nc(OC)ncc2I)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(OC)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 69.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-iodo-2-methoxy-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (120 mg, 0.335 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (144 mg, 0.335 mmol), copper(I) iodide (13 mg, 0.067 mmol), cesium fluoride (102 mg, 0.670 mmol), tetrakis(triphenylphosphine)palladium(0) (38.7 mg, 0.034 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give 2-methoxy-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (86 mg, 0.232 mmol, 69.1% yield). 1H NMR (300 MHz, CDCl3) δ 11.78 (s, 1H); 9.53 (s, 1H); 8.39 (s, 1H); 8.06 (dd, J=8.77, 1.90 Hz, 1H); 6.80 (d, J=8.92 Hz, 1H); 4.01 (s, 3H); 3.96 (s, 3H); 2.63 (s, 6H). m/z (ESI, +ve ion) 372.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[CH3:12][S-:13].[Na+]>C(#N)C>[CH3:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:13][CH3:12])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(Cl)ncnc2o1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2oc(C)cc12
Yield: 90 %

Procedure:
A solution of 6-methyl-4-chlorofuro[2,3-d]pyrimidine (U.S. Pat. No. 3,577,420, example IG) (219 mg) in acetonitrile (25 mL) was heated under reflux with sodium thiomethoxide (190 mg) for 16 hours. The mixture was filtered and the solids washed with acetonitrile. Evaporation of the solvent afforded the title compound as a white solid (230 mg, 90%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:33])=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 98.9 %

Procedure:
To a suspension of 6-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.26 g, 3 mmol) in toluene (20 ml) was added thionyl chloride (0.44 ml, 6 mmol). The resulting mixture was refluxed for 2 h. The reaction mixture was added to a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.30 g, 100%) as an oil.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (550 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (463 mg) and tripotassium phosphate (1080 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1.000 mL) stirred under nitrogen was added Pd(Ph3P)4 (196 mg). The reaction was sealed and heated under microwave at 120° C. for 15 min. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2*8 mL), dried over sodium sulphate, concentrated and purified by column chromatography to afford 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D46) (420 mg) as a solid. MS (ES): C21H19N3O2S requires 377. found 378.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([NH2:15])[CH:5]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([N:15]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])[CH:5]=1
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)c1cc(N)c(Cl)c(S(N)(=O)=O)c1
Solvent: CO
Product: COC(=O)c1cc(N2C(=O)CCC2=O)c(Cl)c(S(N)(=O)=O)c1
Reaction time: 6 h

Procedure:
25.4 g of 4-chloro-3-amino-5-sulphamyl-benzoic acid methyl ester, m.p. 195°-196° C., are thoroughly mixed with 25 g of succinic acid anhydride and melted for 6 hours at 180° C. The melt is allowed to cool slowly and CH3OH is added carefully. The product crystallizes. A small amount of water added completes the crystallisation.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[N-:14]=[N+]=[N-].[Na+].O.[BH4-].[Na+]>CN(C=O)C.CO>[NH2:14][C:7]1[CH:6]=[C:5]([Cl:9])[N:4]=[C:3]([C:10]([OH:12])=[O:11])[C:2]=1[Br:1]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Cl)nc(C(=O)O)c1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of methyl 3-bromo-4,6-dichloropyridine-2-carboxylate (0.9 g, 3.2 mmol) in aqueous DMF was added NaN3 (0.25 g, 3.8 mmol). The resulting mixture was heated at 60° C. for 1 hr, added to H2O and extracted (3×) with Et2O. Organic layer was concentrated to yield a white solid, which was dissolved in 10 mL of MeOH. Excess NaBH4 was added and the reaction mixture stirred at room temperature for 0.5 hr. This material was added to H2O, extracted (3×) with Et2O, dried over MgSO4 and concentrated. The resulting solid was stirred in 1N NaOH for 1 hr, made acidic with conc. HCl and concentrated to dryness. This material was extracted with MeOH, concentrated to give 220 mg of 4-amino-3-bromo-6-chloropyridine-2-carboxylic acid; mp 175° C. dec.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:14].[CH2:15]([S:19][CH2:20][CH2:21][OH:22])[CH2:16][CH2:17][CH3:18].[OH-].[K+]>CS(C)=O>[CH2:15]([S:19][CH2:20][CH2:21][O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCCCN1CCCCCBr
Reactant: CCCCSCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCSCCOCCCCCN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
5.24 g of 1-(5-bromopentyl) azacycloheptane-2-one, 1.34 g of 2-(n-butylthio) ethanol, 2.24 g of powderly potassium hydroxide and 30 ml of dimethylsulfoxide were mixed together, agitated at room temperature for 10 hours, extracted with dichloromethane to obtain an extract. The thus obtained extract was washed with water, dried, freed from the solvent by distillation off at reduced pressure and then finally distilled to obtain 2.84 g of colorless 1-[5-(2-butylthioethyl) oxypentyl] azacycloheptane-2-one having the following appearance, column temperature and analysis:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19]O)[CH2:16][O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19][O:11][C:10]2[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:16][O:15]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (2.89 g, 17.9 mmol) in THF (80 mL), (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (2.84 g, 21.5 mmol) followed by triphenylphosphine (5.81 g, 21.5 mmol) is added. The mixture is cooled with an ice-bath before DEAD (9.36 g, 21.5 mmol) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 85:15 to give (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g) as a pale yellow oil; LC-MS**: tR=0.75 min, [M+1]+=not detected; 1H NMR (CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 2.65-2.77 (m, 2H), 3.80-3.90 (m, 2H), 3.94-4.00 (m, 1H), 4.21 (t, J=7.3 Hz, 1H), 4.52 (quint, J=5.8 Hz, 1H), 7.35 (s, 1H), 7.38 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=1[O:39][CH3:40])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=3[O:39][CH3:40])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(4-amino-5-chloro-2-methoxyphenyl)-l-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-amino-5-chloro-2-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [N+:1]([CH:4]([CH3:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].CO>C(OCC)C.CN(C)C1C=CN=CC=1>[C:14]([O:6][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]([N+:1]([O-:3])=[O:2])[CH3:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(O)c1ccccc1)[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: CC(=O)OC(c1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-nitro-1-phenylpropan-1-ol (32 g) and acetic anhydride (22 mL) in diethyl ether (300 mL) was added 4-dimethylaminopyridine (0.61 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Methanol was added to the reaction mixture, and the mixture was further stirred for 30 min and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 34 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1NC(c1cccc(N3CCN(C)CC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 12.7 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.5 g, 4 mmol), 1-methyl-piperazine (1.8 mL, 16 mmol), copper(I) iodide (0.46 g, 2.4 mmol), N,N-dimethylglycine hydrochloride (0.45 g, 3.2 mmol), and potassium carbonate (1.66 g, 12 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL×2), washed with saturated aqueous ammonium chloride solution (20 mL×3) and brine (20 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.2 g, 13%) as a white solid: MS (ESI) M+1=394.2.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.128 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.079 g, 10%). MS (ISP) 514.3 [(M+H)+]; mp 198° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[N:11]1.O.S(=O)(=O)(O)O>O1CCCC1>[O:1]=[CH:2][CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[N:11]1
Reactant: O=C(c1cnn(OCCCC2OCCO2)c1)N1CCCCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCOn1cc(C(=O)N2CCCCC2)cn1
Yield: 96.2 %

Procedure:
40 g of 1-[3-(2-dioxolanyl)-propoxy]-4-(N-piperidinylcarbonyl)-pyrazole in a mixture of 150 ml of tetrahydrofuran, 200 ml of water and 4 ml of concentrated sulfuric acid are refluxed for 8 hours. The mixture is cooled and then saturated with sodium chloride, the phases are separated and the aqueous phase is extracted again with tetrahydrofuran. The combined organic phases are evaporated down, the residue is taken up with methylene chloride, the solution is washed with water and the solvent is evaporated off to give 33 g of the title compound in the form of a viscous oil.