Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>CS(C)=O.O>[CH:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)N1CCCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)cc1
Yield: 36.5 %

Procedure:
A solution of ethyl 4-fluorobenzoate (0.293 mL, 2 mmol) and 1-isopropyl-1,4-diazepane (0.539 mL, 4.00 mmol) in dimethylsulfoxide (10 mL), was heated at 120° C. for 18 h. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with saturated sodium chloride solution (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 36.5%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][C:18]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][C:18]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:17][N:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reaction time: 3.5 h
Yield: 85.3 %

Procedure:
A solution of 0.612 g (1.17 mmol) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl]-carbamic acid tert-butyl ester in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (2 mL) is stirred for 3.5 hours in a capped flask. The reaction mixture is concentrated under reduced pressure, diluted with water, and washed with diethyl ether. The pH of the aqueous phase is adjusted to alkaline with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined organic phase is washed with an aqueous solution of sodium carbonate followed by water then dried over anhydrous sodium sulfate and filtered to remove the drying agent. The aqueous phase is re-extracted with a 1:1 mixture of n-butanol:ethyl acetate followed by n-butanol. The organic phases from these extractions are washed with an aqueous solution of sodium carbonate followed by water. The organic phase is then concentrated under reduced pressure co-evaporating with toluene. The residue is dissolved in a mixture of methanol:methylene chloride, dried over anhydrous sodium sulfate and combined with the previous organic washings. The combined organic phase is concentrated under reduced pressure to give 0.422 g (85.0%) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide as a resin.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CC(C)=O.C(OCC)C.O>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:25][CH:26]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2cnc3ccc(Cl)cc3n2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A mixture of 2,7-dichloroquinoxaline (2.8 g, 14.1 mmol), methyl 2-(4-hydroxyphenoxy)propanoate (2.76 g, 14.1 mmol), and pulverized potassium carbonate (3.9 g, 28.2 mmol) in acetone (70 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and methylene chloride and water were added to the reaction mixture. The organic phase was removed, and the aqueous phase was extracted with methylene chloride. The combined organic phase was washed with water, dried over potassium carbonate, concentrated, and dried under high vacuum. The product was purified by flash chromatography with 6:1 petroleum ether:ethyl ether to afford the desired product (2.8 g, 55% yield) as a solid: mp 103° C.; MS m/e 359 (M+ +H). Anal. Calcd for C18H15ClN2 O4 : C., 60.26; H, 4.21; N, 7.81; Cl, 9.88. Found: C, 60.44, H, 4.31; N, 7.69, Cl, 9.98.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (13.4 g), methyl 5-hydroxypyridine-3-carboxylate (9.84 g), anhydrous potassium carbonate (8.90 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (12.42 g, 59%) of methyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(O)CCC.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44]>CO.[I-].[K+].C(OCC)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C(O)C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Solvent: CCOCC
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 68.9 %

Procedure:
A solution of 4.42 g (0.0164 mole) of 4-[(4-fluorophenyl)phenylmethyl]piperidine and 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 0.01 g of potassium iodide and 1-butanol was refluxed for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of oxalic acid, ethyl ether was added, and 6.39 g (68.9%) of white crystalline solid, m.p. 161°-163° C. was obtained.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccc(Cl)c1F

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 3-chloro-2-fluorophenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 3-chloro-2-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 532.7 ([M+NH4]+)
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].C1(P(C2CCCCC2)C2C=CC=CC=2[C:45]2C=CC=C[C:46]=2[N:51](C)C)CCCCC1.C(N)C.C1COCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:46]([NH:51][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:30])([F:31])[F:29])[CH3:45]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCN
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Temperature: 120 °C
Yield: 147.2 %

Procedure:
To a mixture of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50 mg, 0.11 mmol) in dioxane was added 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.4 mg, 0.011 mmol), Pd2dba3 (5 mg, 5.5 μmol, 2 M ethanamine in THF (0.28 mL, 0.55 mmol) and sodium tert-butoxide (21 mg, 0.22 mmol). The reaction mixture was heated at 120° C. for 2 h under microwave irradiation, quenched by saturated NH4Cl solution and extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified first by preparative TLC followed by preparative HPLC to give the title compound (7 mg) as a white solid. LCMS m/z=433.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 2.10-2.17 (m, 1H), 2.62 (dd, J=17.0 and 10.9 Hz, 1H), 2.75-2.86 (m, 4H), 3.23 (q, J=7.1 Hz, 2H), 3.54-3.62 (m, 1H), 4.96 (s, 2H), 6.73 (d, J=8.6 Hz, 1H), 6.83 (dd, J=8.8 and 2.4 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.5 and 1.7 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 8.28 (s, 1H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The scandium salt of dibutylaminosulfonylmalononitrile, obtained in Example 40, was used as catalyst in a Friedel-Crafts reaction of acylation, by operating in the following manner. In 40 ml of anhydrous nitromethane, there is added 570 mg (700 μmoles) of Sc(DBSM)3, and 1.08 g (10 mmoles) of anisol and 2.04 g of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited by using 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml of ether, and the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (97% yield) was recovered, with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:18]3[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 4-benzyloxyaniline and 4,6-dichloro-pyrido[3,4-d]pyrimidine; (CDCl3) 9.11 (1H, s), 8.78 (1H, s), 7.75 (1H, d), 7.56 (2H, dd), 7.40 (5H, m), 7.15 (2H, d), 5.10 (2H, s); m/z (M+1)+ 409.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:57])[C@@H:38]([NH:46][CH2:47][C:48]2[CH:49]=[C:50]3[C:54](=[CH:55][CH:56]=2)[NH:53][CH:52]=[CH:51]3)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:39]([C@H:38]([N:46]([CH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][CH:52]=[CH:51]2)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35]1)=[O:57])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C([C@H](Cc1ccccc1)NCc1ccc2[nH]ccc2c1)N1CCN(Cc2ccccc2)CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc2[nH]ccc2c1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
In an inert atmosphere, trans-4-(trifluoromethyl)cinnamic acid (34 mg, 0.156 mmol) was dissolved in DCM (3 mL) and 1-chloro-N,N,2-trimethylpropenylamine (24 mg, 0.182 mmol) was added at rt. The reaction mixture was stirred for 30 min followed by the addition of 1-(4-benzyl-piperazin-1-yl)-2-[(1H-indol-5-ylmethyl)-amino]-(S)-3-phenyl-propan-1-one (59 mg, 0.13 mmol). Stirring was continued at rt for 3 h. The solvents were evaporated under reduced pressure and the residue was directly purified by prep. HPLC to give 33 mg (39%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(1H-indol-5-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.96 min; [M+H]+=651.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[N:16]([CH:19]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:16][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C=NC1CCCCCCC1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC(NC1CCCCCCC1)C(Cl)(Cl)Cl)c1cc(Br)co1
Yield: 67.7 %

Procedure:
4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125 (0.16 g, 0.47 mmol) and isocyanatocyclooctane (0.08 mL, 0.51 mmol) in benzene (2 mL) with triethyl amine (2 drops) was heated to 95° C. for 1.5 hours. The mixture was concentrated onto silica gel and purified by chromatography (7:3 to 6:4 hexane:CH2Cl2) to give 4-bromo-N-(2,2,2-trichloro-1-(cyclooctylamino)ethyl)furan-2-carboxamide (Compound-51) (142 mg, 67%). 1H NMR (300 MHz, CDCl3): δ=7.50 (d, J=0.9 Hz, 1H), 7.21 (d, J=0.9 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 5.55 (t, J=9.3 Hz, 1H), 2.96-2.85 (m, 1H), 1.79-1.42 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.[F:39][C:40]([F:48])([F:47])[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][S:43]([CH2:42][CH2:41][C:40]([F:48])([F:47])[F:39])(=[O:45])=[O:44])=[CH:29][CH:30]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 8.8 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.54 g, 1.24 mmol) in dichloromethane (30 ml) at 0° C. was added triethylamine (0.20 ml, 1.50 mmol) followed by 3,3,3-trifluoropropane sulfonyl chloride (295 mg, 1.50 mmol). The reaction mixture was subsequently stirred at room temperature for 2.5 hours. Concentration and purification by flash chromatography (heptane:EtOAc gradient) afforded 65 mg (9%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:17])=[C:8]3[C:15](=O)[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:17])=[C:8]3[C:15](=[N:19][OH:20])[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(C)c3n(c2c1)CCCC3=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(C)c3n(c2c1)CCCC3=NO
Yield: 98.2 %

Procedure:
A solution of 6,7,8,9-tetrahydro-3-methoxy-10-methylpyrido[1,2-a]indol-9-one (2.29 g, 10 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) in dry pyridine (40 mL) was refluxed for 2 hours. The reaction mixture was concentrated to 10% of its original volume and distilled water (80 mL) was added. The organic product was extracted with ether (3×60 mL). The combined organic layers were washed with water (100 mL), 5% hydrochloric acid (50 mL), and 10% sodium bicarbonate (50 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated. The residue was recrystallized from methanol/water to afford 2.4 g (98%) of the title compound as gray microcrystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]3[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: OC1CCNC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCC(O)C3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 94 mg of pyrrolidin-3-ol and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1>O.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:38])[C:34]([F:35])([F:36])[F:37])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: O=C(NC[C@H](NC(=O)C(F)(F)F)C(=O)O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Agent: [Pd]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](NC(=O)C(F)(F)F)C(=O)O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
To a solution of N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine trifluoroacetate in water (4 ml) was added Pd/C (10% dry, 16 mg) and the mixture was stirred at room temperature under hydrogen at atmospheric pressure for 4 hours. Catalyst was filtered off and filtrate was evaporated in vacuo to give N-[(R)-1-[3-(4-piperidyl)propanoyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine trifluoroacetate as a colorless oil (45 mg, 54.9%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
The product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.20 mL, 0.40 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was suspended in tetrahydrofuran (10 mL) and adsorbed onto approximately 5 g of silica gel and evaporated. The product was eluted with methanol in chloroform. Product containing fractions were combined and evaporated under vacuum to give the title compound (0.032 g, 42%). MS (ESI−) m/z 417 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01 (d, J=6.62 Hz, 6 H) 1.88 (m, 1 H) 2.83 (s, 2 H) 6.60 (s, 1 H) 7.41 (d, J=4.04 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.65 (d, J=8.46 Hz, 1 H) 7.77 (t, J=7.91 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.35 (d, J=4.78 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H).
Reaction SMILES: ClCCOCC.Br.Br.N1CCC([NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)CC1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH2:15]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: Br
Agent: CCOCCCl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 32 parts of 1-chloro-2-ethoxyethane, 94.5parts of N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 90 parts of sodium carbonate and 540 parts of N,N-dimethylacetamide was stirred overnight at 70° C. After cooling, the reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was boiled in acetonitrile. After cooling, the precipitated product was filtered off and dried, yielding 42.4 parts (58.8%) of N-[1-(2-ethoxyethyl)-4-piperidinyl[-1H-benzimidazol-2-amine; mp. 212° C. (interm. 29).