Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>O1CCCC1.Cl.C(OC(C)C)(C)C>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)=[CH:26][C:19]=1[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])#[N:22]
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of sodium 4-hydroxy-4-(2-methyl-phenyl)butanoate, thought to be the (R)-enantiomer, (3 g) and sodium hydride (1.5 g; 60% w/v dispersion in mineral oil; 37.5 mmol) in tetrahydrofuran (50 mL) is stirred at ambient temperature for 1 hour under an atmosphere of argon, and is then warmed to 55° C. It is then treated with 2-fluoro-4-(3-thienylmethoxy)benzonitrile (3 g), in one portion, and stirring is continued at 55° C. for 15 hours. The mixture is then cooled, diluted with hydrochloric acid (200 mL; 1 N) and extracted with ethyl acetate (4×100 mL). The combined extracts are dried over magnesium sulphate and concentrated in vacuo, to give an oily residue. This residue is boiled in isopropyl ether, and the resulting mixture is filtered while hot, and then allowed to cool. The yellow solid which separates is collected and recrystallized from a mixture of ethyl acetate and hexane, to give 4-[2-cyano-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (1.5 g) in the form of a white fluffy solid, m.p. 145° C. Chiral HPLC assay showed a 98% enantiomeric excess. [Elemental analysis:- C,67.82;H,5.18; N,3.24%; Calculated:- C,67.80;H,5.19;N,3.44%].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39].CC#N.C(Cl)CCl>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:36]([NH:35][C:32]5[CH:33]=[CH:34][C:29]([Cl:28])=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Solvent: ClCCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-Amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Example 253, Step E, 145 mg, 0.4 mmol, 1.0 eq.) was dissolved in CH3CN/DMF (2/1, v/v, 15 ml) and 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (as described in preparation III, 93 mg, 0.4 mmol, 1.0 eq.) as a CH3CN solution was added drop-wise. The reaction was stirred at RT for 16 h. EDC (75 mg, 0.4 mmol, 1.0 eq.) was added and the reaction was heated to 80° C. for 2 h. The mixture was concentrated and the crude product was purified by column chromatography (0-10% MeOH/CH2Cl2/1% NH4OH) to yield 4-[2-(4-chloro-3-trifluoromethyl-phenylamino)-benzoxazol-5-yloxy]-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide. MS m/z=574.2 (M+H)+ Calc'd for C28H27ClF3N5O3: 573.18.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28]
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Reaction time: 1.5 h
Yield: 136.7 %

Procedure:
To a chilled solution of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl}{[(5-chloro(2-thienyl))sulfonyl]amino}carboxamide (0.246 g, 0.55 mmol) in CH2Cl2 (5 mL) was added neat TFA (1.11 mL). The reaction mixture was stirred cold for 1.5 hr, concentrated in vacuo, azeotroped with heptane and dried to give N-(4-amino-3-methylphenyl){[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide (0.26 g) as the mono TFA salt. ES-MS (M+H)+=346.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(OCC)(=O)C.N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[F:11])[NH:1][S:13]([CH3:12])(=[O:15])=[O:14])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1F
Yield: 79.7 %

Procedure:
5'-Amino-2'-fluoroacetophenone (28 g) was dissolved in a mixture of 100 ml of ethyl acetate and 15.9 g of pyridine, a solution of 23 g of methanesulfonyl chloride in 50 ml of ethyl acetate was added with ice-cooling and stirring and the mixture was made to react at room temperature for 3 hours. The reaction mixture was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by silica gel column chromatography (eluting with chloroform) to give 33.7 g of 3'-acetyl-4'-fluoromethanesulfonanilide, m.p. 120°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][C:17]=1[O:26][CH3:27])(=[O:11])=[O:10].C(Cl)CCl.C1C=C[C:44]2N(O)N=[N:47][C:45]=2C=1.C(N)C.C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[NH:47][CH2:45][CH3:44])=[CH:18][C:17]=1[O:26][CH3:27])[C:32]([NH:33][CH2:34][CH3:35])=[O:36])(=[O:11])=[O:10]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(Oc2ccc(CC(=O)O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Agent: CCN
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)Cc1ccc(Oc2ccc(C(=O)NCC)cc2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
A mixture of acid (12) (63 mg, 0.114 mmol), EDC (44 mg, 0.228 mmol), HOBt (18 mg, 0.114 mmol), 114 μL of 2N ethylamine in THF (0.228 mmol) in 1 mL of methylene chloride was allowed to stir for 24 h at room temperature. Upon completion, the solvent was removed and 10 mL of 2N HCl aqueous solution was added and the resulting mixture was extracted with EtOAc (4×20 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on a silica gel column using 50% EtOAc/hexane and EtOAc sequentially as the eluents to give 53.0 mg of the title compound. 1H NMR (CDCl3): δ 7.96 (d, J=8.52 Hz, 1H), 7.87 (d, J=2.08 Hz, 1H), 7.83 (br s, 1H), 7.42 (obscured dd, J=8.52, 2.16 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=8.12, 2.20 Hz, 1H), 6.90 (d, J=1.72 Hz, 1H), 6.77 (d, J=8.20 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J=8.08 Hz, 1H), 6.54 (d, J=8.52 Hz, 1H), 6.17 (br s, 1H), 5.62 (br s, 1H), 3.67 (s, 3H), 3.52 (s, 2H), 3.45 (m, 2H), 3.29 (m, 2H), 1.23 (dd, J=7.48, 7.48 Hz, 3H), 1.12 (dd, J=7.52, 7.52 Hz, 3H). LCMS (ESI−) 579 (M−1).
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH2:17][CH2:18][C:19]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3].C(O)(=O)C.[H][H]>[Pt]=O.Cl>[NH2:20][CH2:19][CH2:18][CH2:17][C:4]1([C:2]([NH2:1])=[O:3])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [H][H]
Reactant: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A 3.3 g. portion of 9-aminocarbonyl-9-(2-cyanoethyl)fluorene from Example 27 was hydrogenated in 95 ml. of glacial acetic acid under 4 atmospheres of hydrogen pressure for two hours at 24° C. in the presence of 1.5 g. of platinum oxide catalyst. The reaction mixture was filtered to remove the catalyst and the solvent was removed by evaporation under reduced pressure. The product which remained was dissolved in ethyl acetate and then extracted into 1 N hydrochloric acid. The aqueous acid layer was separated, made alkaline with 50% sodium hydroxide, and extracted several times with fresh ethyl acetate. The extracts were combined, washed with water and with brine, dried, and the solvent was removed by evaporation under reduced pressure to provide 2.3 g. of a white solid. The solid was dissolved in 1 N hydrochloric acid, filtered, and diluted with water to 100 ml. The aqueous acid solution was lyophilized to provide a white solid, which was crystallized from methanol and ethyl acetate was identified as 1.0 g. of 9-(3-aminopropyl)-9-aminocarbonylfluorene. m.p. 198°-200° C.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O.C(Cl)Cl>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]([OH:10])=[O:2]
Reactant: COC(=O)CCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CCC(=O)O
Reaction time: 4.5 h
Yield: 84.7 %

Procedure:
4,4-Dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 1.0 eq.) was treated with a solution of NaOH (4.0 g, 100 mmol, 2.1 eq.) in water (5 mL). The homogeneous solution was allowed to stir for 4-5 hours. The reaction was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The aqueous layer was acidified with 6M HCl to pH ˜1.5 and extracted with ethyl acetate (50 mL×3). The combined ethyl acetate fractions were dried over MgSO4, filtered and evaporated to provide 4,4-dimethyl-pentanoic acid (5.35 g, 41.1 mmol, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCOCC.[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21][Br:22])=[CH:18][CH:17]=1>O1CCCC1>[Br-:22].[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([CH2:21][N+:2]2[CH:1]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[CH:3]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1ccn2cncc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(C[n+]1cc2ccccn2c1)c1ccc(Cl)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 68.3 %

Procedure:
Imidazo[3,4-a]pyridine (8.3 g., 70 mmoles) dissolved in 125 ml. of ether was mixed with p-chlorophenacyl bromide (16.3 g., 70 mmoles) dissolved in 50 ml. of tetrahydrofuran and stirred at room temperature for 10 minutes at which time a gummy precipitate (approximately 2 g.) was separated by decantation. The decant was stirred for an additional 22 hours at room temperature, by which time product had precipitated heavily. Filtration with ether wash gave 2-(4-chlorobenzoylmethyl)imidazo[3,4-a]pyridinium bromide (16.8 g., m.p. 241°-243° C.).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][Cl:25]>CCO>[ClH:25].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: COc1cccc(CCl)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: COc1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Product: Cl
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-methoxybenzyl chloride (0.288 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 212 mg of the product 218. 1H NMR (DMSO-d6) δ 11.26 (s, 2H), 7.40 (t, 1H), 7.30-7.10 (m, 2H), 7.10-6.90 (m, 7H), 6.90-6.65 (m, 4H), 5.78 (s, 2H), 4.80 (s, 2H); MS: m/z 375 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(NC(=O)c2ccc(CN3C(=O)C4(COc5cc6c(cc54)CCO6)c4ccccc43)cc2)c(C)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,4-dimethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (59%) as a colorless solid: mp 249-251° C.; 1H NMR (300 MHz, CDCl3) δ7.91-7.83 (m, 2H), 7.76-7.69 (m, 1H), 7.56 (s, 1H), 7.50-7.43 (m, 2H), 7.28-7.17 (m, 2H), 7.09-7.01 (m, 3H), 6.80-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 165.2, 161.9, 161.3, 141.7, 139.6, 135.3, 134.6, 132.9, 132.6, 131.2, 129.8, 128.7, 127.7, 127.4, 124.0, 123.6 (2C), 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0, 20.9, 17.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:15]=1[C:16]1[C:17]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([C:27]([OH:29])=[O:28])[N:19]=[CH:20][C:21]=1[NH:22]2>O1CCCC1>[N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:15]=1[C:16]1[C:17]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([C:27]([OH:29])=[O:28])[N:19]=[CH:20][C:21]=1[NH:22]2
Reactant: c1c[nH]cn1
Agent: COCCOCc1c(C(=O)O)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: c1c[n-]cn1
Reaction time: 8 h

Procedure:
1.5 g (0.0022 mol) of imidazole in 20 ml of tetrahydrofuran is mixed with 0.4 ml (0.0054 mol) of thionylchloride dissolved in 5 ml of tetrahydrofuran. The precipitate is suctioned off, the filtrate is instilled in a suspension of 0.693 g (0.00163 mol) of 5-(2-chlorobenzyl)-4-methoxyethoxymethyl-β-carboline-3-carboxylic acid in 30 ml of tetrahydrofuran. After it is left standing overnight the solvent is distilled off, the residue is dissolved in ethyl acetate, the solution is washed imidazole free with water. After concentration by evaporation 0.55 g (71% of theory) of 5-(2-chlorobenzyl)-4-methoxyethoxymethyl-β-carboline-3-carboxylic acid imidazolide remains.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:26]1[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]1.[Cl:33]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[ClH:33].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: COc1ccc(S(=O)(=O)N2CCCc3ccc(C(F)(F)F)cc32)cc1N1CCN(C)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCCc3ccc(C(F)(F)F)cc32)cc1N1CCNCC1
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline (E8) (70 mg, 0.15 mmol) and 1-chloro-ethyl chloroformate (0.08 ml, 0.75 mmol) in 1,2-dichloroethane (2 ml) was heated under reflux for 18 h, and then was cooled to ambient temperature. N,N-Diisopropylethylamine (0.05 ml, 0.26 mmol) was added and the resulting solution was heated under reflux for 2 h. The solvent was removed, the residue was dissolved in methanol (4 ml), and the reaction was heated under reflux for 18 h. The solvent was partially removed, dichloromethane (20 ml) was added, and the solution was washed with saturated aqueous sodium hydrogen carbonate (10 ml), dried (MgSO4), and then evaporated. The residue was purified by column chromatography on silica gel eluting with a methanol-dichloromethane gradient to afford the sulfonamide derivative as a yellowish oil. The oil was dissolved in acetone (0.5 ml) and 1M solution of hydrogen chloride in diethyl ether (0.1 ml) was added. The solution was evaporated, and the residue was coevaporated with dry benzene (3×2 ml) to give the title compound (E25) as a cream solid (38 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])=[CH:36][C:35]=1[CH3:45]>C(Cl)Cl>[C:41]([C:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:35]([CH3:45])[CH:36]=1)([CH3:44])[CH3:43])#[N:42]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1cc(C(C)(C)C#N)ccc1CN
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)(C)C#N)ccc1CNC(=O)Cn1cnc2ccc(F)c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
(6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (91 mg, 0.43 mmol) prepared according to scheme 2 is dissolved in DCM (3 mL). DIPEA (0.1 mL) is added, followed by pivaloyl chloride (53 μL, 0.43 mmol). After 1 hour, 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (80 mg, 0.43 mmol) prepared according to scheme 19 is added. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 30% to 50% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (59 mg, 0.15 mmol, 35%). MS (ESI) (M+1) 369.2. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67 (s, 6H) 4.33 (d, J=5.86 Hz, 2H) 5.10 (s, 2H) 7.23 (ddd, J=11.62, 8.89, 7.62 Hz, 1H) 7.32 (d, J=8.59 Hz, 2H) 7.44-7.51 (m, 3H) 8.21 (s, 1H) 8.80 (t, J=5.86 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:28]([OH:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CC=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.25 h

Procedure:
A solution of 6.0 g (16.3 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 250 ml diethyl ether was cooled to −100 deg C. and treated with 11.9 ml (17.9 mmol) tert-butyllithium (1.5 M in n-pentane). After 15 min, 1.0 ml (0.79 g, 17.9 mmol) acetaldehyde was added and the reaction was stirred for 40 min at the same temperature. After warming to −75 deg C. the reaction mixture was poured onto 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (2:3) as eluant to afford a first batch of compound. The remaining product-containing fractions were pooled and chromatographed again to yield a second batch of compound (56.9% total).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15]C.Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:31][CH2:33]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96–0.99, 1.58, 1.81, 2.26, 2.85, 3.14, 3.26, 4.86, 5.44, 5.63, 7.26–7.50; MS (ESI+) for C23H21Cl2N3O m/z 426 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:17]=[CH:16][C:15]=3[OH:32])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:33][O:32][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:19][C:14]=1[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH:11]2[CH2:13][CH:8]1[CH2:9][CH2:10]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a solution of 1b (200 mg, 0.47 mmol) in DMF (4 mL) was added cesium carbonate (186 mg, 0.57 mmol) followed by methyl iodide (35.0 μL, 0.57 mmol). The mixture was stirred at room temperature for 18 h, diluted with water (20 mL) and extracted three times with EtOAc. The combined organic extracts were washed three times with water, dried (MgSO4) and concentrated. The residue (210 mg) was triturated with a 1:1 mixture of hexane/ether to provide 1c as a solid (113 mg), m.p. 138-139° C.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]([NH2:12])=[S:11]>>[C:3]([C:2]1[S:11][CH:10]=[N:12][CH:8]=1)([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NC=S
Reactant: CCOC(=O)C(Cl)C=O
Product: CCOC(=O)c1cncs1
Yield: 33 %

Procedure:
According to the procedure of Mashraqui and Keehn (J. Am. Chem. Soc. 1982, log, 4461), ethyl α-chloro-α-formylacetate was condensed with thioformamide and vacuum distilled to provide 5.65 g (33%) of the desired compound.