Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].N1C=CC=CC=1.[C:21](Cl)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[C:21]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 75.1 %

Procedure:
39.6 g (0.2mol) of 3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>CCOC(C)=O>[OH:9][C:10]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Pyridine hydrochloride (100 g; 0.87 mol) and 2-methoxy-4-nitro-benzonitrile (17 g; ca 96 mmol) was heated to 200° C. for 2 hours, cooled to room temperature and carefully added H2O and EtOAc. The slurry was stirred until all solid dissolved. The organic layer was isolated, washed twice with H2O, brine then dried, filtered and evaporated to dryness to yield 15 g (95%) pure product
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[CH:16]([C@:17]3([CH3:38])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:35]([CH2:34][CH2:33][C:20]1[C:21]([CH3:32])([CH3:31])[C@H:22]2[C@:17]([CH3:38])([CH2:18][CH:19]=1)[CH:16]1[C@:25]([CH3:30])([C@@:26]3([CH3:29])[C@H:13]([CH2:14][CH2:15]1)[C@H:12]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:11]1([C:9]([OH:10])=[O:8])[CH2:28][CH2:27]3)[CH2:24][CH2:23]2)([OH:37])=[O:36]
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(CCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.4 %

Procedure:
A mixture of (E)-3-((1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-3a-(benzyloxycarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)acrylic acid (20 mg, 0.033 mmol) and 10% Pd/C (25 mg, 0.023 mmol) in MeOH (0.5 mL) and ethyl acetate (1 mL) was connected to a balloon of hydrogen and stirred at room temperature for 5 hours. The reaction mixture was filtered to remove Pd/C and the filtrates were concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep HPLC to provide the desired product (1.59 mg, 9%). LCMS: m/e 509.6 (M−H)−, 2.36 min (method 6). 1H NMR (400 MHz, <DMSOmix>) δ 5.21 (d, J=5.0 Hz, 1H), 4.70 (br. s., 1H), 4.57 (br. s., 1H), 3.05-0.98 (m, 27H), 1.67 (s., 3H), 0.96 (s., 6H), 0.93 (s., 3H), 0.89 (s., 3H), 0.79 (s., 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: COc1ccc(CNC2CC2)cc1OC
Product: COc1ccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][C:13]([CH:15]=O)=O.O>C(O)C>[CH3:15][C:13]1[CH:12]=[N:10][C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[N:11]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CC(=O)C=O
Solvent: O
Solvent: CCO
Product: Cc1cnc2cccc([N+](=O)[O-])c2n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (5.02 g) in ethanol (500 mL) was added at 60° C. a 40% aqueous solution of pyruvic aldehyde (17.72 g). The reaction solution was refluxed for 10 minutes, and thereto was added water (300 mL). The mixture was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to give 2-methyl-8-nitroquinoxaline (4.17 g, 67%) as orange crystals.
Reaction SMILES: [N:1]#[N:2].S(S(O)=O)(O)=O.C([O:13][C:14](=[O:52])[CH2:15][N:16]([C:24](=[O:51])[C@H:25]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])[NH:26][S:27]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][C:34]([O:42][CH3:43])=[C:35]([O:40][CH3:41])[CH:36]=2)[CH:31]=1)(=[O:29])=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[CH3:41][O:40][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][C:34]=1[O:42][CH3:43])[CH:31]=[C:30]([S:27]([NH:26][C@H:25]([C:24]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][C:14]([OH:52])=[O:13])=[O:51])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])(=[O:29])=[O:28])[CH:39]=[CH:38]2
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OC(C)(C)C)Cc3ccccc3)cc2cc1OC
Agent: Cl
Agent: N#N
Agent: O=S(O)S(=O)O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)Cc3ccccc3)cc2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 2.00 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylglycine tert-butyl ester hydrosulfite in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.20 g (70 percent) of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylglycine as an amorphous solid, I.R. (KBr): 3,370, 3,200, 1.615 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:13][CH2:14]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 520 mg (1.95 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 14 ml CH2Cl2 was treated at 0° C. with 0.17 ml (2.14 mmol) methanesulfonylchloride, 0.235 ml (2.92 mmol) pyridine and 238 mg (1.95 mmol) DMAP. The reaction mixture was warmed up over night to room temperature, water (2 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 435 mg (65%) of trans-Methanesulfonic acid 3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-prop-2-ynyl ester, MS: 345 (M).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>CS(C)=O>[CH2:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: CCN1CCNCC1
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1

Procedure:
From 21.4 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 22.8 g. of N-ethylpiperazine in 200 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-ethyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 283°-285° (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:40])[NH:32]2>>[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:7]/[C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])/[C:31](=[O:40])[NH:32]2
Reactant: Cc1nc[nH]c1C=O
Reactant: O=C1Cc2c(ccc([N+](=O)[O-])c2F)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,3-dihydro4-fluoro-5-nitro-2H-indol-2-one (1 g, 5 mmol) in MeOH (10 mL) (Starting Material 10), was successively added, at r.t., 4-methyl-5-imidazolecarboxaldehyde (612 mg, 5.5 mmol) (Aldrich) and tetrabutyl ammonium hydroxide (11 mL, 1.0 M solution in MeOH)(Aldrich). The mixture was stirred at r.t. for 4 h. The resulting greenish precipitate was collected by suction filtration, washed with ether and air dried to yield (Z)-1,3-dihydro-4-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one as a green powder. (Yield 1.14 g, 79%).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:8][O:7][C:6]1[C:4]2[O:5][C:19]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:2][C:3]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C=O)c1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cccc2cc(-c3ccncc3)oc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of o-vanillin (6.0 g) and 4-picolylchloride hydrochloride (6.6 g) in DMF (70 ml) was added potassium carbonate (20.0 g) and potassium iodide (2.0 g). The mixture was stirred vigorously for 8 hours at 150° C. The mixture was filtered hot and the filter cake was washed with ethyl acetate. The organic phases were combined and concentrated in vacuo to a volume of about 10 ml, poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo. Flash chromatography (silica gel, eluting with 1:2 heptane:ethyl acetate) afforded 2.5 g of the product, which was crystallized from heptane/ethyl acetate, m.p. 140°-141° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28]C=4)[N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:90]1([NH2:95])[CH2:94][CH2:93][CH2:92][CH2:91]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:90]1([NH:95][C:2]2[C:3]3[N:4]([C:8]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[N:20]=4)=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:94][CH2:93][CH2:92][CH2:91]1
Reactant: COc1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(Nc3ccccc3)n2)c1
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 150 °C
Yield: 31 %

Procedure:
To a solution of 4-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-N-phenylpyrimidin-2-amine (162 mg, 0.39 mmol) in cyclopentylamine (5 mL) was added, successively, racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15.3 mg, 0.02 mmol), cesium carbonate (376 mg, 1.15 mmol) and palladium (II) acetate (3.5 mg, 0.015 mmol). The resulting mixture was heated in a sealed tube at 150° C. for 24 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added. The phases were separated and the organic layer was washed with water and brine. The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (2:1 hexanes-ethyl acetate) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-8-amine (55 mg, 31%) as a white solid. 1H NMR (CDCl3): δ 8.90 (m, 1 H), 8.08 (d, 1 H), 7.37–7.22 (m, 2 H), 6.96 (m, 1 H), 6.79 (t, 1 H), 6.43 (d, 1 H), 6.30 (d, 1 H), 5.40 (d, 1 H), 5.31 (d, 1 H), 4.37 (m, 1 H), 3.94 (m, 1 H), 3.85 (s, 3 H), 2.14–2.07 (m, 4 H), 1.82–1.56 (m, 12 H); MS m/z 469 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=4[F:31])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4c(F)ccc(F)c4F)cc3)c2)CC1

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(2,3,6-trifluorobenzyl)benzenesulfonamide following procedure C and using 3 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cncnc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncncc1-c1ccc(CBr)cc1

Procedure:
A solution of 4-cyano-5-(p-tolyl)pyrimidine (1.2 g, 6 mmol), N-bromosuccinimide (1.15 g, 6 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (50 ml) was refluxed under light radiation for 1 hour. After cooling, insoluble materials were removed and the filtrate was concentrated to dryness. Recrystallization from ether-isopropyl ether afforded colorless powders (1 g, 59%), m.p. 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH:9]=[CH:8]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a cooled (ice water bath) solution of 7-(methyloxy)-1H-indole (3 g, 20.38 mmol) in DMF (100 mL) was added sodium hydride (0.618 g, 24.46 mmol) portionwise. After 15 minutes a solution of benzenesulfonyl chloride (3.94 mL, 30.6 mmol) in 20 ml of DMF was added dropwise. The reaction mixture was stirred at RT for 24 h, at which time it was concentrated. The residue was dissolved in DCM (100 ml) and washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% DCM:Hex; 50 g-HP-silica gel column) to give 3.65 g of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.65 (s, 3H), 6.60-6.75 (m, 2H), 7.08-7.22 (m, 2H), 7.40-7.62 (m, 3H), 7.77-7.92 (m, 3H). MS(ES) [M+H]+ 288.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:10])[NH:8][CH:9]=1)=[O:4].[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].[OH-].[Li+].Cl>CN(C=O)C.O>[CH3:10][C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: COC(=O)c1c[nH]c(C)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)O)cn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid methyl ester (10.4 g, 74.1 mmol) is taken up in 100 mL DMF, sodium hydride (4.15 g, 60% in mineral oil, 104 mmol) is added portion wise and the reaction mixture is stirred at RT until all gas evolution has ceased. (2-Chloromethoxy-ethyl)-trimethyl-silane (14.4 mL, 81.6 mmol) is added and the reaction mixture is stirred at RT for 0.5 h. Water is added and the reaction mixture is extracted with ethylacetate, the combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue (20.0 g) is taken up in 20 mL dioxane and a solution of lithium hydroxide (3.54 g, 148 mmol) in 100 mL water is added slowly. The reaction mixture is stirred overnight at RT. The reaction mixture is cooled to 0° C., acidified to pH 4 by the addition of 6 N hydrochloric acid and extracted with DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. Yield: 7.01 g. HPLC-MS: tR=2.16 min, (M−H)−=257.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1nc(CN2C(=O)N(c3ccccc3C)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)cs1

Procedure:
The title compound, MS: m/e=611.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 4-chloromethyl-2-methylthiazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)=[N:7][C:6]=1[CH3:23])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:23][C:6]1[N:7]=[C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(CCc2conc2-c2ccccn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a suspension of 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (647 mg, 2.0 mmol) in THF (6.5 mL) was added a solution of lithium hydroxide monohydrate (165 mg, 3.9 mmol) in water (6.5 mL) followed by methanol (4 mL) and the resulting mixture stirred at room temperature for 4 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (578 mg, 93%) which was obtained as a light brown solid. MS: m/e=314.1 [M−H]−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([N:15]([CH2:29][CH3:30])[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[CH3:14].C(O)(=O)C>CCCCCC.O1CCCC1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:29]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][N:18]1[C:22]([OH:23])([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:28])[CH3:30]
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)c2ccccc2C1(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 0.11 mole of butyl lithium in 68 ml of hexane and 150 ml of tetrahydrofuran was added a solution of 15.80 g of 3-bromopyridine in 20 ml of tetrahydrofuran at -78° C. After stirring for 30 minutes at -78° C., a solution of 24.63 g of N-(2-diethylaminoethyl)phthalimide in 30 ml of tetrahydrofuran was added to the mixture. After stirring at -78° C. for 1 hour, a solution of 6.61 g of acetic acid in 30 ml of tetrahydrofuran was added, and the mixture was concentrated under reduced pressure. To the residue were added 300 ml of water and 300 ml of ethyl ether, and pH of the mixture was adjusted to 1.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 200 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 10 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjected to silica gel column chromatography (ethyl acetate:triethylamine=20:1). A major fraction was concentrated under reduced pressure to give 16.99 g of 2-(2 -diethylaminoethyl)-3-hydroxy-3-(3-pyridyl)isoindolin-1-one (Compound 21).