Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12](N1CCOCC1)=[O:13].C([Mg]Cl)(C)C.[Br:25][C:26]1[CH:42]=[CH:41][C:40](I)=[CH:39][C:27]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1>C1COCC1>[Br:25][C:26]1[CH:42]=[CH:41][C:40]([C:12]([C@@H:3]2[O:4][C@H:5]3[O:6][C:7]([CH3:10])([CH3:11])[O:8][C@H:9]3[C@@H:2]2[OH:1])=[O:13])=[CH:39][C:27]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reactant: Brc1ccc(I)cc1Cc1ccc2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)c3ccc(Br)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Temperature: 0 °C
Yield: 6.6 %

Procedure:
Step-V: To a cooled solution of ((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanone (11.05 g, 256 mmol) in THF (200 ml) was added 2.0 M solution of isopropylmagnesium chloride (12.78 ml, 256 mmol) under stirring at 0° C. and stirred for additional 1.5 h. To this was added a solution of 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (4.0 g, 146 mmol) in THF (50 ml) at 0° C. and then stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride solution and extracted with ethyl acetate (200 ml×3). Combined organic layers were washed with brine (500 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 4.7 g of [4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-methanone. 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 3H), 1.53 (s, 3H), 2.92 (d, J=4.0 Hz, 1H), 4.04 (d, J=3.6 Hz, 2H), 4.23 (s, 4H), 4.54 (br s, 1H), 4.56 (d, J=3.6 Hz, 1H), 5.21 (d, J=2.8 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H), 6.67 (s, 2H), 6.79 (d, J=9.2 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.75-7.77 (m, 2H). MS (ES) m/z 490.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CCC(CC(=O)OC)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC(=O)OC)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of 3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-pentanoic acid methyl ester (50 mg, 0.18 mmol) (prepared according to example 2, steps 1-2) in DMF (10 mL) are added 3-bromomethyl-4,6-dimethyl-1,2-benzisothiazole (70 mg, 0.271 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature under a nitrogen atmosphere. The solution is heated at 100° C. for 2 hours. The solution is cooled down and water is added. The solution is extracted with EtOAc and the combined organic layer is dried with MgSO4. The solution is filtered and the filtrate is concentrated. The residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford 3-[1-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (65 mg, 80%) as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH:7]([N:9]1[C:13](=[O:14])[O:12][N:11]=[C:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]1[CH:49]=[CH:48][C:24]([C:25]([N:27]([C:41]2[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)=[O:26])=[CH:23][CH:22]=1)[CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:4](=[O:5])([O:6][CH:7]([N:9]1[C:13](=[O:14])[O:12][N:11]=[C:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([C:25](=[O:26])[N:27]([C:41]2[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:48][CH:49]=1)[CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)OC(C)n1c(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnn2C)noc1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)OC(C)n1c(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCNC4)cc3)cnn2C)noc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
tert-butyl (3R)-3-[{4-[5-(4-{1-[(ethoxycarbonyl)oxy]ethyl}-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (52 mg, 0.08 mmol) was dissolved in DCM (5 mL) and to the solution was added HCl in dioxane (0.5 mL, 4M solution, 2 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was triturated in diethyl ether to yield ethyl 1-{3-[1-methyl-4-(4-{(3-methylpyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1H-pyrazol-5-yl]-5-oxo-1,2,4-oxadiazol-4(5H)-yl}ethyl carbonate as a light yellow solid (40 mg, 80%).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1cccc(N)n1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 60° and 66° C., to a solution of 2-amino-6-picoline (2.2 g) and triethylamine (4.05 g) in dioxane (130 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc) and the solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (5.6 g) is thereby obtained, which is dissolved in boiling acetonitrile (60 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and then twice with diethyl ether (50 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.5 g) in the form of beige-coloured crystals, m.p. 162° C., is thereby obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:54][CH2:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Reactant: NCCCN1CCOCC1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCOCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (25 mg, 0.06 mmol), triethylamine (0.017 mL, 0.12 mmol), and catalytic DMAP in 1.1 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.043 mL, 0.072 mmol). After 5 min at rt, 3-morpholinopropylamine (0.011 mL, 0.072 mmol) was added and the reaction stirred at rt for 1.5 hours. The reaction was partitioned between EtOAc and brine/aqueous NaHCO3 solution, the EtOAc layer washed with brine/aqueous NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/MeOH to give the title compound as an off-white solid (17 mg, 54%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.83-7.92 (m, 2H), 7.54 (d, J=4.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.34-7.41 (m, 1H), 7.20-7.33 (m, 2H), 7.13 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 4.50 (s, 2H), 3.52-3.63 (m, 8H), 3.23 (t, J=5.7 Hz, 2H), 2.87-2.98 (m, 1H), 2.56 (t, J=6.0 Hz, 2H), 2.47 (br. s., 4H), 1.75-1.85 (m, 2H), 1.27 (d, J=7.0 Hz, 6H)
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2cccc(F)c2)c(-c2ccccc2)n1
Yield: 23.2 %

Procedure:
6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (78 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-fluoro phenol (0.27 g, 2.39 mmol) according to the general procedure of Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[F:17][B-](F)(F)F.F[N+]1C(Cl)=CC=CC=1Cl>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: ClCCl
Product: CCOC(=O)c1oc2ccc(F)c(O)c2c1C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Joseph G. Atkinson et al., European patent application 0146243 (1985)) (700 mg) in dichloromethane (20 ml) was added 1-fluoro-2,6-dichloropyridinium tetrafluoroborate (807 mg) at room temperature and the mixture was stirred overnight. The reaction was quenched by the addition of water (10 ml), extracted with ethyl acetate (20 ml), washed with brine and dried over anhydrous magnesium sulfate. The mixture was separated by silica gel column chromatography developed by dichloromethane and methanol. 5-fluoro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (210 mg) was obtained as a white solid. EI-MS: m/z 238 (MH+); 1H-NMR (CDCl3): δ 1.50 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.46 (2H, q, J=7.3 Hz), 6.99 (1H, dd, J=3.3 Hz, 8.9 Hz), 7.15 (1H, dd, J=8.9 Hz, 10.6 Hz). And 7-fluoro-4-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained as a colorless oil. EI-MS: m/z 238 (MH+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7.3 Hz), 2.76 (3H, s), 4.46 (2H, q, J=7.3 Hz), 6.47 (1H, dd, J=3.0 Hz, 8.6 Hz), 6.97 (1H, dd, J=8.6 Hz, 10.2 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH2:14][CH2:15][OH:16]>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH2:15][CH2:14][CH2:13][O:4]1
Reactant: OCCCO
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCCCO2)c1
Reaction time: 5 h

Procedure:
A mixture of 18.3 g [0.1 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 15.2 g [0.2 mol] of trimethylene glycol, 1.9 g [0.01 mol] of p-TsOH hydrate and 150 ml of xylene is heated to boiling with a water trap for about 5 hours. Part of the xylene is then distilled off, and the reaction mixture is extracted at room temperature with 30 ml of saturated aqueous NaCl solution and twice with 100 ml of water each time. The organic phase is dried over sodium sulfate and concentrated in vacuo, and all volatiles are distilled off up to about 87° C. under 0.25 mbar. 22.9 g of residue remain with, according to GC, 83.9% product (79.8% of theory).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30](Cl)[CH:29]=[CH:28][C:27]=4[F:33])=[N:24][CH:23]=[CH:22][N:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1B1OC(C)(C)C(C)(C)O1)[C:41]([O:43][CH3:44])=[O:42].C([O-])([O-])=O.[K+].[K+].C1COCC1>CC#N.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([C:47]5[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:38]=5[CH3:37])[CH:29]=[CH:28][C:27]=4[F:33])=[N:24][CH:23]=[CH:22][N:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1-c1cc(Cl)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(F)c(-c3nccnc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.5 h

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(5-chloro-2-fluorophenyl)pyrazin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (33 mg, 0.062 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 37, 14.39 mg, 0.052 mmol), 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (6.30 mg, 9.27 mmol), K2CO3 (0.155 mL, 0.309 mmol) and THF (1 mL) were sealed in a microwave vessel and subjected to microwave irradiation at 140° C. for 20 min. LCMS of aliquot indicated about 40% conversion. Microwave heating was resumed at 140° C. for an additional 30 min. LCMS of the aliquot indicated about 10% of remaining unreacted starting material. Microwave heating was resumed for an additional 12 min at 140° C. The resulting crude material was diluted with MeCN and filtered. The filtrate was purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min, 20 mL/min) to give a brown glass. The brown glass was further purified by preparative TLC (SiO2, 30% EtOAc/hexanes) to afford a colorless glass as the titled compound. LCMS calc.=647.17; found=648.38 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]#[C:11][Si](C)(C)C)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]#[CH:11])[CH3:2]
Reactant: CCc1nc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1CC

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 12.23 g (56 mmol) 6-ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 3.87 g (28 mmol) K2CO3 in 120 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 4.5 g (85%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25]CSC[CH2:21]1.CN(C)C=O>O>[CH3:21][N:20]([CH3:25])[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1
Reaction time: 5.5 h

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (10 g), thiomorpholine (10 g) and dimethylformamide (20 ml) was heated at 100° for 22 hours and then at 140° for 5.5 hours. The mixture was cooled and poured into water (220 ml). The resulting precipitate was collected and purified by high performance liquid chromatography on silica using dichloromethane:industrial methylated spirit:isopropanol 98.25:0.5:1.25 as the eluent. This gave the novel compound 7-dimethylamino-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 280°-283°.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1>[C:1]([N:23]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: C1CCOC1
Product: O=C(c1ccncc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 50 h
Yield: 42.6 %

Procedure:
2.7 g (21.0 millimoles) of isonicotinic acid are added to 800 ml of absolute tetrahydrofuran, 4.2 g (25.9 millimoles) of N,N'-carbonyl-diimidazole are introduced and the mixture is refluxed for 2 hours. When it has cooled, a solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is added and the batch is stirred for 50 hours at room temperature. It is then freed from solvent on a rotary evaporator, the oily residue is taken up in 500 ml of tetrahydrofuran and the solution is added dropwise, with stirring, to 1.5 liters of 0.1% strength sodium bicarbonate solution. The crystals obtained (6.5 g) are recrystallized once from a 100:140 isopropanol/petroleum ether mixture and once from pure isopropanol. 3.0 g of pure 1-isonicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained, melting point 82.5°-83.5° C. (the product contains 0.5 mole of isopropanol of crystallization).
Reaction SMILES: I.[CH3:2][N:3]([CH2:8][CH2:9][S:10][CH3:11])[CH:4](SC)[CH3:5].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C@@H:18]([OH:39])[C@@H:19]2[NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[CH:27][C:26]=2[F:38])=[O:24])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:11][S:10][CH2:9][CH2:8][N:3]([CH3:2])[C:4](=[N:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C@@H:18]([OH:39])[C@@H:19]2[NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[CH:27][C:26]=2[F:38])=[O:24])=[CH:15][CH:14]=1)[CH3:5]
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3F)cc1F)[C@H](O)C2
Reactant: CSCCN(C)C(C)SC
Agent: I
Solvent: c1ccncc1
Product: CSCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3F)cc1F)[C@H](O)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 22.5 %

Procedure:
Dissolve the crude HI salt of methyl-(2-methylsulfanylethyl)(1-methylsulfanylethyl)amine (90.1 mg, 0.295 mmol) and 3,2′-difluorobiphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (101.3 mg, 0.266 mmol) in 10 mL pyridine. Allow the reaction to stir at 25° C. for 21 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 91.5 mg of crude product. Purify via silica gel column chromatography (2% MeOH/CHCl3 to 5% MeOH/CHCl3) to afford 30.5 mg of the titled product (22% yield). MS (ES): m/z 510.1(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:37])[F:36])[C:26]=2[Cl:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-chloro-3-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 522.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CCCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (250 mg) is dissolved in ethanol (4 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylamino]-heptanoic acid (131 mg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid (131 mg) is dissolved in ethanol (1 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (178 μl), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid sodium salt (133 mg). MS (m/z): 734 [M−Na]−