Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Br:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: CC#N
Solvent: O
Product: CC(C)N(C)c1nc2c(nc1Br)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-bromosuccinimide (342 mg) and acetonitrile (10 ml) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0→40% ethyl acetate/hexane) to give the title compound (122 mg, 20%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:42]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: COc1cccc(C(=O)OCCCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3OCc3ccc4ccccc4c3)cc2)c1

Procedure:
(bb) In an analogous manner to that described in Example 22 (k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with 3-methoxy-benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-{4-[3-(3-Methoxy-benzoyloxy)-propyl]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 610 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2)cc1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinyl methoxy]benzoate (529 mg, 1.15 mmol) in CH2Cl2 (5 ml) was added TFA (5 ml). The mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO3. The mixture was extracted with CHCl3 (2×100 ml). The extracts were dried over K2CO3 and evaporated to give methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinyl methoxy]benzoate (385 mg, 92%) as a yellow oil. 1H-NMR (CDCl3) δ 1.89–1.95 (m, 1 H), 2.28–2.35 (m, 1 H), 3.09 (dd, J=12.5, 4.9 Hz, 1 H), 3.33 (d, J=12.5 Hz, 1 H), 3.60 (m, 1 H), 3.86 (s, 3 H), 4.10 (d, J=5.6 Hz, 2H), 4.84(m, 1H), 6.73–6.89(m, 3 H), 6.91 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1[CH:26]=[C:27]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28]1.[C:42]([OH:45])(=[O:44])[CH3:43].[OH2:46].Cl>C1COCC1>[C:40]([OH:41])(=[O:46])/[CH:27]=[CH:43]\[C:42]([OH:45])=[O:44].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28]1
Reactant: CC(=O)O
Reactant: Cc1c(C=C2CCc3ccc4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CC1CCc2ccc3ccccc3c2C1=O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A solution of 1,2-dihydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methylene]-4(3H)-phenanthrenone (0.5 g) in a mixture of THF (15 ml), acetic acid (5 ml) and water (5 ml) was heated on a steam bath for 45 min. 0.5M Hydrochloric acid (25 ml) was added and the mixture was extracted with ether (2×15 ml; discarded). The aqueous solution was basified with solid potassium carbonate and the mixture was extracted with dichloromethane (3×15 ml). The dried extracts were evaporated and the residue (0.21 g) was dissolved in ethanol (25 ml) and hydrogenated at room temperature and atmospheric pressure over a stirred suspension of 10% palladium on carbon (0.05 g) for 1.5 h. The solution was filtered and the filtrate evaporated to give a gum which was purified by FCC eluting firstly with ethyl acetate and then with ethyl acetate/methanol (3:1) to give the free base of the title compound as a gum (0.13 g). This was dissolved in methanol (20 ml) containing maleic acid (50 mg) and the solution was evaporated to give a gum which on trituration with ether gave the title compound as a solid (0.11 g), m.p. 133°-134° .
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]12([CH2:18][NH:19][C:20](=[O:29])[C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[C:23](Br)[CH:22]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[C:30](=[O:33])([O-])[O-:31].[K+].[K+].O>CN1CCCC1=O>[C:8]12([CH2:18][NH:19][C:20]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[C:23]([N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][NH:7][C:30](=[O:33])[O:31][C:8]([CH3:17])([CH3:15])[CH3:9])[CH:22]=3)=[O:29])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Reactant: NCCNCCO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCN(CCO)c1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
N-(2-Hydroxyethyl)-ethylenediamine (0.208 g) was added to a mixture of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (0.192 g, Example 1(ii)) and potassium carbonate (0.14 g) in anhydrous N-methyl-2-pyrrolidinone (3 ml). The resulting solution heated in a MARS microwave for 10 minutes (300 Watts, 150° C.). The mixture was cooled and poured into water (50 ml) and extracted into ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (2×10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved into ethyl acetate 30 ml and di-tert-butylcarbonate (0.218 g) added. The resulting mixture was left to stand at room temperature for 2 hours and was then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to afford tert-butyl 2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate (0.013 g).
Reaction SMILES: C(OC(=O)C1C=CC=C(C#C[C:13]2[CH:25]=[CH:24][C:16]3[O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:15]=3[CH:14]=2)C=1)C.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])=[CH:31][CH:30]=1)#[CH:28].IC1C=CC2OCC(C)(C)COC=2C=1>>[CH3:22][C:19]1([CH3:23])[CH2:18][O:17][C:16]2[CH:24]=[CH:25][C:13]([C:28]#[C:27][C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: CCOC(=O)c1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1
Reactant: C#Cc1ccc(C(=O)N2CCOCC2)cc1
Agent: CC1(C)COc2ccc(I)cc2OC1
Product: CC1(C)COc2ccc(C#Cc3ccc(C(=O)N4CCOCC4)cc3)cc2OC1

Procedure:
The title compound is prepared in analogy to 3-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester (10) from (4-ethynyl-phenyl)-morpholin-4-yl-methanone and 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5) as a yellow viscous oil, MS (ESI) 392.3 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, heptanoyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.49 g, 66%) as a white solid: mp 130-132° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.44 (t, J=5.7 Hz, 1H), 7.86-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.19-5.12 (dd, J=5.2 and 12.4 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 2.98-2.83 (m, 1H), 2.64-2.50 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.53 (t, J=6.0 Hz, 2H), 1.25 (s, 6H), 0.85 (t, J=5.9 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 172.66, 169.79, 167.47, 166.93, 139.54, 134.66, 133.13, 131.50, 127.06, 121.80, 54.86, 48.85, 37.57, 35.23, 30.96, 28.31, 25.16, 21.97, 13.87; Anal. Calcd. For C21H25N3O5+0.3H2O: C, 62.30; H, 6.37; N, 10.38. Found: C, 62.07; H, 6.29; N, 10.23.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]#[N:27]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[CH:23]=[N:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 42.4 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (151 mg, 42%). MS (ISP) 357.0 [(M+H)+]; mp 236° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C=Cc2cc(OCc3ccccc3)ccc2O1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 9.6 g (33.8 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-ol and 0.2 g of p-toluenesulfonic acid in 85 ml of toluene was heated under reflux on a water separator for 1 h. After cooling, the mixture was washed twice with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 7.6 g of 6-benzyloxy-2,2-dimethyl-2H-chromen.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH2:42][CH2:43][CH3:44]>O1CCCC1>[C:41]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:33])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:45])[CH2:42][CH2:43][CH3:44]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (20 μL, 0.14 mmol) and butyryl chloride (7.6 μL, 0.073 mmol) were added successively. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (27 mg) as a colorless amorphous product. (Yield 92%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH2:20][CH2:21]Cl)[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1C=CC=CC=1.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[CH2:21])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H]1[C@H](CCCl)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: C=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C
Yield: 98.7 %

Procedure:
610 mg of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-chloroethyl)-4-isobutyloxazolidine was dissolved in 3.6 ml of dry benzene, and a solution prepared by dissolving 390 mg of potassium tert-butoxide in 3.6 ml of dimethyl sulfoxide, was added thereto. The mixture was reacted at room temperature for 10 minutes. The reaction solution thus obtained was purified by silica gel column chromatography (packed with 36 g of silica gel, developer: benzene/ethyl acetate (30/1)), and the fraction containing the desired compound was collected and concentrated. The residue thus obtained was dried under reduced pressure to obtain 540 mg (yield: 99%) of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-ethenyl-4-isobutyloxazolidine as a colorless transparent syrup having the following physical properties.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][CH2:36][CH2:37][OH:38]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:35]([CH2:36][CH2:37][OH:38])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OCCNCc1ccccn1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(C)c1cccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][CH:25]=2)=[CH:6][CH:5]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
A solution of 2-[4-(2-aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (140 mg) in dichloro-methane (3.0 mL) was treated benzoic acid (40 mg) and DCC (60 mg) sequentially and allowed to stir at ambient temperature for 17 h. The reaction mixture was then concentrated and fractionated by column chromatography with 5% Et3N in EtOAc to afford the product (141 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:29](=[O:32])[CH2:30][Cl:31])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[ClH:31].[ClH:31].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:29](=[O:32])[CH2:30][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CCl)CC2
Reactant: C1CCNC1
Solvent: CC#N
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CN1CCCC1)CC2
Yield: 173.2 %

Procedure:
4-(Benzyloxy)-1-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (70 mg, 0.15 mmol) was dissolved in MeCN (0.5 mL) and pyrrolidine (54 mg, 0.76 mmol) was added. The reaction mixture was refluxed for 2 h, concentrated and the residue purified by preparative HPLC. The fractions were concentrated, and the residue was converted to the free base by partitioning between CH2Cl2 and sat. Na2CO3 solution. The organic phase was removed, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Conversion to the HCl salt (2 N HCl/Et2O) provided the title compound (74 mg, 97%) as a beige solid: 1H NMR (500 MHz, CD3OD) δ 7.62 (dd, J=7.7, 1.9 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H) 7.46-7.44 (m, 2H), 7.41-7.35 (m, 4H), 7.06 (dd, J=8.0, 1.7 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H), 6.18 (s, 1H), 5.25 (s, 2H), 4.90 (m, 1H, masked by solvent), 4.82 (s, 1H), 4.53 (d, J=14.2 Hz, 2H), 4.09 (t, J=6.5 Hz, 1H), 3.91 (t, J=6.4 Hz, 1H), 3.89-3.86 (m, 2H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 3.05-3.03 (m, 1H), 2.99-2.97 (m, 1H), 2.12-2.10 (m, 2H), 2.08-2.05 (m, 2H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 95.0% (AUC), tR=13.1 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)cs1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)cs1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 35 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (65 mg, yield 35%). 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=1.8 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H), 7.82-7.80 (m, 3H), 7.41 (s, 1H), 7.38-7.36 (m, 2H), 4.05-4.01 (q, J=5.8 Hz, 2H), 3.43-3.40 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O2S: 479.04. found: 480.0 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:21]([C:28](O)=[O:29])=[N:20]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:21]3[C:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[O:19][N:20]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1noc2c1CCCC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1noc2c1CCCC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (90 mg, 0.345 mmol) and 4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid (75 mg, 0.449 mmol). The product was purified with flash chromatography. Yield 111 mg (78%). 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 1.69-1.83 (m, 4H), 2.77-2.83 (m, 4H), 4.25-4.43 (m, 2H), 4.52-4.61 (m, 1H), 6.63 (d, 1H), 7.37 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 7.94 (d, 1H).
Reaction SMILES: C([N:4]=[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:8]=[C:7]([CH3:21])[S:6]1)(=O)C.[ClH:22]>C(O)C.O>[ClH:22].[F:19][C:17]([F:18])([F:20])[C:12]1[CH:11]=[C:10]([N:9]2[CH:8]=[C:7]([CH3:21])[S:6][C:5]2=[NH:4])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CC(=O)N=c1sc(C)cn1-c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc(F)c(C(F)(F)F)c2)c(=N)s1

Procedure:
A mixture of 2-acetylimino-3-(3-trifluoromethyl-4-fluorophenyl)-5-methylthiazoline (3.5 g) and hydrochloric acid (36%, 3.5 ml) in ethanol-water (35 ml) was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure, and the residue was isolated and washed with a little amount of iso-propanol and hexane to give 2.8 g of 3-(3-trifluoromethyl-4-fluorophenyl)-5-methyl-2-iminothiazoline hydrochloride (compound (i)).
Reaction SMILES: C(O)C.[Na].[CH2:5]([N:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O>[CH2:5]([N:12]=[CH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Oc1ccc(C=NCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NCc2ccccc2)cc1
Reaction time: 22 h
Yield: 65.7 %

Procedure:
(a) To 50 ml of absolute ethanol is added 0.573 g of sodium, and 5 g of 4-(N-benzylformimidoyl)phenol and then 5.54 g of ethyl 2-bromo-2-methylpropionate are added to the solution under cooling with water. The mixture is refluxed under heating and with stirring for 22 hours. The ethanol is distilled off from the reaction mixture under reduced pressure. After dissolving the residue in 30 ml of benzene, the insolubles are filtered off. The benzene filtrate is washed with water twice, then dried over magnesium sulfate and thereafter the solvent is distilled off. 6.12 g of the resulting oily product is dissolved in ether. After removing the insolubles from the ethereal solution by filtration, the filtrate is concentrated to give 5.06 g of ethyl 2-[4-(N-benzylformimidoyl)phenoxy]-2-methylpropionate in the form of a pale brown oil.