Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:32]1([CH2:38][C:39]([NH2:41])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:35]3[CH2:36][CH2:37][N:32]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:33][CH2:34]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with 2-piperazin-1-yl-acetamide hydrochloride (Matrix) to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide in an analogous manner as described in example 1. LR-MS: 586.2 [(M+H)+]
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:26][C:27](N)=[S:28].S1(CCCC1)(=O)=[O:31].Cl>O>[CH3:25][C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]2[S:28][C:27](=[O:31])[NH:26][C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: O
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 27 g of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate, 11 g of thiourea and 60 ml of sulfolane is heated at 110° C. for 6 hours and, then, boiled with 10 ml of 2 N-sulfuric acid (or 2 ml of 6 N-HCl) for 16 hours. After cooling, 1 l of water is added and the oil is separated and allowed to stand for a while, whereupon crystals separate out. These crystals are recrystallized from benzene-ligroin. By the above procedure is obtained 19.9 g of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:19])[F:20])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1cc(Cl)ccc1OC(F)F
Reaction time: 1 h

Procedure:
To a solution of (E)-tert-butyl 3-(5-chloro-2-(difluoromethoxy)phenyl)acrylate (458 mg, 1.503 mmol) in DCM (4.0 mL) was added TFA (2.0 mL, 26.0 mmol). After 1 h, the solvent was removed to give Intermediate 15 as a white solid. MS (ESI) m/z: 249.0 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:26]2[C:21](=[C:22]([CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[CH:27]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[CH2:31][CH3:32])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(N2CCCCCC2)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 420 (M+H)+; MS (ESI−) m/z 418 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.90 (t, J 7.5, 3H), δ 1.55 (m, 4H), 1.76 (m, 6H), 2.20 (m, 1H), 3.34 (m, 5H), 4.18 (m, 2H), 6.81 (m, 1H), 7.62 (m, 1H), 8.00 (m, 2H), 8.27 (d, J 7.1, 1H), 8.45 (d, 1H), 8.77 (d, 1H), 8.82 (m, 1H), 9.90 (s, 1H), 10.18 (br s, 1H); Anal. Calcd for C26H30FN3O+0.45 H2O: C, 73.02; H, 7.28. Found: C, 73.05; H, 7.20.
Reaction SMILES: B.[Na].FC(F)(F)C(O)=O.CO[N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH:15]=1.O>O1CCCC1.Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][NH2:12])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CON=Cc1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCc1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Suspended in 160 ml of anhydrous tetrahydrofuran were 3.783 g (0.100 mol) of sodium boron hydride, and a solution of 11.402 g (0.100 mol) of trifluoroacetic acid in 20 ml of anhydrous tetrahydrofuran was added dropwise to the suspension at room temperature. The resultant mixture was stirred for 10 minutes. A solution of 5.726 g (0.02 mol) of O-methyl-3-(4-nitrobenzyloxy)benzaldoxime in 20 ml of anhydrous tetrahydrofuran was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours and heated under reflux further for 2 hours. After cooling the mixture, 20 ml of water were added under chilling with ice water, and the solvent was then distilled off under reduced pressure. The residue was extracted with chloroform, and the solvent was distilled out of the resultant extract under reduced pressure, thereby obtaining a crude product. The crude product was dissolved in 800 ml of 2 N hydrochloric acid, and the solution was washed with chloroform and then neutralized with 50% sodium hydroxide, followed by extraction with chloroform. The solvent was distilled out of the resultant extract under reduced pressure, thereby obtaining 4.234 g (yield: 82%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:28][N:27]=[CH:26][N:25]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1)#[N:9]
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 120 °C
Yield: 75.2 %

Procedure:
A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Example 337, 68.14 mg, 0.149 mmol) (3-fluorophenyl)boronic acid (62.5 mg, 0.446 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.05 mg, 7.44 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.27 mg, 0.015 mmol), and potassium phosphate (158 mg, 0.744 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (676 μl) and water (67.6 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. LCMS showed >95% conversion to the desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 7.5% MeOH/DCM). The resulting material was taken up in DCM, sonicated, filtered, washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (58.22 mg, 0.112 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J=1.9, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.6, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:31]1([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2C(F)(F)F)=[O:38])CCNCC1>CN(C=O)C.O>[C:37]([NH2:31])(=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (397 mg, 3.08 mmol) was added drop wise to 4-(hydroxybenzoyl amino)-acetic acid (200 mg, 1.03 mmol) in DMF (6 mL). EDCI (294 mg, 1.54 mmol) and HOBT (166 mg, 1.23 mmol) were added consecutively and, after 15 mins, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone (390 mg, 1.33 mmoles) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded 4-hydroxy-N-[2-Oxo-2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl]-benzamide in 65% yield. LC-MS purity: 93%, 1H NMR (DMSO-D6): δ 10 (s, 1H), 8.3 (d, 1H), 7.8 (m, 5H), 7.5 (t, 1H), 6.8 (d, 2H), 4.1 (d, 2H), 3.6 (m, 5H), 3.1 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:7]([C:22](OC)=[O:23])=[CH:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.O.[NH2:28][NH2:29].O>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1[C:6]2[C:7](=[CH:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[C:22](=[O:23])[NH:28][N:29]=1
Reactant: NN
Reactant: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Solvent: CCO
Solvent: O
Product: CC(C)Cc1n[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrrole-3-carboxylate (0.35 g) prepared as described in Example 1c) above and hydrazine hydrate (0.2 ml) were stirred in ethanol (10 ml) for 2 days. The reaction mixture was poured into water to give a solid which was collected and recrystallised from ethyl acetate-cyclohexane to afford the sub-title pyrrole (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:39]N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:39][C:33]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: NNc1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-phenylhydrazine hydrochloride: ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[CH:13][C:12]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)=[C:11]([Cl:64])[C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[C:14]([CH:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[O:16]2)=[CH:13][C:12]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)=[C:11]([Cl:64])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1c(Cl)c(Cc2ccc(OCC)cc2)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCC(=O)O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of ethyl 2-(2-bromo-6-chloro-5-(4-ethoxybenzyl)-3-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H- pyran-2-yl)phenoxy)acetate (1.09 g, 1.14 mmole) in a mixture of THF/MeOH/H2O (12 mL/4 mL/4 mL) was added LiOH.H2O (144 mg, 3.42 mmole). The resulting solution was stirred at rt overnight. The reaction mixture was concentrated in vacuo and diluted with water. The resulting solution was acidified with 1N—HCl solution followed by extraction with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound (1.03 g, 98%) as a brown gum.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27](O)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C)C=O>[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:28])[CH2:21][O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 8.90 g of H-Asn-Leu-OMe and 11.0 g of Z-Ser(tBu)-OH in 100 ml of freshly distilled dimethylformamide is cooled to 0° C. and mixed with 3.90 g of N-hydroxysuccinimide and 8.70 g of dicyclohexyl carbodiimide. After allowing the batch to stand for 30 minutes at 0° C. and then for 18 hours at 25° C. the precipitated dicyclohexylurea is suctioned off and the filtrate poured into 800 ml of ice water. The resulting crystalline precipitate is dried under vacuum at 40° C. and then recrystallized from aqueous methanol. The resulting analytically pure product - Z-Ser(tBu)-Asn-Leu-OMe -melts at 202°-205° C. Optical rotation [α]D20 =18° (c=1.05 in glacial acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][Br:31]>>[Br-:31].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:26][C:27]2[CH:34]=[CH:33][CH:32]=[C:29]([CH3:30])[CH:28]=2)[CH:7]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Product: Cc1cccc(Cn2cc[n+](CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)c1
Product: [Br-]

Procedure:
mp. 99°-101° C., by the reaction of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazole and m-methylbenzyl bromide.
Reaction SMILES: S(OS([O-])(=O)=O)([O-])(=O)=O.[Ce+3].S(OS([O-])(=O)=O)([O-])(=O)=O.S(OS([O-])(=O)=O)([O-])(=O)=[O:21].[Ce+3].C([O:33][CH2:34][CH3:35])(=O)C.[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40]C>>[C@@H:35]1([CH2:34][OH:33])[CH2:36][CH2:37][CH2:38][C@H:39]1[CH2:40][OH:21]
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: [Ce+3]
Product: OC[C@@H]1CCC[C@H]1CO

Procedure:
TLC: Rf =0.25, silica gel, ethyl acetate:hexane (1:1), cerium disulfate.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[C:14]1(=O)[O:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]2[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C1CCCN1c1cccc2cccnc12
Temperature: 25 °C
Yield: 5.4 %

Procedure:
Potassium hydride in oil was washed with dry pentane (in a dry nitrogen atmosphere) leaving 2.5 g (0.062 mole) of potassium hydride which was covered with dry tetrahydrofuran (25 ml). To the slurry of potassium hydride (at room temperature) was added dropwise a solution of 8-aminoquinoline (5 g, 0.035 mole) in dry tetrahydrofuran (25 ml), with stirring, followed by addition of dry hexamethylphosphoric triamide (25 ml). After stirring for 1 hour at room temperature, the reaction was cooled in an ice bath and a solution of γ-butyrolactone (2.8 ml, 0.036 mole) in dry tetrahydrofuran (10 ml) was added and the reaction stirred for 1 hour. The reaction was warmed to room temperature and a solution of p-toluenesulphonyl chloride (8 g, 0.042 mole) in dry tetrahydrofuran (10 ml) was added. The reaction was poured into ice water, filtered and the pH was adjusrted to pH 3.5. The product was extracted with methylene chloride and washed with cupric chloride to remove traces of 8-aminoquinoline. The product organics were dried, concentrated under reduced pressure and the residue was crystallized from ether/pentane affording 1-(8-quinolyl)-2-pyrrolidinone, yield 5.4%, which was identical by tlc and NMR in comparison with the product of Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:18][N:17]=1)[CH2:14][CH3:15]>CN(C=O)C.O>[N:1]1([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][N:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(Br)c1ccc(-c2cccc(OC)c2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(c1ccc(-c2cccc(OC)c2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 12 %

Procedure:
To a solution of imidazole (0.2 g, 2.9 mmol) in DMF (5 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-(1-bromopropyl)-5-(3-methoxyphenyl)pyridine under nitrogen and the reaction was heated to 50° C. for 3 h. The contents were cooled to rt, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The layers were separated, the organic layer was washed with brine solution (2×30 mL), dried over sodium sulphate and distilled off to get the crude product. The product was purified by preparative TLC (2000μ; pure ethyl acetate) to provide 2-(1-(1H-imidazol-1-yl)propyl)-5-(3-methoxyphenyl)pyridine (50 mg, 12% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.09 (d, 1H), 7.81 (s, 1H), 7.40 (m, 2H), 7.36 (s, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.89 (s, 1H), 5.37 (q, 1H), 3.80 (s, 3H), 2.25 (m, 2H), 0.82 (t, 3H); LC-MS m/z calcd for [M+H]+ 294.15. found 294.2.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CC#N>[N:31]1([CH2:2][C:3]2[S:7][C:6]3[CH:8]=[C:9]([O:12][C:13]4[S:14][C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[N:17]=4)[CH:10]=[CH:11][C:5]=3[CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: ClCc1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2sc(Oc3ccc4cc(CN5CCCCC5)sc4c3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
To a solution 2-(2-chloromethyl-benzo[b]thiophen-6-yloxy)-benzothiazole (86 mg, 0.26 mmol) in MeCN (3 mL) was added DIEA (0.014 mL, 11 mg, 0.8 mmol) followed by piperidine (0.051 mL, 44 mg, 0.52 mmol) and stirred (rt, 12 h). The reaction mixture was partitioned between DCM (15 mL) and saturated NaHCO3(5 mL). The organic layer was washed with saturated NH4Cl (10 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to provide the title compound as colorless solid (48 mg, 49%). MS (ESI): mass calcd. for C21H20N2OS2, 380.1; m/z found, 381.1[M+H]+. 1H NMR (400 MHz, CDCl3): 7.79 (d, J=2.3, 1H), 7.75-7.72 (m, 1H), 7.70 (d, J=8.6, 1H), 7.65 (dd, J=8.0, 0.7, 1H), 7.40-7.35 (m, 1H), 7.29 (dd, J=8.6, 2.3, 1H), 7.28-7.21 (m, 1H), 7.13 (5, 1H), 3.75 (5, 2H), 2.55-2.40 (m, 4H), 1.69-1.54 (m, 4H), 1.52-1.32 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Temperature: 120 °C

Procedure:
To 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (2 g) was added Trimethyl Phosphite (30 eq) and the reaction was refluxed at 120° C. for 90 minutes. The reaction was cooled and concentrated to dryness under vacuum. To the dried crude was added water, upon which a yellow solid crashed out and was filtered and dried overnight under vacuum to afford 2 g of pure dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(O)CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C1=CCNCC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of of 4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine (0.56 g, 2.5 mmole) (Intermediate 8) in acetic acid (20 mL) at room temperature was added 2 drops of concentrated sulfuric acid and the resulting solution heated to reflux for 2 days. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The solution was basified with 50% NaOH solution until PH=10, the layers separated and the organic layer was washed with brine (25 mL). The combined aqueous layers were extracted three times with EtOAc (3×25 mL), and the combined organic layers were dried over Na2SO4 and concentrated to afford 0.49 g (95% yield) of 4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine as a yellow oil.