Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:30])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:7])=[C:4]([NH:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:3]=1.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1B(O)O)#[N:43].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:30])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:7])=[C:4]([NH:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:3]=1)#[N:43]
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCCC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(Cl)nc1NCCC1CCCCO1)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCCN2C(=O)CCCNC(=O)OCc2ccccc2)c(NCCC2CCCCO2)n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A mixture of benzyl 4-((R)-2-((6-chloro-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (62 mg, 0.101 mmol), 2-cyanophenyl boronic acid (23 mg, 0.156 mmol), PdCl2(dppf)2 (11 mg, 0.02 mmol), K2CO3(92 g, 0.667 mmol) and anhydrous DMF (1 mL) was stirred at 125° C. for 1 hr. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified on RP-HPLC using a mixture of acetonitrile and H2O to give benzyl 4-((R)-2-((6-(2-cyanophenyl)-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (50 mg, 77%). LRMS (M+H+) m/z 653.3.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9]
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1
Reactant: OCCO
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of n-butyllithium in hexanes (13.0 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (30 ml) at 10° C. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1-(2-methylphenyl)-1-phenyl-1-propene (9.3 g, 32 mmol) was added and the reaction mixture was stirred at room temperature for 100 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts was dried (Na2SO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and THF (4:1) as eluent provided 3.9 g (45%) of 2-(3-(2-methyl-phenyl)-3-phenyl-2-propen-1-yloxy)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(O)(C)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:22])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 90.7 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 200 mg of methyl 2-(2,4-diflurophenylamino)-5-fluoro-6-hydroxynicotinate, and thereto were added 110 mg of potassium carbonate and 0.11 g of methyl iodide at room temperature, after which the resulting mixture was subjected to reaction at the same temperature for 1 hour. To the reaction mixture were added 20 ml of water and 20 ml of ethyl acetate, and the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and then to the crystalline material thus obtained was added 5 ml of isopropyl alcohol, after which crystals were collected by filtration to obtain 190 mg (yield 90.7%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate. The physical properties of this compound were identical with those of the compound obtained in Example 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:7]1[C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:10][C:3]=2[C:4]([F:9])=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(F)ccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)ccc(F)c2N1
Yield: 93.6 %

Procedure:
2-Amino-3,6-diflourophenol (0.44 g, 3.0 mmol), 2-chloroacetyl chloride (0.38 g, 3.3 mmol) and K2CO3 (0.88 g, 6.4 mmol) were mixed according to GP1. Purified by extraction gave the title compound (0.52 g, 93%). Rf=0.57 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 8.02 (s, 1H), 7.78-6.69 (m, 2H), 4.72 (s, 2H); 13C NMR (CDCl3) d 163.7, 148.0 (dd, J=242.4 Hz, J=2.1 Hz), 145.9 (d, J=237.9 Hz), 132.9 (dd, J=16.7 Hz, J=4.4 Hz), 117.2 (dd, J=16.9 Hz, J=3.8 Hz), 110.2 (dd, J=20.5 Hz, J=8.6 Hz), 108.6 (dd, J=20.0 Hz, J=7.7 Hz), 67.4.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCCCCSC1=CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCSC1=CCCC1=O
Yield: 51.9 %

Procedure:
2-(5-Carbomethoxypentylthio)cyclopent-2-en-1-one (133 mg) was treated with 0.8 ml of a 3 N aqueous solution of sodium hydroxide in 5 ml of methanol and 2 ml of water at room temperature for 45 minutes. After the reaction, the reaction mixture was extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid, and extracted with diethyl ether. The extracts were treated in a customary manner to afford 125 mg of a crude product. The crude product was chromatographed on a thin layer plate with diethyl ether/isopropyl ether/acetic acid (=75/30/3) to afford 65 mg of 2-(5-carboxypentylthio)cyclopent-2-en-1-one in a yield of 49%. The product had the following characteristics.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=[NH:13])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23](=O)[C:24]([F:27])([F:26])[F:25]>CC#N.CCOC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11]2[NH:12][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[N:13]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 5.3 %

Procedure:
To a suspension of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester (488 mg, 2.45 mmol) and K2CO3 (676 mg, 4.90 mmol) in MeCN (14 mL) at 85° C. was added a solution of 3-Bromo-1,1,1-trifluoro-propan-2-one (400 mg, 2.09 mmol) in MeCN (10 mL) drop wise over 30 min. The dilute reaction mixture (0.1 N) was stirred at 85° C. for 3 h before cooled to room temperature. Diluted with EtOAc and extracted three times, washed with water and Brine. Dried over MgSO4, filtered and concentrated down in vacuo. The mixture was purified by reverse phase preparation HPLC to give 32 mg of [1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a yellow solid, m/z 292.42 [M+1]+
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.CC1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Agent: Cc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)NCCN(C)C)CC2)cc1
Yield: 47 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 1.9 g (0.01 mole) of 1,1'-carbonyldiimidazole, 1.0 g (0.01 mole) of unsym-dimethylethylenediamine, and 2.0 g (0.1 mole) of 1-(4-methylphenyl)piperazine in a total volume of 100 ml of tetrahydrofuran gave an oil which solidified. The solid was triturated with petroleum ether (30°-60° C.) to give 1.5 g (47%) of the title compound as a white solid, m.p. 85°-88° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([CH3:18])[C:5]=1[C:6]#[N:7])[CH3:2].N.S(=O)(=O)(O)[OH:21]>O>[CH2:1]([S:3][C:4]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:9]=[C:8]([CH3:18])[C:5]=1[C:6]([NH2:7])=[O:21])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCSc1cc(N2CCOCC2)cc(C)c1C#N
Agent: N
Solvent: O
Product: CCSc1cc(N2CCOCC2)cc(C)c1C(N)=O

Procedure:
A solution of 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzonitrile (0.30 g, 1.14 mmol) in concentrated sulfuric acid (15 ml) is stirred at 100° C. for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture is diluted with water (30 ml), basified with aqueous ammonia, and extracted with ethyl acetate (3×15 ml). The organic layer is washed with water (20 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzamide, which is used in the next step without further purification (0.26 g, 0.92 mmol, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][C:34]([CH3:37])([S@:32]([NH:31][C@:9]([C:4]1[CH:3]=[CH:2][C:7]([F:8])=[C:6](/[CH:40]=[CH:39]/[C:38]([O:42][CH3:43])=[O:41])[CH:5]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33])[CH3:35]
Reactant: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(Br)c1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc([C@@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of (R)—N—((S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide, prepared as described in Procedure 3, 62, 5 and 6, (500 mg, 0.82 mmol) in DMF (5 mL) at rt was added methyl acrylate (0.74 mL, 8.22 mmol), Pd2(dba)3 (75 mg, 0.082 mmol), tri-t-butyl phosphine (89 μL, 0.33 mmol), and cesium carbonate (536 mg, 1.64 mmol). The reaction mixture was degassed with argon and was heated at 100° C. for 4 h. The reaction mixture was poured into water and the aqueous phase extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO chromatography (4 g column, 0-40% EtOAc/hexane) to yield (E)-methyl 3-(5-((R)-1-((R)-1,1-dimethylethylsulfinamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-fluorophenyl)acrylate as a white foam (485 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=16.42 Hz, 1H), 7.59 (dd, J=6.69, 2.15 Hz, 1H), 7.41 (m, 1H), 7.16 (m, 4H), 6.94 (dd, J=7.33, 1.77 Hz, 2H), 6.86 (d, J=8.84 Hz, 1H), 6.73 (t, J=4.93 Hz, 2H), 6.53 (d, J=16.17 Hz, 1H), 5.88 (m, 1H), 4.29 (s, 1H), 4.03 (d, J=12.38 Hz, 1H), 3.79 (s, 3H), 3.62 (d, J=12.38 Hz, 1H), 1.24 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[C:20]1([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NC(c3ccccc3)c3ccccc3)cc2)n1
Yield: 8 %

Procedure:
Sulfamethazine (105 mg, 0.38 mmol) and diphenylchloromethane (77 μl, 0.38 mmol) were dissolved in 3 ml pyridine. Solution was stirred and refluxed overnight. The reaction mixture was evaporated to dryness and dissolved to 1 M NaOH. Product was precipitated with 1 M acetic acid. Precipitation cycle was repeated for three times to give white crystals of the title compound with a yield of 8%. MS (ESI+): m/z 467(M+Na)+, 445 (M+H)+.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[C:13]1(C)[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1.C1CCC=CC=1>C1(C)C=CC=CC=1>[CH:9]1[C:10]2[C:1]3[O:11][C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:2]=3[CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1cccc2ccccc12
Solvent: C1=CCCC=C1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)ccc1c3c(oc12)CCCC3
Temperature: 25 °C
Yield: 25 %

Procedure:
144 g of 1-naphthol, 190 g of p-toluenesulfonic acid monohydrate, 80.1 g of 1,3-cyclohexadiene and 4 L of toluene were placed in a flask. The resulting mixture was stirred under reflux for 24 hours. After cooling to room temperature, the reaction solution was washed with 600 mL of water. After drying an organic phase with magnesium sulfate, the solvent was distilled off under reduced pressure. Residues were purified by silica gel column chromatography, whereby 55.5 g (yield: 25%) of 7,8,9,10-tetrahydrobenzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[CH2:6][CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][S:13][CH2:12]2)[CH2:8][C:9]=1[OH:10])(=O)[CH3:2].[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][NH2:26])=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][N:26]=[C:1]([C:4]2[C:5](=[O:17])[CH2:6][CH:7]([CH:11]3[CH2:16][CH2:15][CH2:14][S:13][CH2:12]3)[CH2:8][C:9]=2[OH:10])[CH3:2])=[CH:21][CH:20]=1
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: NOCc1ccc(Cl)s1
Solvent: CCO
Product: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution containing 5.1 g (0.020 mol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)cyclohex-2-en-1-one and 3.4 g (0.021 mol) of (5-chlorothien-2-yl)methoxyamine in 200 ml of ethanol was stirred overnight (about 14 hours) at room temperature and then evaporated to remove ethanol. The concentrate was diluted with 150 ml of methylene chloride and then washed with 100 ml of water and then with 100 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure to afford a white solid. Recrystallation of this solid with absolute ethanol afforded 7.6 g of the title compound, m.p. 154°-155° C. cl EXAMPLE 2
Reaction SMILES: Cl.C(O[C@H](C)C([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH:22]([CH3:24])[CH3:23])=O)C1C=CC=CC=1.ClC1N=C(Cl)C=C(OC)N=1>C(O)C>[CH:22]([CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)([CH3:24])[CH3:23]
Reactant: CC(C)C1Cc2ccccc2N1C(=O)[C@@H](C)OCc1ccccc1
Agent: COc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CC(C)C1Cc2ccccc2N1
Temperature: 120 °C
Yield: 43.5 %

Procedure:
5.6 ml of concentrated hydrochloric acid are added to a solution of 1.2 g of (R)-2-benzyloxy-1-(2-isopropyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (2) in 34 ml of absolute ethanol. The reaction mixture is microwave-heated at 120° C. for 1 hour, and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of water and is then alkalinized with concentrated sodium hydroxide. The mixture is extracted with 2×120 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 30 g cartridge of 15-40 μm silica, elution being carried out with a 98/2 cyclohexane/ethyl acetate mixture, at a flow rate of 30 ml/min. 0.26 g of (+)-2-isopropylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:21]([OH:26])[OH:22])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 24 (31.4 g, 0.15 mol), n-butyllithium (15 cm3, 10.0M in hexanes, 0.15 mol) and triisopropyl borate (56.4 g, 0.3 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [C:1]12[C:9](=[O:10])[O:8][C:6](=[O:7])[C:2]=1[CH2:3][CH2:4][CH2:5]2.Cl.[CH3:12][O:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.CCN(CC)CC>C1COCC1>[C:6]([C:2]1[CH2:3][CH2:4][CH2:5][C:1]=1[C:9]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([O:13][CH3:12])=[O:20])=[O:10])([OH:8])=[O:7]
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)C1=C(C(=O)O)CCC1
Temperature: 10 °C

Procedure:
2.76 (20 mmol) of 1-cyclopentene-1,2-dicarboxylic anhydride was dissolved in 50 ml of THF at 25° C. under a nitrogen atmosphere. The solution was cooled to 10° C. and 3.31 g (20 mmol) of L-proline methyl ester HCl was added, followed by 2.78 ml (20 mmol) Et3N, which produced a slight exothermic reaction. The mixture was heated at reflux for 12 hours, cooled and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed with 1N hydrochloric acid and brine. The organic phase was then dried over magnesium sulfate and evaporated in vacuo to afford the title compound which crystallized from methylene chloride/ether as an off-white solid (4.20 g; 79%). TLC (90:10/CH2Cl2 :MeOH): Rf =0.35. 1 H NMR δ: 8.15-8.42(bs,1H); 4.35-4.60(m,1H); 3.38-3.76(m,5H); 2.48-2.98(m,4H); 1.70-2.32(m,6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[C:9]=2[C:25]#[N:26])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[C:25]([C:9]1[C:10]([O:17][S:18]([C:21]([F:23])([F:24])[F:22])(=[O:20])=[O:19])=[N:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:36])=[CH:7][CH:6]=1)#[N:26]
Reactant: N#Cc1c(-c2ccc(N)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Reactant: O=C=Nc1ccccc1F
Product: N#Cc1c(-c2ccc(NC(=O)Nc3ccccc3F)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Yield: 66 %

Procedure:
In analogy to GP 4, reaction of 200 mg trifluoromethanesulphonic acid 4-(4-amino-phenyl)-3-cyano-6-cyclopropyl-pyridin-2-yl ester (0.522 mmol) and 71 μl 1-fluoro-2-isocyanato-benzene yielded 179 mg product (0.343 mmol, 66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: CCCCc1ccc(B(O)O)cc1
Product: CCCCc1ccc(Nc2cc(C(=S)OC)sc2C)cc1
Yield: 19.3 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 128 mg (2 equiv, 0.72 mmol) of 4-butylphenyl boronic acid to give 22.2 mg (18.3%) of methyl 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ0.97 (t, 2H, J=7.4 Hz), 1.38 (m, 2H), 1.59 (m, 2H obscured by water), 2.39 (s, 3H), 2.58 (t, 2H, J=7.6 Hz), 3.90 (s, 3H), 6.12 (bs, 1H), 6.97 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=8.4 Hz), 7.73 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][OH:7].F[C:11]1[C:20]([CH3:21])=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=1>C1COCC1.O>[CH3:21][C:20]1[C:11]([O:7][CH2:6][CH2:5][C:4]([F:9])([F:8])[F:3])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: OCCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cnc1OCCC(F)(F)F
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of sodium hydride (0.844 g, 21.1 mmol) in THF (10 mL), 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0° C., and stirred for 5 minutes. Then methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol, Step-1) in THF (10 mL) is added dropwise to the reaction mixture and stirred at rt for 2 hours. The reaction mixture is diluted with water (30 mL) and stirred overnight. After removal of THF, the mixture is acidified with 2 M hydrochloric acid (11 mL). The resulting white precipitate is collected by filtration and dried to give 1.76 g (>99% yield) of the title compound as white solid. This material is used for the next reaction (Step-3) without further purification.