Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([CH3:17])[C:10]2=[O:18])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[N+](=[CH2:25])=[N-].[Na+].[Cl-]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14]([O:16][CH3:25])=[O:15])[CH2:12][N:11]([CH3:17])[C:10]2=[O:18])=[CH:5][C:4]=1[C:19]([F:21])([F:22])[F:20])#[N:2]
Reactant: CN1C[C@H](C(=O)O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: C=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a solution of (R)-3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylic acid (25e) (0.280 g, 0.894 mmol) in THF (10 mL), cooled to 0° C., Diazomethane [prepared from N-Nitrosomethyl urea (0.276 g, 2.68 mmol) and 40% KOH solution (15 mL) in ether (10 mL)] was added under nitrogen atmosphere. The resulting reaction mixture was warmed up to room temperature and stirred for 1 h. After completion (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to afford the methyl ester 25f (0.210 g, 72%) as a colorless syrup.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[O:18][CH3:19])=[O:4].O.[Li+].[OH-]>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:18][CH3:19])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(Cl)cc2)ccc1C(=O)O
Yield: 91 %

Procedure:
To a solution of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester, 8, (0.615 g, 2.22 mmol) in THF (20 mL) and H2O (5 mL) at room temperature is added LiOH (0.932 g, 22.2 mmol). The resulting suspension is heated to reflux for 2 hours. The reaction is cooled and concentrated under reduced pressure. The crude product is acidified using conc. HCl and the resulting solid is collected by filtration washed with H2O and dried to afford 0.532 g (91%) of the desired product as a grey solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (1H, br s), 8.26 (1H, d, J=8.1 Hz), 7.53-7.58 (2H, m), 7.44-7.50 (2H, m), 7.33 (1H, dd, J=8.1, 1.6 Hz), 7.20 (1H, d, J=1.3 Hz), 4.17 (3H, s). HPLC-MS: m/z 263 [M+H]+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Br[C:12]1[C:13](=[O:25])[N:14]([C:18]([CH:22]([CH3:24])[CH3:23])([CH3:21])[C:19]#[N:20])[C:15](=[O:17])[CH:16]=1.C(O)(C)C.C([O-])(=O)C.[Na+]>CCOCC>[C:19]([C:18]([N:14]1[C:13](=[O:25])[CH:12]=[C:16]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])[C:15]1=[O:17])([CH3:21])[CH:22]([CH3:23])[CH3:24])#[N:20]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.5 %

Procedure:
A mixture of anthranilic acid, (13.7 g, 0.1 mol), 3-bromo-α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (27 g, 0.1 mol), isopropanol (200 ml) and sodium acetate (8.2 g) is stirred at room temperature 3 days and then is heated at reflux 1 hour. On cooling, and with the addition of ether, a yellow solid 31.6 g, (19.7%) is obtained, mp 262°-266° C. after crystallizing from acetic acid. Anal. calcd. for C17H17N3O4 : C, 62.37; H, 5.24; N, 12.84. Found: C, 62.24; H, 5.19; N, 12.70.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[ClH:28].[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCCCN3CCCCC3)ccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc2c(cc1OCCCN1CCCCC1)CCNC2

Procedure:
To a round-bottom flask, equipped with stir bar and septum, is placed 6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1 g, 2.6 mmol), DCM (20 mL) and 4M HCl/dioxane (5 mL). The reaction is allowed to stir at room temperature for 3 h. After this time, the reaction is concentrated, dissolved in MeOH and concentrated again affording 6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride as a white solid (800 mg, 87%). Mass spec hit M+1, 275; LCMS>95% @ 230 nm and ELSD.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfinyl-6-phenyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+]>O1CCOCC1>[CH3:13][C:4]1[CH:3]=[C:2]([O:1][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:7]([CH3:8])=[CH:6][C:5]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C)c(O)cc1C
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C)c(OCCN2CCOCC2)cc1C
Yield: 89 %

Procedure:
To a suspension of N-(4-hydroxy-2,5-dimethyl-phenyl)-acetamide (8.0 g, 44.6 mmol) and 4-(2-chloro-ethyl)-morpholine hydochloride (9.97 g, 53.6 mmol) in 50 mL of dioxane was added a solution of NaOH (4.29 g in 50 mL of water). The mixture was refluxed for 2 h and evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2 and washed with 0.5 N NaOH. The organic phase was dried (Na2SO4), evaporated, and crystallized from CH2Cl2-hexane to give N-[2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide as gray solid (11.6 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.NN>[Ni].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Raney Nickel (60 mg, 20% wt) was added portionwise to a solution of 6-methoxy-8-nitroquinoline (300 mg, 1.40 mmol) in MeOH (10 ml), under argon. Hydrazine hydrate (270 μl, 5.6 mmol) was added and the reaction stirred at room temperature for 1 h. The mixture was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo, re-dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (250 mg, 100%) which was used in the next step without purification.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([OH:9])(=[O:8])[CH:6]=[O:7]>CC(C)=O>[C:1]([NH:4][CH:6]([OH:7])[C:5]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CC(N)=O
Solvent: CC(C)=O
Product: CC(=O)NC(O)C(=O)O

Procedure:
A mixture of commercially available acetamide 34 and glyoxylic acid 41 was heated at reflux in acetone to give pure N-acetyl-2-hydroxyglycine 42 as a viscous yellow oil in quantitative yield. The 1H n.m.r. spectrum supported formation of the α-hydroxyglycine derivative 42 with the appearance of a methine (H2) doublet and broad amide (NH) doublet at δ 5.39 and δ 8.65 respectively. Spectroscopic data were in agreement with those reported in the literature.195
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:30](=[O:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Product: O=C(COc1ccc(Cl)cc1)N1CCN(c2ncnc3sc(-c4ccc(F)cc4)nc23)CC1
Yield: 48 %

Procedure:
This compound was prepared from 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>O>[N:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc(N2CCNCC2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-methoxypyridine (20 g) and piperazine (32.9 g) with potassium carbonate (20.1 g) in water (50 ml) is stirred at 100° for 24 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is dissolved in ether. The organic phase is extracted with hydrochloric acid (10%). The aqueous phase is washed with ether, neutralized with sodium hydroxide (10%) and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated to give 2-piperazino-6-methoxypyridine. This material is stirred in acetonitrile (100 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (3.01 g) and potassium carbonate (1.3 g) at 20°-25° for 16 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed over silica gel (2% methanol in methylene chloride to 4%) to give the free base of the title compound which is 92% pure by HPLC. This material is dissolved in ethyl acetate and treated with methane sulfonic acid (0.606 g). The salt is filtered and recrystallized from methanol and ethyl acetate to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1C(O)=O)=O)[CH3:2].[CH3:27][S:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)(=[O:30])=[O:29]>C(OC(=O)C)(=O)C>[CH:20]([O:19][C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][N:7]3[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:26])=[C:35]([CH2:34][CH2:33][CH2:32][O:31][S:28]([CH3:27])(=[O:29])=[O:30])[C:36]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[C:8]32)=[CH:13][C:12]=1[O:17][CH3:18])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(=O)N1CCc2cc(OC)c(OC(C)C)cc2C1C(=O)O
Reactant: CS(=O)(=O)OCCCC#Cc1cccs1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(CCCOS(C)(=O)=O)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Yield: 58.1 %

Procedure:
A solution of 280 mg of 6b and 165 mg of 2b in 6 ml of acetic anhydride was heated in a microwave oven for 15 min at 140° C. The reaction mixture was cooled and residual solvents were removed by sequential coevaporation with toluene. The residue was purified by chromatography on silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 215 mg of 6c; MS-ESI: [M+1] 548.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7]Br.[CH2:13]([NH2:16])[CH2:14][CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:16][CH2:13][CH2:14][CH3:15]
Reactant: CCCN
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Agent: Cl
Product: CCCNCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 34 from 2-(3,5-dichlorophenoxy)-1-bromoethane, n-propylamine and hydrogen chloride. The free base was obtained as an oil. The hydrochloride salt melted at 185°-186° C.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)([OH:36])=O.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[N:47]1([C:34]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41](=[O:46])[CH2:40]3)=[O:36])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
PyBOP (3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), morpholine (0.5 mL, 6.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 4 hours, the reaction was diluted with more dichloromethane, washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>C(#N)C>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:18][CH:20]1[CH2:21][O:22]1
Reactant: BrCC1CO1
Reactant: CNC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)c1ccccc1OCC1CO1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
To a solution of 2-Hydroxy-N-methyl-benzamide (0.5 g, 3.31 mmol prepared according to Cohen, Seth M et al J. Am. Chem. Soc., (1998), 120(25), 6277-6286.) and cesium carbonate (2.16 g, 6.62 mmol) in acetonitrile was added epibromohydrin (0.274 ml, 3.31 mmol). The mixture was heated at 50° C. for 2 hours and then after cooling to room temperature partitioned between water (50 ml) and dichloromethane (100 ml). The dichloromethane was dried and evaporated. Chromatography (EtOAc) gave 0.43 g (64%) of the product as a solid.
Reaction SMILES: CO.[OH-].[Na+].C([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[N:15][C:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH:34]5[CH2:36][CH2:35]5)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:18]=2)[C:9]1=[O:37])(=O)C>O>[CH:34]1([C:30]2[CH:31]=[C:32]([CH3:33])[C:27]([N:24]3[CH2:25][CH2:26][N:21]([C:19]([C:16]4[N:15]=[N:14][C:13]([N:10]5[CH2:11][CH2:12][NH:8][C:9]5=[O:37])=[CH:18][CH:17]=4)=[O:20])[CH2:22][CH2:23]3)=[N:28][CH:29]=2)[CH2:35][CH2:36]1
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nn2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)nn2)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-acetylimidazolidin-2-one (64 mg) and by the reaction and treatment in the same manner as in Example 511, 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one was obtained as a crude product (170 mg). Methanol (1.2 mL) and 1N aqueous sodium hydroxide solution (0.57 mL) were added to the obtained crude product (170 mg) of 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one, and the mixture was stirred at 40° C. for 1 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (48 mg).
Reaction SMILES: ClC1C=C(C=C(C)[C:8]=1[O:9]C1C=C2C(=CC=1)NC=C2C(C)C)N.[Cl:23][C:24]1[CH:25]=[C:26]([NH:44][C:45](=[O:51])[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:27]=[C:28]([CH3:43])[C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]([CH3:42])[CH3:41]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:44][C:45](=[O:51])[CH2:46][C:47]([O:49][CH2:50][CH2:8][OH:9])=[O:48])[CH:27]=[C:28]([CH3:43])[C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]([CH3:41])[CH3:42]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Product: Cc1cc(NC(=O)CC(=O)OCCO)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
This compound can be prepared starting from 3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylaniline (Example III) or methyl 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxo-propanoate (Example 4a) according to methods known from the literature.
Reaction SMILES: F[C:2]1[C:3](=[O:20])[N:4]([CH2:12][C:13]2[N:17]([CH3:18])[C:16](=[O:19])[NH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:21][CH:22]([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>O>[F:21][CH:22]([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][C:2]2[C:3](=[O:20])[N:4]([CH2:12][C:13]3[N:17]([CH3:18])[C:16](=[O:19])[NH:15][N:14]=3)[CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])[CH:30]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(O)cc(C(F)F)c1
Reactant: Cn1c(Cn2ccc(C(F)(F)F)c(F)c2=O)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(Cn2ccc(C(F)(F)F)c(Oc3cc(C#N)cc(C(F)F)c3)c2=O)n[nH]c1=O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluoro-1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)pyridin-2(1 H)-one (8-8; 30 mg; 0.103 mmol), 3-(difluoromethyl)-5-hydroxybenzonitrile (8-7; 34.7 mg; 0.205 mmol) and K2CO3 (28.4 mg; 0.205 mmol) was heated to 75° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with water and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by mass-directed HPLC provided 2.1 mg (0.0048 mmol; 4.6%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO): δ 11.70 (s, 1 H); 7.90 (d, J=7.3 Hz, 1 H); 7.80 (d, J=8.5 Hz, 2 H); 7.57 (s, 1 H); 7.05 (t, J=55.2 Hz, 1 H); 6.69 (d, J=7.3 Hz, 1 H); 5.17 (s, 2 H); 3.10 (s, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[CH:22][C:21]3[N:27]([CH3:42])[C:28](=[O:41])[N:29]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([CH3:40])([CH3:39])[C:37]#[N:38])=[CH:32][CH:31]=4)[C:20]=3[C:19]=2[CH:18]=1>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:36]([C:33]1[CH:32]=[CH:31][C:30]([N:29]2[C:20]3[C:19]4[CH:18]=[C:17]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH:26]=[CH:25][C:24]=4[N:23]=[CH:22][C:21]=3[N:27]([CH3:42])[C:28]2=[O:41])=[CH:35][CH:34]=1)([CH3:40])[C:37]#[N:38]
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4ccncc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
37 mg (0.3 mmol) of 4-pyridineboronic acid (Aldrich, Buchs, Switzerland), 8 mg of bis(triphenylphosphine)palladium (II) dichloride (Fluka, Buchs, Switzerland) and 0.5 ml of a 1 M solution of Na2CO3 are added to a solution of 84 mg (0.2 mmol) of 2-[4 (8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1i) in 2 ml of DMF. The mixture is stirred for 1 h at 100° C. After this time, the mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is loaded on silica gel and purified by flash chromatography (CH2Cl2-MeOH 97:3 to 18:1) to give the title compound as an off-white solid. ES-MS: 420 (M+H)+; analytical HPLC: tret=2.40 min (Grad 1).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)s1
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(4-methoxybenzoyl)thiophene-2-sulfonamide (5.48 g) and pyridine hydrochloride (50 g.) was heated to 200° C. for 0.5 hour. Water (400 mL) was added to the cooled reaction mixture and the solid collected by filtration. This solid was stirred with 1N hydrochloric acid (100 mL) for 0.5 hour, filtered, washed with water and dried at 70° C., 4.11 g, m.p. 183°-190° C. Treatment of this material with acetonitrile, followed by sodium bicarbonate solution then 3N hydrochloric acid, and recrystallization from water gave 1.70 g, m.p. 200°-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH3:16][Mg]Br>C1COCC1>[CH3:16][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Solvent: C1CCOC1
Product: Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 0 °C

Procedure:
A 270 mg (1 mmol) sample of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine, from Example 28 above, was dissolved in 10 mL of THF, 3.25 mg of Ni(dppp)Cl was added, and the mixture was cooled to 0° C. To this solution was added 0.47 mL of methylmagnesium bromide, then the mixture was stirred at reflux for 20 hours. Another 0.2 mL of methylmagnesium bromide was added, and the reaction mixture was stirred for 2 hours. The reaction was quenched by addition of NH4Cl solution, and the mixture was evaporated to dryness. The residue was partitioned between H2O and CHCl3, and the organic extract was dried and concentrated. The residue was purified by chromatography on silica gel, eluting with 5:1 chloroform:methanol, to give 120 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.13 (d, J=2.7 Hz, 1H), 8.05 (s, 1H), 7.03 (m, `H), 4.04-3.89 (m, 2H), 2.66 (m, 1H), 2.48 (s, 3H), 2.32 (s, 3H), 2.35-2.26 (m, 1H), 2.09-1.98 (m, 1H), 1.92-1.68 (m, 3H).