Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.NC1C=CC=CN=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Nc1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (example 1, 100 mg, 0.26 mmol), aminopyridine (34.0 mg, 0.28 mmol), and methanesulfonyl chloride (31.9 mg, 0.28 mmol) were dissolved in THF (5 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was purified by flash chromatography on silica gel using methylenehloride/MeOH 98:2→95:5 to give N-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydroisoquinolin-7-yloxy}-ethyl)-methanesulfonamide (90.0 mg, 0.21 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C(=O)([O-])O.[Na+].C(O)C>CCCCCC.C(Cl)Cl>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCO
Product: c1ccc(-c2cn3ccccc3n2)cc1
Yield: 90 %

Procedure:
Placing 2-aminopyridine in an amount of 3.5 g (36 mmol), α-bromoacetophenone in an amount of 7.2 g (36 mmol) and sodium hydrogen carbonate in an amount of 3.6 g (43 mmol) into a flask, the resultant mixture reacted among 120 milliliter of ethanol for 4 hours at the room temperature and subsequently for 2 hours under refluxing. Separating insoluble by filtration, the resultant filtrate was concentrated. Extracting with the use of methylene chloride in an amount of 150 milliliter, the resultant extract was washed three times using 200 milliliter of water. After drying an organic layer with the use of magnesium sulfide and removing the solvent, brown crystals were obtained. Refining the crystals by means of silicagel column (hexane/methylene chloride), 6.3 g of 2-phenylimidazo[1,2-a]pyridine Intermediate 1-1b as white crystals was obtained (yield: 90%). The white crystals were confirmed as the aimed compound from 1H-NMR spectrum. The measurement result is shown as follows:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:16][C:10]1[CH:15]=[CH:14][C:13]([C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc(C)cc1

Procedure:
Toluene (0.3 mL), acryloyl chloride (0.23 g), and aluminium chloride (0.33 g) were treated in the same manner as described in Example 1 to obtain the title compound (90 mg).
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:35][C@H:36]1[CH2:40][N:39]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])[C@H:38]([C:54]([C:56]2[N:57]=[CH:58][N:59]3[CH:63]=[C:62]([C:64]4[C@H:65]([CH3:88])[C@@H:66]5[C@@H:83]([C@H:84]([OH:86])[CH3:85])[C:82](=[O:87])[N:67]5[C:68]=4[C:69]([O:71][CH2:72][C:73]4[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=4)=[O:70])[S:61][C:60]=23)=[O:55])[CH2:37]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:35][C@H:36]1[CH2:40][N:39]([C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[O:42])[C@H:38]([C:54]([C:56]2[N:57]=[CH:58][N:59]3[CH:63]=[C:62]([C:64]4[C@H:65]([CH3:88])[C@@H:66]5[C@@H:83]([C@H:84]([OH:86])[CH3:85])[C:82](=[O:87])[N:67]5[C:68]=4[C:69]([O:71][CH2:72][C:73]4[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=4)=[O:70])[S:61][C:60]=23)=[O:55])[CH2:37]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@@H](O)CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.5 %

Procedure:
Acetic acid (0.219 ml) and 1.27 ml of a 1 M tetra-n-butylammonium fluoride/THF solution were added to a solution of 369 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7[(2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 10 ml of THF, and the mixture was stirred at room temperature for 7 hr. Brine was added to the reaction solution. The mixture was adjusted to pH 8.2 by the addition of a saturated sodium hydrogencarbonate solution and was then extracted twice with ethyl acetate. The organic layers were combined, and the combined organic layers were washed with brine and were dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 239 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].O.N.[ClH:14]>[Ni].CO>[ClH:14].[NH2:2][CH2:1][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
In order to carry out the reaction advantageously on an industrial scale, trans-4-cyanocyclohexane-1-carboxylic acid is hydrogenated at a room temperature under pressure in a hydrous methanol made alkaline by the addition of ammonia water in the presence of Raney nickel, and then the catalyst is filtered and the solvent is removed by distillation. When lower alkyl trans-4-cyanocyclohexane-1-carboxylate is used as a starting material, it is subjected to the same reaction and treatment as above, and the residue is hydrolyzed with dilute hydrochloric acid in a hot water bath to produce trans-4-aminomethyl-cyclohexane-1-carboxylic acid hydrochloride. The reaction solution is passed through a column of a weakly basic ion-exchange resin to obtain trans-4-aminomethylcyclohexane-1-carboxylic acid in an yield of from 85 to 95 percent.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])#[N:8]>O1CCCC1>[NH2:8][CH2:7][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[F:18]
Reactant: N#Cc1ccc(C(=O)O)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(CO)cc1F
Temperature: 40 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
Add 1M lithium aluminum hydride in tetrahydrofuran (121 mL, 121 mmol) to anhydrous tetrahydrofuran (100 mL) under argon gas. Warm the reaction mixture to 40° C. and add in small portions 4-cyano-3-fluorobenzoic acid (5.0 g, 30.28 mmol) over a 1 hr period. Stir the reaction mixture at 40° C. for 4 hrs and then at room temperature overnight. Cool the reaction mixture to 0° C. and quench by the sequential addition of water (5 mL), 15% sodium hydroxide solution (17 mL), and water (5 mL). Allow the mixture to warm-up to room temperature and stir for 1 hr. Filter the precipitate through diatomaceous earth and concentrate the filtrate to provide the title compound (4.4 g, 28.4 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+].Cl>CCOCC.O>[OH:3][C:1]([CH3:2])([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[C:17]#[N:18]
Reactant: [C-]#N
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(O)(C#N)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 2-acetylfluorene (5.32g.) in ether (20ml.) and water (40ml.) is cooled to 5° and agitated vigorously. Sodium cyanide (2.45g.) is added portionwise and the solution is then treated with conc. HCl (4.8ml.) while maintaining the temperature between 5°-10°. The mixture is then stirred for 2 hr. at room temperature, diluted with water and extracted with ether. The ether extracts are dried (MgSO4) and evaporated to give the titled compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=O)[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].[OH-].[K+].[Cl-].[NH4+].[C:35](#[N:37])[CH3:36]>>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=[CH:36][C:35]#[N:37])[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=O)cccc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=CC#N)cccc21
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-4-carbaldehyde (237 mg, 0.586 mmol) and powdered KOH (33 mg, 0.59 mmol) in acetonitrile (10 mL) was heated at 70° C. for 1.5 hr. After cooling to ambient temperature saturated ammonium chloride was added followed by the removal of acetonitrile at reduced pressure. The residue was extracted with ethyl acetate (2×15 mL) and the combined organic phases washed with water, brine and dried (MgSO4). Purification by flash chromatography (eluent hexane:ethyl acetate 2:1) afforded 3-[2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acrylonitrile (120 mg, 48%) as an off white foam:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([N:36]1[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]1)[N:12]2[CH2:31][C:32]([F:35])([F:34])[F:33].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([N:36]1[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]1)[N:12]2[CH2:31][C:32]([F:34])([F:33])[F:35]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(NC(=O)OC(C)(C)C)nc2)nc2c1nc(N1CCN(S(C)(=O)=O)CC1)n2CC(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1nc(N1CCN(S(C)(=O)=O)CC1)n2CC(F)(F)F
Yield: 83.8 %

Procedure:
A methylene chloride (5 ml) solution of tert-butyl (5-{6-[(3S)-3-methylmorpholin-4-yl]-8-[4-(methylsulfonyl)piperazin-1-yl]-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-yl)carbamate (199 mg, 0.30 mmol) and trifluoroacetic acid (1 ml) was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the residue and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=96:4) to give a solid. The resulting solid was washed with ether-hexane and dried to give the title compound (140 mg, 83%) as a powder.
Reaction SMILES: C(C1C=CC([S:9]([Cl:12])(=[O:11])=[O:10])=CC=1OCC)#N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[N+]([O-])=O>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:20]=1)#[N:23]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COc1ccc(C#N)cc1[N+](=O)[O-]
Product: COc1ccc(C#N)cc1S(=O)(=O)Cl

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 4-methoxy-3-nitro-benzonitrile.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (200 mg, 0.70 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (180 mg, 0.82 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.7 mL, 4 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [OH-].[K+].C([S:6][CH2:7][CH2:8][C:9]([N:11]1[CH:16]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:15][S:14][C:13]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:12]1)=[O:10])(=O)C.C(O)(=O)C>CO.O>[CH:27]1([C:13]2[S:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[N:11]([C:9](=[O:10])[CH2:8][CH2:7][SH:6])[N:12]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(=O)SCCC(=O)N1N=C(C2CCCCC2)SCC1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CSC(C2CCCCC2)=NN1C(=O)CCS
Reaction time: 2 h
Yield: 39.1 %

Procedure:
1M Potassium hydroxide solution in methanol (5.83 ml) was added to a solution of the product of step (b) (0.87 g) in methanol (10 ml) and water (5 ml). The mixture was stirred under an atmosphere of nitrogen for 2 hours. Acetic acid was added and the solvent evaporated under reduced pressure. The mixture was purified by flash chromatography using 1% acetic acid/ethyl acetate as eluent to yield the title compound (0.24 g) as a white solid. mp 95°-97°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[N:6]=1
Reactant: Cc1nc(O)c2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cc(Cl)ccc2n1
Yield: 48.1 %

Procedure:
6-Chloro-2-methyl-quinazolin-4-ol (0.75 g, 3.90 mmol, 1 eq.), phosphorous oxychloride (3.47 mL, 37.4 mmol, 9.64 eq.) and triethylamine (1.62 mL, 12.5 mmol, 3.21 eq.) were refluxed for 4 hours. The mixture was stripped twice from toluene and the residue dissolved in ethyl acetate. The organic layer was washed with saturated NH4Cl (2×), dried and stripped. The residue was flash chromatographed in 3:2 ethyl acetate/hexanes to yield 400 mg of a light yellow solid product. MS (ES+)=213/215/217 (M+H)++.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16].CCCCCC.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[CH:30]([C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16])=[O:31]
Reactant: CN(C)C=O
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C)c(C=O)c(OC)c2ccccc12
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
A solution cf 5.0 g (17.8 mmol) of 2-bromo-1,4-dimethoxy-3-methylnaphthalene in 30 ml of tetrahydrofuran was cooled to -78° C., to which 11.2 ml (17.9 mmol) of 1.6 M n-butyllithium hexane solution was added dropwise, and stirred at the same temperature for 10 minutes after completion of the addition. Then 1.3 g (17.8 mmol) of dimethylformamide was added dropwise to the reaction mixture, and stirred at room temperature for 1 hour after completion of the addition. Water was added to the reaction mixture, from which the product was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (hexane-isopropyl ether (8:2)), and crystallized from hexane-isopropyl ether, to give 2.0 g (48.9%) of 2-formyl-1,4-dimethoxy-3-methylnaphthalene. m.p. 95°-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH2:18][CH3:19]
Reactant: CCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCNCC1
Reaction time: 36 h

Procedure:
To a solution of 7.5 g piperazine-1,4-dicarboxylic acid propyl ester tert-butyl ester in 70 ml dichloromethane were added 10 ml TFA. After stirring for 36 h the solution was concentrated and the residue codistilled with toluene twice. Yield: 9.2 g.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])[N:3]12.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21]([NH:22][CH2:23][CH2:24][CH3:25])=[O:26])[N:3]2[C:2]1=[O:1]
Reactant: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Agent: Cl
Solvent: C1COCCO1
Product: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask was added tert-butyl (4S,7S,10aS)-5-oxo-7-(propylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (43 mg, 0.11 mmol) and 4 M HCl in dioxane (1 mL). The mixture was stirred at rt for 1 hr. The reaction mixture was concentrated to give (4S,7S,10aS)-4-Amino-5-oxo-N-propyloctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxamide hydrochloride salt (36 mg, 0.11 mmol, 100% yield).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=O)[CH:7]([CH3:9])[CH3:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:22]>C(O)(=O)C>[CH2:11]([C:5]1[NH:4][C:1]([CH3:2])=[N:22][C:6]=1[CH:7]([CH3:9])[CH3:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [NH4+]
Reactant: CC(=O)NC(Cc1ccccc1)C(=O)C(C)C
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(C(C)C)c(Cc2ccccc2)[nH]1
Yield: 0.1 %

Procedure:
To a solution of 1.00 g of 4-acetylamino-2-methyl-5-phenyl-3-pentanone (4.29 mmol) in 20 ml of acetic acid is added 5.00 g of ammonium acetate (64.9 mmol), and the resultant mixture is heated under reflux. One hour later, the reaction mixture is concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is recrystallized from ether/n-hexane to give 0.90 mg of the objective 5-benzyl-4-isopropyl-2-methylimidazole 6. Yield, 97.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([F:40])[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:6][CH:7]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cc(F)cc(F)c4)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d of Example 1D above (0.2 g), 3,5-difluorophenyl boronic acid (0.135 g), tetrakistriphenylphosphinepalladium (0) (0.023 g), and potassium carbonate (0.2 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (3 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.205 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:11](Cl)([Cl:14])([Cl:13])=[O:12]>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][P:11]([Cl:14])([Cl:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(NP(=O)(Cl)Cl)cc1

Procedure:
To 300 ml of phosphorous oxychloride was carefully added 69 g (0.5 m) of 4-nitroaniline. The mixture was heated at reflux for 3 hours, then chilled to 10°. The crude product was collected by filtration, washed with ether and air-dried to give 93.6 g, m.p. 156.5°-157.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][C:29]2[N:25]([CH2:24][CH2:23][N:22]([CH3:32])[CH3:21])[N:26]=[C:27]([CH3:31])[CH:28]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cc1cc(N)n(CCN(C)C)n1
Product: Cc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)n(CCN(C)C)n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-5-amine (17.0 mg, 0.10 mmol). The title compound was obtained as a solid (20.8 mg, 23% yield). MS m/z: 501.02, 503.02 [M+H]+.