Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]([CH:44]=[CH:45][C:46]=1[OH:47])[C:13]([N:15]([CH:41]([CH3:43])[CH3:42])[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH:24]1[CH2:33][CH2:32][C:31]2[CH:30]=[C:29]([O:34]C(=O)C(C)(C)C)[CH:28]=[CH:27][C:26]=2[CH2:25]1)=O.Cl[CH2:49][C:50]([N:52]([CH3:54])[CH3:53])=O.[Cl-].[Al+3].[H-].[Al+3].[Li+].N>O1CCCC1>[CH3:53][N:52]([CH3:54])[CH2:50][CH2:49][O:47][C:46]1[CH:45]=[CH:44][C:12]([CH2:13][N:15]([CH:41]([CH3:42])[CH3:43])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[CH:24]2[CH2:33][CH2:32][C:31]3[CH:30]=[C:29]([OH:34])[CH:28]=[CH:27][C:26]=3[CH2:25]2)=[CH:11][C:10]=1[F:9]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CN(C)C(=O)CCl
Agent: N
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN(C)C)c(F)c2)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To cesium carbonate (36 mg) and potassium iodide (5.0 mg) were sequentially added a solution of pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) in tetrahydrofuran (0.8 ml) and a solution of 2-chloro-N,N-dimethylacetamide (11 mg) in tetrahydrofuran (0.2 ml), and the solution was stirred for 1.5 hours at 60° C. The reaction solution was let to cool, then lithium aluminum hydride-aluminum chloride (1.0 M solution in tetrahydrofuran) (0.57 ml) was added dropwise thereto followed by stirring for 1 hour at room temperature. Tetrahydrofuran and ammonia solution were sequentially added thereto, the solution was filtered through celite pad and concentrated under a nitrogen stream; purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS, the title compound (9.1 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[C:27](O)(=[O:30])[CH2:28][OH:29]>>[OH:30][CH2:27][C:28]([N:1]1[CH2:2][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:4]1)=[O:29]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: O=C(O)CO
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(C(=O)CO)C3)ccc1OCC2

Procedure:
Following the procedure for 116, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with glycolic acid to give 150 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.87 (d, J=2.09 Hz, 1H); 7.28-7.21 (m, 1H); 7.24-7.19 (m, 1H); 6.87 (s, 1H); 5.68-5.59 (m, 1H); 4.60-4.48 (m, 4H); 4.20 (dd, J=9.89, 6.11 Hz, 1H); 4.16-4.07 (m, 1H); 4.05 (d, J=3.28 Hz, 2H); 4.03-3.96 (m, 1H); 3.18 (t, J=5.91 Hz, 2H); 1.58 (d, J=6.62 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=8.95 min, M+H+=409
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18](N)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[OH2:22]>CC(C)=O>[ClH:21].[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:19])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: NC(=O)COCCN1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)COCCN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
III.1A. 13.9 g (0.05 mol) of 2-(4-benzyl-1-piperazinyl)ethoxyacetamide are dissolved in 15 ml of water in a 100 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 31 ml (0.375 mol) of aqueous 37% hydrochloric acid solution are added. The mixture is heated at 60° C. for 1 hour. The water is removed on a rotary evaporator under reduced pressure at 60° C. The white solid obtained is taken up in 75 ml of acetone and is stirred for 1 hour at room temperature. The mixture is filtered and 19.7 g of 2-(4-benzyl-1-piperazinyl)ethoxyacetic acid dihydrochloride are obtained in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[N:7]=[C:6]2[Cl:16].S(Cl)(Cl)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[Cl:16]
Reactant: COc1cc2[nH]c(=O)nc(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 85 %

Procedure:
4.12 g (20 mmol) of 6,7-dimethoxy-4-chloro-quinazolinone was placed in a 500 mL single-necked round-bottom flask, and then 120 mL of distilled thionyl chloride containing a drop of DMF was slowly added. The mixture was refluxed. After the completion of the reaction monitored by TLC, the excess amount of thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate, and then washed to neutrality with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (Vpetroleum ether:Vethyl acetate=4:1-2:1) to give 6,7-dimethoxy-4-chloro-quinazoline in 85% yield. 1H NMR (DMSO-d6, 400 MHz): 4.01 (s, 6H, 2CH3), 7.38 (s, 1H), 7.45 (s, 1H), 8.88 (s, 1H); ESI-MS (100%): 224 ((M)+, 100).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:39][CH:38]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(Br)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.2 g), 4-bromophenol (0.93 g) and triphenylphosphine (1.4 g) were dissolved in tetrahydrofuran (1.5 mL), a solution of diisopropyl azodicarboxylate (2.8 mL, 1.9 M toluene solution) in tetrahydrofuran (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 40%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[CH3:31][C:29]1[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=[C:24]([C:25](=[O:26])[NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])[CH:28]=1
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: COC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(C)n1
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (110 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (97 mg, 0.36 mmol, Amine-17, single enantiomer) and 2-(methoxycarbonyl)-6-methylisonicotinic acid (70 mg, 0.36 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:36]=[C:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:41]3[CH2:40][CH2:39][NH:38][C:37](=[O:36])[CH2:42]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCNC(=O)C3)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole prepared in Step B (1.0 g, 2 mmol) was dissolved in DCM (10 mL). Et3N (560 uL, 4 mmol) was added, 2-oxo-piperazine (300 mg, 3 mmol) was added, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, saturated aqueous NH4Cl solution was added, and the reaction mixture was extracted with DCM. After drying, the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the title compound (825 mg, Yield 78%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCOC(=O)C1CCCNC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a mixture of ethyl 2-oxopiperidine-3-carboxylate (2.0 g) in DMF (20 mL) was added sodium hydride (60%, 0.47 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. 4-(Bromomethyl)-1,2-difluorobenzene (1.50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.82 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:17]>>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[S:17])[N:11]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC(N)=S
Product: CN(C)c1nc(=S)[nH]c2ccccc12

Procedure:
Prepared as in Example 46 from 2-chloro-N,N-dimethylquinazolin-4-amine (Example 40) and thiourea. 1H NMR (400 MHz, DMSO-d6) δ 3.31 (s, 6H), 7.24-7.19 (m, 1H), 7.40-7.38 (m, 1H), 7.65-7.61 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 12.35 (s, 1H). MS 206 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:33])[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[C:21]=3[CH3:22])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[C:21]([CH3:22])[C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][CH3:11])=[N:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C(#N)C>[CH2:15]([O:14][C:12]([C:6]1[N:7]=[C:8]([NH:10][CH3:11])[S:9][C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)CBr
Reactant: Nc1ccccn1
Solvent: CC#N
Product: CCOC(=O)c1nc(NC)sc1-c1cn2ccccc2n1
Yield: 61 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-methylamino-4-thiazolecarboxylate (2.5 g) and 2-aminopyridine (2.3 g) in acetonitrile (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added water and ethyl acetate and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-methylamino-5-thiazolyl)imidazo[1,2-a]pyridine (1.5 g). mp 197°-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.[CH2:25](Br)[CH:26]=[CH2:27].O>C(O)C>[CH2:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])[CH:26]=[CH2:25]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: C=CCBr
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: C=CCOn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a solution of 0.4 g (1.5 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 40 ml ethanol was added 20 ml 0.5 M phosphate buffer pH 7.4. The mixture was added 0.8 ml (9.3 mmol) allyl bromide, and then stirred at 25° C. for 4 h. Addition of 80 ml water gave 0.33 g (72%) 1-allyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione as a precipitate. M.p. 239° C. decomp. (methanol-water). NMR (DMSO-d6) 7.9 (1H, s), 7.6 (1H, s), 6.1 (1H, m), 5.4 (2H, m), 4.7 (2H, d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH:19]1[CH:25]=[CH:24][NH:23][C:21](=[S:22])[CH:20]=1>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:22][C:21]3[CH:20]=[CH:19][CH:25]=[CH:24][N:23]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: S=c1cccc[nH]1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccn2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-thiopyridine using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.31 (s, 3H) 7.40 (dd, J=7.20, 4.93 Hz, 1H) 7.55 (t, J=7.58 Hz, 2H) 7.73 (s, 1H) 7.77-7.87 (m, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.06 (d, J=8.08 Hz, 1H) 8.58 (d, J=3.79 Hz, 1H); ESI-MS: m/z calc'd for C18H14N4OS 334.09. found 335.2 (M+H)+.
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)C=CC=CC=1.[Li]CCCC.[O:27]=[C:28]1[NH:33]C2C=C(C=O)C=CC=2[S:30][CH2:29]1>C1COCC1>[CH:8]([C:9]1[CH:10]=[CH:11][C:12]2[S:30][CH2:29][C:28](=[O:27])[NH:33][C:13]=2[CH:14]=1)=[CH2:15]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a stirred suspension of triphenylmethylphosphonium bromide (20.0 mmole) in dry THF (40 mL) at RT was added 2.5 M n-BuLi (7.5 mL, 3.0 mmole). After 3 h, 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (1.93 g, 10.0 mmole) was added and the reaction contents were stirred at RT overnight. The reaction solution was filtered and the filtrate concentrated, dissolved in EtOAc and washed with 1 M HCl (20 mL). The organic solution was dried (Na2SO4) and concentrated under vacuum. Purification on silica (EtOAc/hexanes, 1:4) afforded the title compound (1.20 g, 63%) as light yellow solid: LC-MS (ES): m/e 192 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[C:20]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]2[C:26](=O)[N:25]([C:33]3[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=3[CH3:42])[CH2:24][CH2:23][C:22]=2[N:21]=1>>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH3:12])[C:14]=1[C:20]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]2[CH2:26][N:25]([C:33]3[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[CH:36]=[CH:35][C:34]=3[CH3:42])[CH2:24][CH2:23][C:22]=2[N:21]=1
Reactant: COc1cc(-c2c(C)cccc2C)nc2c1C(=O)N(c1cc(C(C)C)ccc1C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.0 M solution of lithium aluminum hydride in THF (405 μL, 0.405 mmol) was added to a vessel containing 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (42 mg, 0.101 mmol). The reaction mixture, which bubbled and turned clear orange, was stirred at room temperature. After 1 h, the reaction mixture was diluted with 1 mL of THF and cooled to 0° C. with an ice bath. 150 μL of a 9:1 THF/H2O mixture was added dropwise, followed by the slow addition of 100 μL of 1 N aqueous NaOH. After stirring for 5 min, the ice bath was removed and 100 μL of H2O and 1 mL of THF were added in sequence. The mixture was stirred for 10 min, then 150 mg of magnesium sulfate were added and the flask was stirred and shaken gently. The mixture was then filtered over Celite® and the filter cake washed with EtOAc. The filtrate was concentrated and the residue purified by FCC (0-20% EtOAc/heptane) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.19 (dd, J=8.4, 6.8 Hz, 1 H) 7.09-7.14 (m, 3 H) 7.03 (d, J=1.5 Hz, 1 H) 6.89 (dd, J=7.7, 1.6 Hz, 1 H) 6.81 (s, 1 H) 4.00-4.03 (m, 2 H) 3.86 (s, 3 H) 3.22 (t, J=5.7 Hz, 2 H) 2.97 (t, J=5.6 Hz, 2 H) 2.86 (spt, J=6.8 Hz, 1 H) 2.25 (s, 3 H) 2.03 (s, 6 H) 1.19 (d, J=7.1 Hz, 6 H); MS (ESI+) m/z 401.3 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].CO.C(Cl)(Cl)Cl.[NH:31]([C:35]1[S:36][CH:37]=[C:38]([CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([NH2:46])[CH2:41]2)[N:39]=1)[C:32]([NH2:34])=[NH:33]>CO>[NH:31]([C:35]1[S:36][CH:37]=[C:38]([CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([NH:46][C:20]3[C:19](=[O:22])[C:18](=[O:23])[C:17]=3[NH:16][CH:12]3[CH2:13][CH2:14][CH2:15][CH:10]([C:8]4[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=4)[CH2:11]3)[CH2:41]2)[N:39]=1)[C:32]([NH2:34])=[NH:33]
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NC4CCCC(c5csc(NC(=N)N)n5)C4)c(=O)c3=O)C2)cs1
Reaction time: 6 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.1 g.) in 15 ml. of methanol/chloroform (50:50 v/v) was added a solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.07 g.) in methanol (3 ml.) and the resulting solution was allowed to stand at room temperature for 6 hours. After heating under reflux for 6 hours, the reaction mixture was concentrated and cooled to give, as a white amorphous solid, 1,2-bis[3-(2-guanidinothiazol-4-yl)cyclohexylamino]cyclobutene-3,4-dione. The carbon-13 magnetic resonance spectrum (δ relative to tetramethylsilane) in d6DMSO included one carbon singlets at 181.9, 175.0 167.0, 156.8, 155.4, 100.3, 52.4 and a series of signals from 52.4 to 24.1 (including resonances attributable to solvent) p.p.m.
Reaction SMILES: [Na+].[CH:2]1([C:8]([O-:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:12]([O:9][C:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10])[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: O=C([O-])C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOC(=O)C1CCCCC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
To cyclohexanecarboxylic acid sodium salt (5.0 g, 33.3 mmol) in THF (80 mL) tetrabutylammonium bromide (1.074 g, 3.33 mmol) and 1-bromopropane (4.545 g, 49.95 mmol) in THF (120 mL) were added. The mixture was stirred 72 h at 50° C., cooled to room temperature and filtered. The precipitate was washed with THF. The filtrate was concentrated and the residue diluted with TBME. The solution was washed with water and the aqueous phases were re-extracted with TBME. The organic phases were combined, dried over sodium sulfate and evaporated to afford 4.2 g (74%) cyclohexanecarboxylic acid n-propyl ester as a liquid, GC purity 99% (area). 1H-NMR (CDCl3, 400 MHz): ppm 0.94 (t, 3H), 1.15-1.36 (m, 3H), 1.38-1.50 (m, 2H), 1.55-1.81 (m, 5H), 1.85-1.92 (m, 2H), 2.23-2.32 (m, 1H), 4.02 (q, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[S:15][C:16]=2[CH2:17][OH:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CS(Cl)(=O)=O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[S:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: OCc1sc2ccccc2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Methanesulfonyl chloride (127 μL, 1.63 mmol) was added dropwise to a solution of (3-phenylbenzo[b]thiophen-2-yl)methanol (356 mg, 1.48 mmol) and DIPEA (322 μL, 1.85 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2.5 h stirring at RT, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzo[b]thiophen-2-yl)methyl methanesulfonate as a yellow oil (408 mg, 87%). 1H NMR (DMSO, 400 MHz): δ 8.07-8.02 (1H, m), 7.62-7.56 (2H, m), 7.55-7.37 (6H, m), 4.96 (2H, s), 3.33 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: O=C(Cl)c1ccccn1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccccn3)CC2)C1

Procedure:
Compound 762 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and pyridine-2-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-20%-30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0476 g, 39% yield). HRMS (M+H) calcd for C25H28N4Cl2O5: 532.15184. found: 532.1514.