Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH3:31][C:27]1[N:26]=[C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1nccc(-c2cccc(N)c2)n1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1nccc(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-(3-aminophenyl)-2-methylpyrimidine (71 mg, 0.386 mmol) similar to Example 58. The mixture was extracted with ethyl acetate (50 ml), washed with water (1×25 ml) and with aqueous 2N HCl (1×25 ml). The acidic aqueous solution was basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water and isolated as a light tan solid (18 mg, 23%). 1H NMR (CDCl3): 9.71 (d, J=2.4 Hz, 1H), 8.77-8.72 (m, 3H), 8.38 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.69-7.54 (m, 4H), 7.45-7.41 (m, 1H), 6.95 (s, 1H), 2.83 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([NH2:5])[CH2:4][CH2:3]1.[Na].[C:7]([NH:9][C:10](N)=[NH:11])#[N:8]>C(O)CCC.O>[C:7]([NH:9][C:10]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[NH:11])#[N:8]
Reactant: N#CNC(=N)N
Reactant: NC1CC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCO
Product: N#CNC(=N)NC1CC1
Yield: 62 %

Procedure:
9.36 g (0.1 mole) of cyclopropylamine hydrochloride and 8.9 g (0.1 mole) of the sodium salt of cyanoguanidine are suspended in 100 ml of n-butanol and 8 ml of water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the filter cake is washed with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml of acetonitrile. The mixture is heated to reflux, filtered hot and the filter cake is washed with acetonitrile. The filtrate is evaporated off and the oil obtained crystallizes slowly. 7.7 g of N-cyano-N'-cyclopropylguanidine are obtained. Yield: 62%. M.P.: 106° C. (isopropyl alcohol/diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc([C@@H]2CCCN2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 136° C., [a]D20=172° (c=0.1 in CHCl3) and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (S)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]([CH3:20])[C:10]=2[CH:21]=1.[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:1][C:2]2[CH:24]=[CH:23][CH:22]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:13]=[C:12]([NH:14][C:15]([CH:17]5[CH2:19][CH2:18]5)=[O:16])[N:11]([CH3:20])[C:10]=4[CH:21]=3)[CH:3]=2)=[O:34])[CH2:28][CH2:29]1)#[N:26]
Reactant: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cc21
Yield: 26.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide (168 mg, 522 μmol) produced in Example C4(vi), 3-(1-cyanocyclopropyl)benzoic acid (303 mg, 1.62 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 1.99 mmol) and N,N-dimethylpyridine-4-amine (39.1 mg, 320 μmol) as starting materials, and in the same manner as in Example C4(vii), the title compound (67.4 mg, 26%) was obtained as colorless crystals.
Reaction SMILES: S(=NC(N)=O)(=O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([Cl:28])[C:24]([NH:26][CH3:27])=[CH:25][C:18]=3[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:31][C:32](=O)[NH:33][S:34]([C:37]1[S:38][C:39]([Cl:42])=[CH:40][CH:41]=1)(=[O:36])=[O:35])C>>[Cl:42][C:39]1[S:38][C:37]([S:34]([NH:33][C:32]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:20](=[O:21])[C:19]4[CH:22]=[C:23]([Cl:28])[C:24]([NH:26][CH3:27])=[CH:25][C:18]=4[O:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:31])(=[O:36])=[O:35])=[CH:41][CH:40]=1
Reactant: CNc1cc2c(cc1Cl)C(=O)N(c1ccc(N)cc1)CO2
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: NC(=O)N=S(=O)=O
Product: CNc1cc2c(cc1Cl)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2

Procedure:
Analogues to the sulfonylurea formation described in Ex. 5, 3-(4-aminophenyl)-6-chloro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (Ex. 47) (44 mg, 0.15 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (59 mg, 0.22 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-chloro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)urea. RP-HPLC: 2.70 min; ES-MS (M+H)+=528.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.4 (s, 2), 6.2 (s, 1), 6.9 (d, 1), 7.1 (d, 2), 7.39 (d, 1), 7.48 (d, 2), 7.7 (s, 1).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)=[O:48])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][C:45]=1[CH:46]([CH3:56])[C:47]([OH:48])([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1)[C:2]([F:4])([F:3])[F:1])[O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M solution of (trifluoromethyl)trimethylsilane in THF (0.23 ml) and a 0.1M solution of tetrabutylammonium fluoride trihydrate in THF (0.42 ml) were added to 4-{3-chloro-4-[1-methyl-2-(2-methyl-pyridin-4-yl)-2-oxo-ethyl]-phenoxy}-benzonitrile (80 mg) in THF (1 ml). The mixture was stirred for 1 h at room temperature and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:1) to give the title compound (60 mg) as a light yellow solid. MS (m/e)=447.1 [M+H+].
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[C:20]([C:23]1[C:28]2[O:29][CH2:30][C:31](=[O:33])[NH:32][C:27]=2[C:26]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].C(O)(=O)C.S(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C.O>[CH2:35]([O:34][C:26]1[C:27]2[NH:32][C:31](=[O:33])[CH2:30][O:29][C:28]=2[C:23]([C:20](=[O:22])[CH2:21][Cl:8])=[CH:24][CH:25]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: O=C1COc2c(C(=O)CCl)ccc(OCc3ccccc3)c2N1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
Benzyltrimethylammonium dichloroiodate (14.17 g) was added to a stirred solution of 8-acetyl-5-(benzyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one (example 11, step d) (5.5 g) in a mixture of dichloromethane (100 mL), acetic acid (33 mL) and water (5.5 mL) and the reaction mixture stirred at 65° C. for 20 h. The reaction was cooled to ambient temperature, treated with aqueous sodium bisulphite (5.78 g in 100 mL) and stirred for a further 30 min. The mixture was diluted with diethyl ether (200 mL) and the resulting solid collected by filtration, washed with water and diethyl ether, and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 5.6 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccsc1
Product: COc1cc2ncn(-c3nc(-c4ccsc4)c(C(=O)O)s3)c2cc1OC
Yield: 77.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and thiophene-3-boronic acid (19.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-thiophen-3-yl-thiazole-5-carboxylic acid (30.1 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.74 (br.s., 1 H); 8.84 (s, 1 H); 8.55 (dd, 1 H); 7.91 (dd, 1 H); 7.86 (s, 1 H); 7.66 (dd, 1 H); 7.40 (s, 1 H); 3.891 (s, 3 H); 3.85 (s, 3 H)═. MS m/z 388 (M+1).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:15]([CH3:16])=[N:14][NH:13][C:10]2=[N:11][CH:12]=1.CN([CH:20]=[O:21])C>C1COCC1>[CH3:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([CH:20]=[O:21])[CH:8]=2)[NH:13][N:14]=1
Reactant: CN(C)C=O
Reactant: Cc1n[nH]c2ncc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1n[nH]c2ncc(C=O)cc12
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
80 ml anhydrous THF were charged into a 250 ml round bottom flask and was chilled to −78° C. t-BuLi (1.70 M in THF, 17.6 ml, 30 mmol) was added to the flask via syringe. After stirring for 5 min, 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2.12 g, 10 mmol) was added dropwise via syringe. After 30 min, DMF (3.65 g, 50 mmol) in 20 ml THF was added dropwise and the mixture was stirred for overnight. The reaction was quenched by saturated aqueous ammonium chloride. After evaporating the excess THF, the reaction mixture was extracted by ethylacetate twice. The combined organic layer was washed with brine once and dried over sodium sulfate. The crude product was chromatographed with 50% ethylacetate in hexane to afford the desired product (0.23 g, y=20.5%).
Reaction SMILES: [Si](=O)=O.[F-:4].[K+].[F:6][C:7]([F:21])([C:11]([F:20])(F)[C:12]([F:18])(F)[C:13]([F:16])([F:15])[F:14])C(O)=O>>[F:4][C:7]([F:6])([F:21])[C:11]([F:20])=[C:12]([F:18])[C:13]([F:14])([F:15])[F:16]
Reactant: [F-]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=[Si]=O
Agent: [K+]
Product: FC(=C(F)C(F)(F)F)C(F)(F)F
Temperature: 265 °C

Procedure:
A 0.3 dm3-capacity tubular reactor made from stainless steel, provided with electric heating, with a thermocouple sheath, with pipes for feeding the starting components and discharging the reaction products, is charged with about 0.23 dm3 of a catalyst which is silicon dioxide promoted with potassium fluoride in an amount of 35 wt. %. The catalyst is heated in a stream of dry nitrogen with a gradual temperature increase from 180 to 350° C. for four hours. Then the temperature is lowered to 240° C., and 40 g of methyl ester of perfluorovaleric acid are fed with the rate of 20 g/hour. The gas mixture outgoing from the reactor is condensed in a trap cooled down to −30° C., and subjected to low-temperature rectification, as a result of which 27.4 g of perfluoro-2-butene are obtained. The yield of the target product is 95.1%.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1)=[O:18].[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:29]([O:33][C:34](=[O:35])[NH:36][C@@H:37]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:38]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:19]1[C:17](=[O:18])[NH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])=[O:39])([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(Nc1c(F)cccc1F)[C@H]1NCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of (S)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate (52 mg, 129 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (33.3 mg, 129 μmol, Eq: 1.00) and HATU (54.1 mg, 142 μmol, Eq: 1.1) in DMF (300 μL) at 0° C. was added DIEA (50.1 mg, 67.7 μL, 388 μmol, Eq: 3). The reaction was stirred at RT for 1 h diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (62 mg) as a white foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:20]Br>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH:11]([Br:20])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: BrBr
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Solvent: CC(=O)O
Product: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone of Step B (2 g, 7.83 mmol) in acetic acid (15 mL) was slowly added a solution of bromine (0.40 mL, 1 equiv) in acetic acid (5 mL). The resulting reaction mixture was stirred at ambient temperature for 1 h, concentrated in vacuo, diluted with diethyl ether (20 mL) and methylene chloride (10 mL). The resulting suspension was stirred at ambient temperature for 16 hours, and then filtered to yield the title compounds as a light beige solid (3.0 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]=[CH:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[OH:13]
Reactant: O=Cc1ccccc1O
Reactant: Nc1c(Br)cccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=Nc1c(Br)cccc1Br
Yield: 109.8 %

Procedure:
A solution of 2,6-dibromoaniline (9 g, 35.9 mmol), salicylaldehyde (2.79 mL, 35.9 mmol) and p-toluenesulfonic acid (20 mg, 0.1 mmol) in toluene (180 mL) was heated to reflux in a Dean-Stark apparatus for 2 h. After adding some triethylamine the reaction mixture was evaporated resulting in crude compound 2-[(2,6-dibromophenyl)iminomethyl]phenol (14 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:6]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1ccc(F)c(Cl)c1)c1ccccc1
Yield: 97.1 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-chloro-4-fluorobenzoyl chloride (3.00 g, 15.5 mmol) was dissolved in dichloromethane (60 mL), and the solution was treated with cumylamine (2.45 mL, 17.1 mmol), triethylamine (3.24 mL, 23.3 mmol) and DMAP (189 mg, 1.05 mmol), followed by purification by slurry using diisopropylether to obtain 3-chloro-4-fluoro-N-(1-methyl-1-phenylethyl)benzamide (4.39 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([S:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][C@H:11]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:22]1[CH2:23][CH2:24][CH:19]([S:16]([N:13]2[CH2:14][CH2:15][C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=3)[C@H:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:12]2)(=[O:17])=[O:18])[CH2:20][CH2:21]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(S(=O)(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(S(=O)(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in step 1 and acetyl chloride, and by the reaction and purification in the same manner as in Example 39, the title compound was obtained as a white powder.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3)cs2)CC1
Yield: 58.9 %

Procedure:
A solution of 2-bromo-4-(3-chlorophenyl)-1,3-thiazole (6.36 g, 23.2 mmol), tert-butyl piperazine-1-carboxylate (6.47 g, 34.7 mmol) and potassium carbonate (3.20 g, 23.2 mmol) in dimethylformamide (80 ml) was stirred at 120° C. for 14 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 5.19 g (59.0%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([C:22]4[NH:30][C:29]5[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=5[CH:23]=4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccc(Cl)cc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
NaH (60% in mineral oil; 0.071 g, 1.763 mmol) was suspended in 1 mL DMF and p-chlorophenol (Aldrich; 0.174 ml, 1.763 mmol) was added. After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added, and the reaction was sealed and heated at 70° C. for 2 h, then at 90° C. for 1 h. The reaction mixture was then treated with TFA (0.136 ml, 1.763 mmol) and 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 20-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo to give 2-(2-(4-chlorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.044 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (1H, br. s), 8.50 (1H, d, J=9.0 Hz), 8.11 (1H, dt, J=7.6, 0.7 Hz), 7.80 (1H, dt, J=7.9, 0.7 Hz), 7.60-7.71 (2H, m), 7.31-7.55 (4H, m), 6.94 (2H, dd, J=2.0, 0.4 Hz), 3.31-3.42 (2H, m), 2.47-2.51 (2H, m). m/z (ESI, +ve) 389.9 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19]Cl)[CH:10]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]=[CH2:19])[CH:10]=1
Reactant: COc1ccc(Br)cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=COc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To 2 L of toluene solution containing 217 g (containing an amount corresponding to 790 mmol) of 4-bromo-2-(2-chloroethoxy)-1-methoxybenzene obtained in Reference example 7-(a) were added 780 ml of 50% aqueous solution of sodium hydroxide and 268 g (789 mmol) of tetrabutylammonium hydrogensulfate under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water, the organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained concentrate was applied to distillation under reduced pressure (79 to 83° C./100 Pa) to obtain 122 g of the title compound as a colorless oil. (Yield: 68%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][C:12]([CH3:20])([CH2:16][C:17](O)=[O:18])[C:13](O)=[O:14]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:17](=[O:18])[CH2:16][C:12]([CH3:20])([CH3:11])[C:13]2=[O:14])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
Sixty-nine grams (0.5 mole) of m-nitroaniline and 76 grams (g.) (0.52 mole) of 2,2-dimethylsuccinic acid were mixed with 200 milliliters (ml.) of xylene and heated to reflux until approximately 20 ml. of water was removed in a modified Dean Stark apparatus. On cooling, the product crystallized from solution. The mixture was diluted with 300 ml. of ether, the solid filtered off, washed with an additional 100 ml. of ether and dried. Yield was 117.5 g. of a product having a melting point (m.p.) of 134°-134.5° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[CH:18]=1)([O-])=O.S.[Na].CO.O>C(Cl)Cl>[N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:18][N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Agent: S
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C

Procedure:
Sulfide reduction. Into a round bottom flask was charged 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (250 mg, 1.04 mmol), Sodium hydrogensulfide (351 mg, 6.24 mmol), methanol (6 ml) and water (2 ml). The reaction mixture was refluxed overnight. TLC indicated that the reaction was complete (5% MeOH in CH2Cl2). The mixture was cooled to room temperature, concentrated to dryness and to the white/yellow salts was added water (1 mL), CH2Cl2 (10 mL) and MeOH (1 mL). The layers were separated and the aqueous layer was back extracted with CH2Cl2 (2×10 ml). The combined organic layers were dried over Na2SO4, and concentrated to dryness to obtain the product as a tan solid (MS, M++H=210.1).