Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:32][C:33](=O)[CH2:34][C:35]1[NH:39][CH:38]=[N:37][N:36]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:33](=[O:32])[CH2:34][C:35]1[NH:36][N:37]=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3ncn[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 0.7 %

Procedure:
Prepared using the same procedure described in Example 275 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a colorless solid (0.9 mg, 0.7%). LC/MS (Method B) 3.32 min, [M+1]+ 511.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6](=[O:30])[CH:7]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 1.19 g (2.6 mmol) trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester in 20 ml of anhydrous THF was cooled to −78° and treated dropwise with a 1M solution of lithium bis-(trimethylsilyl)-amide in THF (6.2 ml, 2.5 eq). The mixture was allowed to reach RT within ca. 1 h and cooled again to −78°. A solution of 0.18 ml (2.9 mmol, 1.1 eq) of iodomethane in 2.5 ml of THF was added and the mixture allowed reach RT within ca. 1 h. After addition of ice, the mixture was extracted with EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 600 mg (49%) of trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid tert-butyl ester as a colorless solid, MS: 483 (M+NH4+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(CCO)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-ethyl-pyridine-2-yl)-ethanol (25.34 g) and triethylamine (46.7 mL) in DCM (130 mL) at 0° C. under nitrogen was added methane sulfonyl chloride (15.56 mL), then the reaction mixture was allowed to warm to room temperature and stirred overnight. A further portion of methane sulfonyl chloride (3.88 mL) was added and the reaction stirred for 30 min. The reaction was diluted with DCM and washed with H2O and brine. The organic layer was dried (MgSO4) and the solution concentrated to give the title compound as a red oil (38.24 g). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J=2.2 Hz, 1H), 7.47 (dd, J=7.7, 2.3 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 4.64 (t, J=6.5 Hz, 2H), 3.19 (t, J=6.5 Hz, 2H), 2.90 (s, 3H), 2.64 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH2:23]>>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride Sigma), the title compound was prepared as a solid (mp=191-193° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:20][N:21](C)[CH:22]=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([N:21]([CH3:22])[CH3:20])=[O:8]
Reactant: O=C(O)c1cc(I)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(I)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Iodo-2-nitrobenzoic acid (15.5 g) was dissolved in chloroform (30 mL). Oxalyl chloride (13.4 g) was added thereto at 0° C., and then DMF (dimethylformamide) (0.1 mL) was further added. The mixture was stirred at room temperature for 2 hours, and then concentrated. After addition of toluene to the residue, the mixture was further concentrated. A solution of the concentrated residue in ethyl acetate (60 mL) was added dropwise to a mixed solution of 50% (w/w) aqueous dimethylamine (7.5 mL) saturated aqueous sodium bicarbonate (60 mL), and toluene (60 mL) under stirring and ice-cooling. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and concentrated to give the title compound (15.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)[Br:20]>C(O)(=O)C.O>[Br:20][CH2:19][CH:21]([OH:23])[CH2:22][NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][CH2:22][CH:21]([OH:23])[CH2:19][Br:20])=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CBr)ccc(NCC(O)CBr)c21
Temperature: 80 °C
Yield: 209.3 %

Procedure:
1,4-Diaminoanthraquinone (2,5 g, 10.49 mmole) was slurried in 20 ml of glacial acetic acid. Water (1.8 ml) was added, followed by epibromohydrin (0.76 ml, 8.88 mmol). The mixture was heated to 80° C. The remaining epibromohydrin (2.24 ml, 26.18 mmol) was dripped in slowly during 5 hours, while the reaction temperature was held at 80° C. After the addition was complete, the 80° C. temperature was maintained for an additional 2 hours for a total of 7 hours. The reaction mixture was diluted with 20 ml of acetic acid and 28 ml of water. After stirring for a few minutes, the resultant mixture was filtered and the filter-cake was rinsed with 20% aqueous acetic acid followed by water, then air dried. After further drying in vacuo over P2O5, 4.76 g of 1,4-bis(3-bromo-2-hydroxypropylamino)-9,10-anthracenedione was obtained.
Reaction SMILES: O[CH2:2][C:3]1([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[O:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:11]2[C:10]([C:9]3[O:23][CH2:2][C:3]4([CH2:4][CH2:5][CH2:6][CH2:7]4)[N:8]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:18]=1
Reactant: O=C(NC1(CO)CCCC1)c1cccnc1Oc1cccnc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1cncc(Oc2ncccc2C2=NC3(CCCC3)CO2)c1
Yield: 49.4 %

Procedure:
A solution of N-(1-Hydroxymethyl-cyclopentyl)-2-(pyridin-3-yloxy)-nicotinamide (0.045 grams, 0.144 mmole) and phosphorus oxychloride in toluene (5 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate was added. The mixture was concentrated to give a crude product that was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil (0.021 g). HRMS 296.1417; 1H NMR (400 mhz, CDCl3) d 1.65-1.74 (m, 4H), 1.86-1.91 (m, 2H), 1.96-2.03 (m, 2H), 4.25 (s, 2H), 7.08 (dd, J=7.5 Hz, 5.0 Hz, 1H), 7.32 (dd, J=8.3 Hz, 4.8 Hz, 1H), 7.51-7.54 (m, 1H), 8.15-8.22 (m, 2H), 8.43-8.50 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].Br[CH:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].C(N(CC)CC)C>O1CCCC1>[OH:11][CH2:12][CH2:13][CH:8]1[N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:9]1=[O:10]
Reactant: O=C1OCCC1Br
Reactant: CNCCNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C)C(CCO)C1=O

Procedure:
The mixture of sym. dimethylethylenediamine (1 eq, 53 g), bromobutyrolactone (1 eq, 100 g) and triethylamine (1 eq, 120 ml) in 1000 mL of tetrahydrofuran was refluxed overnight. The crude precipitate was filtered and thoroughly washed with diethyl ether. The ether was evaporated and the residue was purified by elution through a silica gel column using 2% (v/v) methanol in chloroform to obtain the title compound. A small sample was converted into a picrate and crystallized from methanol to obtain the picrate salt of the title compound: mp 157°-159° C.; IR (KBr) 3220, 1650, 1565 and 1330 cm-1 ; UV max (MeOH) 353 nm (ε 18090); and NMR (DMSO-d6) δ 2.1 (m, 2H), 2.9 and 2.93 (singlets, 6H), 3.5 (m, 6H), 3.95 (m, 1H), and 8.55 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:26]([F:29])([F:28])[F:27])[C:6]=1[CH3:30].[OH-].[Na+]>CO.C1COCC1>[CH2:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]2[CH3:30])=[C:16]([C:26]([F:28])([F:29])[F:27])[CH:17]=1)(=[O:23])=[O:22])[CH3:25]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of [1-(4-ethanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.6 g, 1.32 mmol) in methanol/THF (8 ml of a 1:1 mixture) is added 1M NaOH (3 ml). After stirring at room temperature for 1.5 hours, the solvent is removed in vacuo and the residue is dissolved in water (3 ml). The solution is acidified to pH1 using 6M HCl and the resulting suspension is filtered and dried to yield the titled product. (MH+ 441)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)=[N:7]1.C1C[O:29][CH2:28]C1>>[O:12]=[C:11]1[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]3[NH:25][C:28](=[O:29])[NH:1][C:2]=3[CH:3]=2)[N:7]=[C:8]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[CH:9]=[CH:10]1
Reactant: C1CCOC1
Reactant: Nc1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)cc1N
Product: O=c1[nH]c2ccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 g (2.89 mmol) of 2-(3,4-diaminobenzyl)-6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one are dissolved in 10 ml of THF, 702 mg (4.33 mmol) of 1,1″-carbonyldiimidazole (CDI) are added, and the mixture is stirred at room temperature. After 15 h, the precipitate formed is filtered off with suction, washed with THF and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([O:19]CC)=O)[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[NH3:22]>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([NH2:22])=[O:19])[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: N
Reactant: CCOC(=O)c1nc(-c2cc(Cl)c(OC)c(OC)c2)cs1
Solvent: OCCO
Product: COc1cc(-c2csc(C(N)=O)n2)cc(Cl)c1OC

Procedure:
A solution of ethyl 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxylate (21.8 g) in 1,2-ethanediol (150 ml) at 120° C. was treated with ammonia gas for 25 min. The mixture was cooled in an ice-bath and the resultant suspension was filtered, washed with methanol, and dried at 60° C. under vacuum to give 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxamide (18.7 g), m.p. 178°-180° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][NH:12][C:11](=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[N:19]=1>O1CCCC1>[Br:17][C:18]1[N:19]=[C:20]([CH2:24][N:12]2[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11]2=[O:14])[CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(Cc2cccc(Br)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}pyrrolidin-2-one (1.08 g, 5.02 mmol) was dissolved in tetrahydrofuran (21.13 mL) and cooled to 0° C. Sodium hydride (0.23 g, 5.86 mmol) was added and the solution was allowed to stir for 15 minutes. In a separate flask, 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.05 g, 4.18 mmol) was dissolved in THF (10.57 mL) and cooled to 0° C., and added dropwise to the reaction mixture. The solution was stirred for 15 minutes at 0° C. and then at room temperature. The reaction mixture was quenched with water, and the product extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12]C(=O)C)[C:9]=1[Cl:10])=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])([OH:4])=[O:2]
Reactant: COC(=O)c1scc(COC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1scc(CO)c1Cl
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene (83 g, 0.33 mol) in 1,4-dioxane (350 mL) was added a solution of sodium hydroxide (26.5 g, 0.66 mol) in water (200 mL) and the mixture stirred at ambient temperature. After 1 hour the dioxane was removed in vacuo and the aqueous solution washed with ethyl acetate (2×1 00 mL). The aqueous layer was brought to pH 2 by addition of concentrated HCl, then extracted with n-butanol (4×200 mL). The combined extracts were concentrated and the resulting solid dried in vacuo to afford 63 g (90% yield) of 2-carboxy-3-chloro-4-(hydroxymethyl)thiophene as a tan powder; NMR (DMSO-d6) 7.7 (s, 1), 4.4 (s, 2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=3)[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCC3)CC2)c1

Procedure:
Example 38 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.52 (s, 1H), 7.45–7.36 (m, 1H), 7.34–7.29 (m, 1H), 7.23 (t, 1H, J=8.0 Hz), 7.17–7.13 (m, 1H), 6.95–6.90 (m, 2H), 6.00–5.94 (m, 1H), 3.30 (q, 2H, J=6.4 Hz), 2.92–2.84 (m, 2H), 2.57–2.38 (m, 3H), 2.47–2.39 (m, 1H), 2.31 (t, 1H, J=7.2 Hz), 1.95–1.73 (m, 7H), 1.68–1.48 (m, 8H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][OH:17])=[N:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([OH:24])=[O:23].[H-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][O:17][CH2:21][C:22]([OH:24])=[O:23])=[N:8]2)=[CH:18][CH:19]=1
Reactant: O=C(O)CBr
Reactant: OCc1nn(Cc2ccc(F)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCc1nn(Cc2ccc(F)cc2)c2ccccc12
Temperature: 0 °C
Yield: 57.8 %

Procedure:
A suspension containing [1-(4-fluorobenzyl)-1H-indazol-3-yl]methanol (6 g; 0.022 mol), bromoacetic acid (4 g; 0.03 mol) and 50% NaH (3 g; 0.066 mol) in THF (170 ml) was stirred at reflux for 72 hours. The reaction was then stopped by diluting with a suspension with water and ice (300 ml) and washing the aqueous phase with diethyl ether (3×150 ml). The aqueous phase was acidified with concentrated HCl. The solid thus formed was filtered off and purified by crystallization from isopropanol. 4 g of {[1-(4-fluorobenzyl)-1H-indazol-3-yl]methoxy}acetic acid were thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 87.7 %

Procedure:
Ten grams of methyl 4-[2-(4-chlorobenzamido)ethoxy]benzoate was dissolved in 100 ml of hot ethanol. A solution of 2.4 g of sodium hydroxide in 20 ml of water was added to the above ethanolic solution and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated in vacuo, 100 ml of water was added to the residue, the mixture was neutralized with 10% hydrochloric acid, crystals separated out were collected by filtration, washed with water, dried and recrystallised from ethanol to give 8.4 g (yield: 87%) of crystalline product. M.p. 219°-220° C.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].Cl.[CH2:16](I)[CH3:17]>C(#N)C.O1CCOCC1>[CH2:16]([S:3][C:2](=[NH:4])[NH:1][C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: CCI
Reactant: CN(C)Cc1cccc(NC(N)=S)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCSC(=N)Nc1cccc(CN(C)C)c1
Yield: 18.6 %

Procedure:
To a solution of the compound (43.5 mg) obtained in Example 40 in acetonitrile (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4N, 0.1 ml) and ethyl iodide (50 mg) were added and heated under reflux for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride methanol=5:1) to give 9.2 mg of the titled compound (yield, 19%).
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[Se:10]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:21]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][Se:10](=[O:19])[C:14]=2[CH:15]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: O=[Se]1C=Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1ccc2c(c1)[Se](=O)C=N2
Temperature: 45 °C

Procedure:
9.9 ml (0.13 mol) of dimethylformamide are introduced dropwise and with stirring into a 250-ml flask containing 61.3 g (0.46 mol) of aluminum chloride, and the flask is fitted with a reflux condenser and heated in an oil bath to a temperature in the region of 45° C. 7.9 g (0.04 mol) of benzoselenazolinone and 10.6 g (0.06 mol) of nicotinoyl chloride hydrochloride are introduced.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([CH3:24])[CH2:22][NH2:23]>>[OH:20][CH:21]([CH3:24])[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CC(O)CN
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC(C)O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-hydroxy-propylamine to afford the title compound. MS: m/e=316 (M+H).
Reaction SMILES: [CH2:1](N)[CH2:2][NH2:3].Cl.C(O[C:9](=[NH:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:12]1[Cl:25])C>C(O)C.C(Cl)(Cl)Cl>[Cl:25][C:12]1[N:11]([CH2:10][C:9]2[NH:26][CH2:1][CH2:2][N:3]=2)[C:19]2[C:14]([C:13]=1[S:21]([CH3:24])(=[O:22])=[O:23])=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2
Reactant: NCCN
Reactant: CCOC(=N)Cn1c(Cl)c(S(C)(=O)=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1c(Cl)n(CC2=NCCN2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of ethylene diamine(0.065 g, 1.092 mmole) in ethanol:chloroform (30 ml, 1:1) at 0° C. under a nitrogen atmosphere was added 2-(2,5-dichloro-3-methanesulfonyl-indol-1-yl)-acetimidic acid ethyl ester hydrochloride (0.351 g, 0.91 mmole) dissolved in chloroform (5 ml). The reaction mixture was stirred at room temperature for 2 h and then evaporated to dryness. The residue was purified by column chromatography (silica gel) eluting the product with 7:93 methanol:methylene chloride with 0.1% ammonium hydroxide added. The resulting product, pure 2,5-dichloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indole weighed 0.314 g (99.7% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:30])([F:15])[F:29])=[CH:20][CH:21]=3)[CH2:26][CH3:27])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CCC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CCC(c1ccc(OCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (112 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (154 mg, 0.57 mmol, Amine-18, single enantiomer) in a similar manner to Intermediate-2.