Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:15]1([C:21]2[C:26]([C:27]3[CH:37]=[CH:36][C:30]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:38][C:39]1[C:43]([CH:44]=O)=[C:42]([CH3:46])[N:41]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[N:40]=1.[ClH:53]>C1COCC1>[ClH:53].[CH3:38][C:39]1[C:43]([CH2:44][N:18]2[CH2:19][CH2:20][N:15]([C:21]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:36][CH:37]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)=[C:42]([CH3:46])[N:41]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[N:40]=1
Reactant: Cc1nn(-c2ccccn2)c(C)c1C=O
Reactant: CC(=O)NCc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3c(C)nn(-c4ccccn4)c3C)CC2)cc1
Reaction time: 3 h
Yield: 54 %

Procedure:
Add sodium triacetoxyborohydride (231 mg, 1.04 mmol) to a solution of N-[4-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-benzyl]-acetamide (215 mg, 0.69 mmol) and 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxaldehyde (208 mg, 1.03 mmol) in THF (3.5 mL). Maintain stirring for 3 hr. and quench by adding NaHCO3 (5 mL). Extract with DCM (3×10 mL) and discard the aq. phase filtering through an IST phase separator Frit®. Concentrate to dryness and purify by preparative HPLC then purify by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH to give the free base. Prepare the hydrochloride salt by adding HCl and lyophilise the solution to give the title compound (200 mg, 54%). MS (ES): m/z=497 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:38])[CH:31]2[Si:34](Cl)([CH3:36])[CH3:35])=[C:27]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:26]=1[O:49][CH3:50])([CH3:24])([CH3:23])[CH3:22].O>CCOCC.C([Cu])#N>[C:21]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:38])[CH:31]2[Si:34]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:36])[CH3:35])=[C:27]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:26]=1[O:49][CH3:50])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Agent: N#C[Cu]
Solvent: CCOCC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 7.88 g (30.0 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 200 ml of ether 12.0 ml (30.0 mmol) of 2.5 MnBuLi in hexanes was added in one portion at −40° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 215 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution 13.2 g (30.0 mmol) of [6-tert-butyl-4-(4-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl](chloro)dimethylsilane (prepared as described above) in 150 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water were added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by 2×75 ml of dichloromethane. The combined organic elute was evaporated to dryness, and the residue was dried in vacuum. This procedure gave 20.1 g of the title product (on the evidence of NMR spectroscopy, it has ca. 90% purity and is a ca. 1:1 mixture of the distereomers) as yellowish glass which was further used without an additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:4]([C:3]3[CH:7]=[CH:8][C:9]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])=[N:10][C:2]=3[CH3:1])=[O:6])[CH2:29][CH2:30]2)=[N:23][CH:24]=1)[CH3:18]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1nc(N2CCCC2=O)ccc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3C)CC2)c(C)c1

Procedure:
Using a crude product (0.605 mmol) of 2-methyl-6-(2-oxopyrrolidin-1-yl)nicotinic acid which is an intermediate described in Example 791, and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (124 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Example 93, the title compound (4 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH2:19].[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH:19][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NCc1c[nH]c2ccc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Triethylamine (0.152 mL; 1.08 mmol) was added at 0° C. to a mixture of (5-chloro-1H-indol-3-yl)methanamine (0.150 g; 0.830 mmol) and 4-(chloromethyl)benzoyl chloride (0.170 g; 0.872 mmol) in dichloromethane (12 mL). The mixture was stirred for 15 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 0.262 g (95%) of N-((5-chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([O:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=3[N:8]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3OC3CCCC3)nc2c1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
To a mixture of 0.28 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 0.28 g of potassium carbonate and 2 ml of DMF, a mixture of 0.29 g of cyclopentyl bromide and 2 ml of DMF was added at room temperature. The reaction mixture was stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.29 g of 2-(3-cyclopentyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 115”).
Reaction SMILES: C(O[C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][O:19][C:17]([C:15]1[O:14][C:11]2[CH2:12][NH:13][CH:8]([CH3:6])[CH2:9][C:10]=2[N:16]=1)=[O:18]
Reactant: COC(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc2c(o1)CNC(C)C2
Reaction time: 0.17 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (500 mg) in methylene chloride (15 ml) was added trifluoroacetic acid (15 ml) at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure. To the resulting residue were added methylene chloride (20 ml), triethylamine (495 μl), acetic acid (205 μl), formalin (230 μl) and sodium triacetoxyborohydride (570 mg) at room temperature. After stirring for 15 minutes, methylene chloride (20 ml) and a saturated aqueous solution (50 ml) of sodium bicarbonate were added to the reaction mixture to separate it into layers. The water layer was extracted with methylene chloride (3×20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (chloroform:methanol=20:1→10:1), whereby the title compound (257 mg) was obtained as a colorless transparent oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[N:1]1([CH2:6][C:7]2[C:12]([O:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1cccnc1Cn1ccnc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2cccnc2Cn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A solution of 2-(imidazol-1-ylmethyl)-3-hydroxypyridine (3.0 g.) in dry N,N-dimethylformamide (40 ml.) was treated with sodium hydride (0.90 g., 50% suspension in mineral oil) at 0° C., while under a dry nitrogen atmosphere and the resulting suspension was stirred at 0° C. for a period of 30 minutes. Benzyl bromide (2.90 g.) was then added dropwise to the stirred solution and stirring of same was continued for a further hour at 0° C., followed by stirring at room temperature (~25° C.) for a period of two hours. At this point, water (10 ml.) was added to the mixture and the resulting aqueous solution was evaporated to dryness while under reduced pressure. The residue was taken up in chloroform and the inorganic material which remained was subsequently removed by means of filtration. The filtrate so obtained was then concentrated in vacuo and the residue subsequently chromatographed on silica gel. The resulting column was then eluted first with petroleum ether (b.p. 60°-80° C.) to remove the mineral oil and then with chloroform to remove the product. Evaporation of the chloroform solution then gave an oil, which subsequently crystallized on cooling. The latter material was then recrystallized from ethyl acetate/petroleum ether (b.p. 60°-80° C.) to afford pure 2-(imidazol-1-ylmethyl)-3-benzyloxypyridine (yield, 1.5 g.), m.p. 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:14]=[CH:13][O:12][C:11]=1[C:15](OC)=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:11]2[O:12][CH:13]=[CH:14][C:10]=2[CH3:9])=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: COC(=O)c1occc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Cc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (25.8 mL 236 mmol) and methyl 3-methyl-2-furoate (33.08 g, 236 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (472 mL, 1.0 M in tetrahydrofuran, 472 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resultant solution was stirred at room temperature for 15 hours. The solution was concentrated. Methanol was added to quench the reaction resulting in a yellow solid precipitating. The precipitate was collected by filteration and washed with a small amount of cold methanol. 2-(6-Chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone (52.2 g, 94%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.61 (t, 1H), 7.43 (s, 1H), 7.23 (m, 2H), 6.40 (s, 1H), 4.36 (s, 2H), 2.37 (s, 3H). MS m/z 236 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:24](Br)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[C:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)Br
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Yield: 60.2 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (25 mg, 0.076 mmol) and acetylbromide (0.017 ml, 0.23 mmol) were added into dichloromethane (2.0 ml). Then, at room temperature triethylamine (0.032 ml, 0.23 mmol) was added, stirred for an hour so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using a mixed organic solvent (diethylether/isopropanol/n-hexane=1/1/5, v/v/v). As a result, 16.9 mg of the present compound (productive yield 60%) was obtained as a white solid crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C1(CN(CC2C=CC=CC=2)[C:17]2[C:26]3[N:27]=[C:28]([CH2:30][CH2:31][CH2:32]Cl)[NH:29][C:25]=3[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=2)C=CC=CC=1.[CH3:41][C:42]([CH3:44])=O>>[C:42]1([CH2:44][N:29]([CH2:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[N:18]=[CH:17][C:26]2[N:27]=[C:28]4[CH2:30][CH2:31][CH2:32][N:29]4[C:25]3=2)[CH:32]=[CH:31][CH:30]=[CH:28][CH:41]=1
Reactant: CC(C)=O
Reactant: ClCCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: c1ccc(CN(Cc2ccccc2)c2cccc3c2ncc2nc4n(c23)CCC4)cc1

Procedure:
Potassium carbonate (10X excess) and sodium iodide (5X excess) were added to a solution of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.8 g, 1.8 mmole) in acetone. The reaction was heated at reflux for 2 hours, filtered and then concentrated under vacuum. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-30% ethyl acetate in hexanes v/v) to provide 0.25 g of N,N-bis(phenylmethyl)-9,10-dihydro-8H-pyrrolo[1',2':1,2]imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+].CO>C(Cl)Cl.CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([S:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc(Sc2ccc3[nH]ccc3c2)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Sc4ccccn4)cc23)CC1

Procedure:
5-(Pyrid-2-ylthio)indole (0.347 g, 1.53 mmol), 1-methylpiperid-4-one (0.347 g, 0.38 mL, 3.06 mmol), sodium methoxide (0.497 g) and some finely ground molecular sieves were heated in refluxing MeOH (20 mL) for 24 hr. After work-up and chromatography (silica gel; CH2Cl2 /MeOH; 0-15%), 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole was obtained as a yellow solid (0.35 g). This was treated with fumaric acid (0.189 g, 1.6 mmol) in MeOH/Et2O to give, as a pale yellow crystalline solid: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole fumarate, 0.227 g (34%), m.p. 226°-28° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[C:13]([CH3:35])([CH3:34])[CH2:12]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[C:13]([CH3:35])([CH3:34])[CH2:12]2
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(C)(=O)=O)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a suspension of 60% sodium hydride (294 mg, 7.4 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (713 mg, 7.5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (300 mg, 0.75 mmol) and 1,1′-carbonyldiimidazole (244 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (107 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.0.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Cl.[CH2:22]([N:24]1[CH2:29][CH2:28][P:27]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)(=[O:30])[CH2:26][CH2:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH2:25][CH2:26][P:27]([C:31]2[CH:37]=[CH:36][C:34]([NH:35][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:33][CH:32]=2)(=[O:30])[CH2:28][CH2:29]1)[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CCN1CCP(=O)(c2ccc(N)cc2)CC1
Agent: Cl
Product: CCN1CCP(=O)(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)phenyl]-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 2-Chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (133 mg, 0.434 mmol) and 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)aniline hydrochloride (131.01 mg, 0.47689 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid (31.56 mg, 14%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.54 (d, J=8.3 Hz, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.01 (d, J=8.0 Hz, 2H), 7.80-7.67 (m, 5H), 7.08 (t, J=13.6, 7.0 Hz, 1H), 3.13-2.90 (m, 7H), 2.61 (m, 2H), 2.27-2.02 (m, 4H), 1.13 (t, J=13.6, 6.4 Hz, 3H). MS=510 (MH)+.
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:15]([OH:18])(=[O:17])[CH3:16]>>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([O:18][C:15](=[O:17])[CH3:16])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Reactant: CC(=O)O
Product: CC(=O)OC1Oc2ccc(C#N)cc2C1(C)C
Temperature: 0 °C

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (2 g), prepared as in Example 45, was heated under reflux in glacial acetic acid (20 ml) for 31/4 hours. The solution was then added to ice/water and the product was separated by filtration and dried. The crude yield was 1.8 g. Recrystallisation from ethanol gave 1.6 g of title product, mp 138°-140° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.C(O)(=O)C.N1CCCCC1>C(COC)OC.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)[S:13][C:12]1=[S:17]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: C1CCNCC1
Product: O=C1C(=Cc2cccc(C(F)(F)F)c2)SC(=S)N1N=c1sc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3-[(1,3-benzodithiol-2-ylidene)amino]-2 -thioxo-4-thiazolidinone (see example 37), m-trifluoromethylbenzaldehyde (10 ml, excess) and acetic acid/piperidine (1 ml) in 250 ml of anhydrous glyme is heated at reflux for seven days. The reaction mixture is concentrated in vacuo and the oily residue extracted with hexane. The solid thus obtained is slurried in 1000 ml of dichloromethane and stirred at room temperature overnight. The slurry is filtered and the filtrate concentrated in vacuo. The solid residue thus obtained is recrystallized from dimethylformamide to yield 500 mg of the title compound, melting point 268°-269° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25]1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:23][N:24]1[C:28]([NH:29][C:12]([C:11]2[C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)=[O:14])=[CH:27][CH:26]=[N:25]1
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Reactant: Cn1nccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(OC)ccc(C(=O)Nc3ccnn3C)c2s1
Yield: 30 %

Procedure:
Starting from 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.2 g), oxalyl chloride (0.15 ml), dichloromethane (20 ml) and dimethylformamide (1 drop), followed by 2-methyl-2H-pyrazol-3-ylamine (0.17 g), triethylamine (0.24 ml) and dichloromethane (40 ml). Purification by flash chromatography (eluent 10% methanol/dichloromethane) yielded the title compound as a yellow solid (0.08 g). TLC Rf 0.52 (10% methanol in dichloromethane), Mpt 185-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:65]([NH:72][CH2:73][CH2:74][CH2:75][NH2:76])([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].Cl>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:76][CH2:75][CH2:74][CH2:73][NH:72][C:65](=[O:66])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:29])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.69 mmol), HATU (288 mg, 0.76 mmol) and N,N-diisopropylethylamine (196 mg, 1.52 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (180 mg, 1.03 mmol). The mixture was stirred for another 30 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=6. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as brown solid. Yield: 380 mg, 93%.