Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][NH:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.[CH3:27][C:28]([O:31][C:32](=[O:47])[C@H:33]([CH2:45][NH2:46])[NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])([CH3:30])[CH3:29].[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:28]([O:31][C:32](=[O:47])[C@H:33]([CH2:45][NH:46][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][NH:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1)[NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CCCc1c(Cl)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 60.8 %

Procedure:
A mixture of 600 mg (1.62 mmoles) of 4-chloro-5-propyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 590 mg (2 mmoles) of (1,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 380 mg (2.51 mmoles) of caesium fluoride, 76 mg (0.083 mmole) of tris(dibenzylideneacetone)dipalladium(0), 102 mg (0.163 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane are heated under reflux for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of methylene chloride-diisopropyl ether-ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0 then 0-0-100-0 and finally 0-0-90-10. 620 mg (Yield=61%) of expected product is obtained in the form of an amorphous yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1.[OH:21]O.O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1)=[O:21]
Reactant: OO
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a slurry of 10.0 g (0.0350 moles) of 2-(4-(methylthio)phenoxy)-5-nitrobenzonitrile in 100 ml of glacial acetic acid was added a solution of 4.0 g of aqueous 30 percent (30%) hydrogen peroxide (0.0350 moles) dissolved in 20 ml of glacial acetic acid over 5 minutes. The reaction mixture was stirred at room temperature for 16 hrs and heated at 50° C. for 3 hrs. The reaction mixture was poured into water and the product collected by filtration, washed well with water and dried to obtain 9.8 g of product (92.8% yield). Recrystallization from ethanol afforded purified 2-(4-(methylsulfinyl)phenoxy)-5-nitrobenzonitrile, mp 159°-160° C.
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])([CH3:21])C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)CCC[CH2:27]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:27][CH2:26][CH2:21]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OC1CCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2

Procedure:
3.5 g (7.7 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 10 g (116 mmol) of cyclopentanol and 0.8 g (3 mmol) of tetraethyl orthotitanate are stirred at 125° overnight, the solution obtained is evaporated and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered over siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By a rapid filtration through about 200 g of silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate there is obtained cyclopentyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 184°-185°.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][C@@H:26]([CH2:31][OH:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:31][OH:32])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
220 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 134.53 mg D-leucinol and 197.52 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered, washed and dried. The diastereomers are separated by preparative HPLC (method B). 43.9 mg of Diastereomer 1 (Example 53) and 46.9 mg of Diastereomer 2 (Example 69) are obtained as an oil. Analytical HPLC-MS (method B): Diastereomer 1, RT=1.86 min, Diastereomer 2, RT=1.90 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[C-:16]#[N:17].[Na+]>CN(C=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16]#[N:17])=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: Oc1ccc(NCCCCCCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCCNc1ccc(O)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 58.6 g (0.19 mol) of 4-[(6-bromohexyl)amino]phenol from part b in about 400 mL of DMF was added dropwise to a slurry of 46.6 g (0.95 mol) of sodium cyanide in 370 mL of DMF in a 2 L flask at 70° C. over the course of two hours. Heating was continued for two hours. After cooling, the reaction was filtered and diluted with about 2 L of water and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed three times with saturated sodium chloride solution, and dried over magnesium sulfate. The solution was stripped to a red-orange solid which was dissolved in warm ethyl acetate, treated with decolorizing carbon, cooled, and recrystallized by the addition of a small amount of hexane to yield 7-[(4-hydroxyphenyl)amino]heptanenitrile, mp 75°-76° C., in 53% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11](Br)=[C:10](Br)[S:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(Br)c(Br)sc2c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2ccsc2c1
Reaction time: 3 h
Yield: 107.8 %

Procedure:
6-Acetyl-2,3-dibromobenzo[b]thiophene (6.68 g, 20 mmole) was dissolved in a mixture of ethanol and ethyl acetate (100 ml each) and MgO (1.6 g) and (20% Pd(OH2)/C (800 mg) were added under a N2 atmosphere. Hydrogenolysis was carried out at 40 psi of H2 at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (100 ml) and H2O (50 ml). The CHCl3 layer was washed with H2O (50 ml). The aqueous layers were combined and back-extracted with CHCl3 (30 ml). The CHCl3 solutions were combined, dried over Na2SO4 and the solvent evaporated in vacuo to yield 3.8 g of product which was used in the next step without further purification.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH2:21]([C:25]1[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]#[N:34])=[N:29][CH:30]=1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:32]=[C:33]([NH2:34])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[N:29][CH:30]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ccc(/C=C/C#N)nc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: CCCCc1ccc(-c2cc(N)n3nc(-c4ccco4)nc3c2)nc1

Procedure:
The title compound, MS m/e (%): 334 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(5-butyl-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A solution of (R)-piperidine-3-carboxylic acid (XXVII) (5.0 g, 39 mmol) in a mixture of 50 ml of THF and 20 ml of water was cooled to 0° C. and sodium bicarbonate (6.5 g, 77.4 mmol) and benzyl chloroformate (8.0 g, 46.4 mmol) were added simultaneously. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 hours and concentrated under reduced pressure. The remaining aqueous phase was extracted with ethyl ether to remove excess of benzyl chloroformate, then it was acidified with 1 M HCl solution to pH 6 followed by extraction with ethyl acetate. The organic layer was separated, dried over sodium sulfate and evaporated to provide (R)-piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXVIII) (3.7 g, 36%).
Reaction SMILES: [N:1]([CH:4]1[CH:9]([OH:10])[C:8]([CH3:12])([CH3:11])[O:7][C:6]2[CH:13]=[CH:14][S:15][C:5]1=2)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:1][CH:4]1[CH:9]([OH:10])[C:8]([CH3:11])([CH3:12])[O:7][C:6]2[CH:13]=[CH:14][S:15][C:5]1=2
Reactant: CC1(C)Oc2ccsc2C(N=[N+]=[N-])C1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)Oc2ccsc2C(N)C1O
Yield: 92.7 %

Procedure:
7-Azido-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (2.0 g, 8.88 mmol) Was added carefully in small portions to a mixture of lithium aluminum hydride (0.67 g, 17.8 mmol) in diethyl ether (40ml). The resultant mixture was stirred an additional 1 h at rt and quenched with successive dropwise addition of water (0.7 ml), 15% aqueous sodium hydroxide (0.7 ml) and water (2.0 ml). The aluminum salts were removed by filtration and the ether solution was dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product 1.64 g (93%) as a beige solid; mp 111°-116° C.; IR(KBr):3110, 2971, 1565 and 1403 cm-1 ; MS:m/z 200 (MH+); 1H NMR (CDCl3):δ 1.24(s,3H), 1.48(s,3H), 1.85(bs,3H, exchanges with D2O), 3.38 (d,J=8.6 Hz,1H), 3.70 (d,J=8.6 Hz,1H), 6.55 (d,J=5.4 Hz,1H) and 7.07(d,J=5.4 Hz,1H).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2[C:38]([O:39]C)=CC=CC=2N=1>>[CH3:38][O:39][C:3]1[C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=[CH:28][CH:2]=1
Reactant: COc1cccc2nc(Cl)sc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: COc1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-7-methoxy-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.80 (d, J=2.0 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.13 (d, J=7.6 Hz, 1H), 4.66 (m, 1H), 4.06 (s, 3H), 3.59-3.62 (m, 2H), 2.33-2.39 (m, 4H). MS(ES+): m/z=407.13 [MH+]. HPLC: tR=1.78 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl-].[Na]>CCCCCC.O1CCCC1.O.CO.ClC1C=CC=CC=1>[C:2]([C:1](=[NH:6])[C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C#N
Agent: [Cl-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CC(C)(C)C(=N)C(C)(C)C
Reaction time: 1 h

Procedure:
This was prepared by the method of J. Chem. Soc., Perkin I, 2087 (1976); ibid, 1797 (1974). Pivalonitrile (33.2 g.) and t-butyl, chloride (44.4 g.) were added under nitrogen to a well stirred suspension of sodium sand (18.4 g.) in a mixture of hexane (80 ml.), tetrahydrofuran (20 ml.) and methanol (1 ml.) over one hour at 15°-20° C. The mixture was stirred three hours, a solution of chlorobenzene (2 g.) in tetrahydrofuran (5 ml.) added dropwise over 10 minutes and stirring continued for one hour. Methanol (20 ml.) was added with caution over 0.5 hr. followed by water until phases separated. The aqueous phase was extracted with ether and the combined organic phases dried and evaporated in vacuo. The residue was distilled to afford di-t-butylketone imine, b.p. 62°-63° C./19 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)[CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:23])[C:11](=[O:24])[C:10]([CH3:26])([CH3:25])[N:9]=1.[H][H]>N.[Ni]>[NH2:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:23])[C:11](=[O:24])[C:10]([CH3:25])([CH3:26])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)[CH3:20]
Reactant: [H][H]
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Agent: [Ni]
Agent: N
Product: CC(N)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C

Procedure:
2.5 g of Raney-nickel paste are added to a solution of 2.22 g (6.28 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 100 ml of 2 N methanolic ammonia and the mixture is stirred at room temperature for 24 hours in a hydrogen atmosphere. The catalyst is filtered off and the solvent is concentrated in vacuo. After filtration over 50 g of silica gel using chloroform as the elution agent, the residue gives 7-(1-aminoethyl)-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one as a foam of melting point 50°-51°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 4-methylbenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 534.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[CH3:26][C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1>CC(O)C>[C:1]([C:3]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=3[CH:6]=2)[C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[NH:32][C:23]=1[CH3:24])#[N:2]
Reactant: Cc1cc(N)on1
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)c2c(C)noc2N1

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A), 59 mg (0.604 mmol) 3-methyl-1,2-oxazol-5-amine and a trace amount of powdered 4 Å molecular sieve in 2-propanol (2 ml) was stirred at 90° C. for 12 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 100% methanol) to yield 64 mg (26% of th.) of the racemic title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].[NH2:20][OH:21].[OH-].[K+].CO>C1COCC1>[OH:21][NH:20][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)C=CC=CCS(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)CC=CC=CC(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 6-(4-methoxybenzenesulfinyl)-hexa-2,4-dienoic acid methyl ester (0.32 g, 1.14 mmol) in distilled THF (6 mL) containing an aqueous solution of hydroxylamine (50%, 0.7 ml, 10.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 1.8 ml, 1.8 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 hour, distilled water (6 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×20 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.11 g, 34%) as a pale brown powder, mp 145-147° C. (decomp).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>>[C:12]([N:15]1[CH2:16][CH2:17][CH:18]([C:21](=[O:22])[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:19][CH2:20]1)(=[O:14])[CH3:13]
Reactant: Brc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred and warm (40° C.) mixture of 600 parts of bromobenzene and 223 parts of aluminum chloride were added portionwise 168.8 parts of 1-acetyl-4-piperidinecarbonyl chloride. Upon completion, stirring was continued for 1 hour at 50° C. and overnight at room temperature. The reaction mixture was poured onto a mixture of 1500 parts of crushed ice and hydrogen chloride. The whole was stirred thoroughly. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dissolved in a mixture of 2250 parts of trichloromethane and 200 parts of water. The layers were separated. The organic layer was dried, filtered and evaporated. The solid residue was suspended in 280 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 94 parts (34%) of 1-acetyl-4-(4-bromobenzoyl)piperidine; mp. 120° C. (intermediate 15).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[C:14]([F:23])=[C:15]([OH:22])[C:16]([OH:21])=[C:17]([O:19][CH3:20])[CH:18]=1.Cl>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[O:21][CH2:2][CH2:3][CH2:4][O:22][C:15]=2[C:14]=1[F:23]
Reactant: BrCCCBr
Reactant: COc1cc(Br)c(F)c(O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(F)c2c1OCCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
After adding 830 mg of 1,3-dibromopropane and 1.4 g of potassium carbonate to a solution of 880 mg of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diol (Example (41a)) in 10 ml of DMF, the mixture was stirred at 80° C. for 6 hours. After adding 1N hydrochloric acid to the reaction mixture, the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (548 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-])=O)[CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 45.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-methyl-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 265) (1.3 g, 3.79 mmol), SnCl2 (2.87 g, 15.1 mmol), 6N HCl (2 drops) and EtOH (10 ml) at 85° C. for 6 h gave the title compound (540 mg, 45%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: O=C(Cl)c1ccco1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccco2)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
6.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 200 ml. of methylene chloride and 10 ml. of triethylamine. The mixture, cooled to about 0° C., is treated while stirring with 3 ml. of furan-2-carboxylic acid chloride in 50 ml. of methylene chloride. After stirring for 1 hour, the mixture is diluted with 100 ml. of water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}-2-furamide having a melting point of 159°-162° C.