Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=O)[C:7]=2[C:6]([CH3:22])=[N:5]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>C(Cl)Cl>[CH3:62][C:61]1[CH:60]=[C:59]([CH3:63])[NH:58][C:57](=[O:64])[C:56]=1[CH2:55][NH:54][C:19]([C:8]1[C:7]2[C:6]([CH3:22])=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:21]
Reactant: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred solution of 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid (0.5 g, 1.69 mmol) in DCM (30 mL) was added EDC.HCl (0.39 g, 2.03 mmol), HOBT (2.74 g, 2.03 mmol) followed by DIPEA (1.47 mL, 8.45 mmol) and stirred at room temperature for 15 min. To the resulting reaction mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.257 g, 1.69 mmol) was added and stirred at room temperature for overnight. The reaction mixture was filtered and the precipitate was washed with water followed by ether and dried. The solid compound was further purified by silica gel chromatography (eluent: 10% MeOH in ethyl acetate) to afford the title compound as an off-white solid (225 mg, 31%). 1H NMR (DMSO-d6, 400 MHz): 1.461 (d, J=6.4 Hz, 6H), 2.109 (s, 3H), 2.240 (s, 3H), 2.438 (s, 3H), 4.372 (d, J=4.8 Hz, 2H), 5.042-5.107 (m, 1H), 5.870 (s, 1H), 7.410 (s, 1H), 7.501-7.533 (m, 1H), 8.061 (s, 1H), 8.215 (d, J=8 Hz, 1H), 8.461 (t, J=4.8 Hz, 1H), 8.593 (d, J=4.8 Hz, 1H), 9.036 (s, 1H), 11.489 (brs, 1H). LCMS (ES+) m/z: 430.12
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([F:38])=[CH:11][C:12]([F:37])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:30])=[C:22]([F:29])[C:23]=3[O:25][CH:26]([CH3:28])[CH3:27])[C:18](=[O:31])[C:17]([C:32]([O:34]CC)=[O:33])=[CH:16]2)[CH:14]=1)=O)(C)(C)C.Cl>C(O)(=O)C>[NH2:8][C:9]1[C:10]([F:38])=[CH:11][C:12]([F:37])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:30])=[C:22]([F:29])[C:23]=3[O:25][CH:26]([CH3:28])[CH3:27])[C:18](=[O:31])[C:17]([C:32]([OH:34])=[O:33])=[CH:16]2)[CH:14]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(OC(C)C)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)Oc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Yield: 70.6 %

Procedure:
Ethyl 1-[5-(tert-butoxycarbonylamino)-2,4-difluorophenyl]-6,7-difluoro-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (530 mg) were added to a mixed liquid of 4N hydrochloric acid (2 ml) and acetic acid (2 ml), and the mixture was stirred and heated under reflux for 50 minutes. The reaction mixture was concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (285 mg) as a pale brown powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1>C(#N)C>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), 5-fluoro-2-nitropyridine (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride (1.3 g, 11.9 mmol). The mixture was heated at 60° C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 314a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+ 196.0.
Reaction SMILES: [NH:1]1[C:4]2([CH2:9][CH2:8][CH2:7][N:6]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5]2)[CH2:3][CH2:2]1.CC1N([C:25]([CH2:27][C:28]#[N:29])=[O:26])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:26]=[C:25]([N:1]1[C:4]2([CH2:9][CH2:8][CH2:7][N:6]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5]2)[CH2:3][CH2:2]1)[CH2:27][C:28]#[N:29]
Reactant: c1nc(N2CCCC3(CCN3)C2)c2cc[nH]c2n1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
An optically-active compound of 4-(1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.55 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (1.56 g), N,N-diisopropylethylamine (1.66 ml) and 1,4-dioxane (31 ml), and the mixture was heated to 100° C. to stir for 2 hours. The mixture was cooled to room temperature. Then, thereto was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=20/1 to 9/1) to give the titled compound (1.50 g).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1.C(O[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]1[O:24][C:25](=[O:27])[CH3:26])(=O)C>C1(C)C=CC=CC=1>[C:25]([O:24][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:39][C@H:22]1[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[NH2:11])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: NC(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-hydroxybenzyl)benzamide (0.063 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.33 g) in toluene (3 mL) was added boron trifluoride diethyl-ether complex (0.11 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. To a solution of the obtained 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in methanol (5 mL) was added sodium methoxide (0.005 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/ethanol=5/1) to give 2-(4-carbamoylbenzyl)phenyl β-D-glucopyranoside (0.068 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:34]([C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)#[N:35]
Reactant: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(Br)c4)oc3C)C2)c1C(=O)O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(C#N)c4)oc3C)C2)c1C(=O)O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
13 mg of 2-{3-[2-(3-bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-methylbenzoic acid and 25 mg of zinc cyanide were dissolved in 5 ml of dimethylformamide. The reaction mixture was degassed and charged with argon, and 20 mg of tetrakistriphenylphosphinepalladium were added. The mixture was stirred at 100° C. for 12 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 68 as an amorphous light-yellow solid. C27H28N2O5 (460.53), MS(ESI): 461.20 (M+H+).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)[CH3:5])[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:8]=1
Reactant: CC(Oc1cccc(CO)c1)C1CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cccc(CCl)c1)C1CC1
Temperature: 78 °C

Procedure:
[3-(1-cyclopropylethoxy)phenyl]methanol (0.418 g, 2.17 mmol) in carbon tetrachloride (8.70 ml) was added triphenylphosphine resin (1.14 g, 4.35 mmol). The reaction was refluxed overnight with minimal stirring at 78° C. The next day the mixture was filtered through a fritted funnel and washed with dichloromethane. The filtrate was concentrated and no purification was necessary.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[OH:9][C:10]1[N:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>CN(C)C=O>[OH:9][C:10]1[N:17]=[CH:16][C:15]([I:1])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cccnc1O
Solvent: CN(C)C=O
Product: N#Cc1cc(I)cnc1O
Temperature: 60 °C
Yield: 188 %

Procedure:
9 g (0.5 eq) of N-iodosuccinimide at room temperature is added to a solution of 10 g (83 mmol) of 2-hydroxynicotinonitrile in 150 ml of anhydrous dimethylformamide. The reaction mixture is stirred at 60° C. After 30 minutes of stirring, 9 g (0.5 eq) of N-iodosuccinimide is added and then the reaction mixture is stirred at 60° C. for 5 hours. The solvent is evaporated and the precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 18.5 g (90%) of 2-hydroxy-5-iodonicotinonitrile in the form of a beige powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[OH:28])[CH3:2].[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[O:28][CH2:29][C@@H:31]1[CH2:32][O:33]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg, 931 μmol) and (R)-epichlorohydrine (861 mg, 9.31 mmol) in 3 M aq. NaOH (4 mL) and isopropanol (15 mL) is stirred at rt for 18 h before a second portion of (R)-epichlorohydrine (430 mg, 4.65 mmol) is added. Stirring is continued at rt for 8 h. The mixture is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH solution (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[(2S)-3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(1-ethyl-propyl)-6-methoxy-pyridine (272 mg) as a white powder; LC-MS: tR=1.25 min, [M+H]+=438.09.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1([F:34])[CH2:33][O:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2([F:34])[CH2:33][O:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: FC1(CBr)COC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC4(F)COC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with 3-bromomethyl-3-fluoro-oxetane (described in US2005215599) gave the title compound. ES-MS m/e (%): 469.2(M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(NC(C)C)(C)C.[Li].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:22][C:23]1[C:24]([C:25]([NH:1][C:2]2[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=2[C:8]([F:9])([F:11])[F:10])=[O:26])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
To a cooled (-78° C.) solution of 2.1 g of the 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 ml of THF was added dropwise over 3 min. 7 ml of lithium diisopropylamine (LDA, 1.5M in cyclohexane). The mixture was stirred 5 min., and 0.9 g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 min. After 5 min. an additional 3 ml of LDA solution was added followed by an additional 0.5 g of the acid chloride in 1 ml of THF. The resulting mixture was stirred 10 min. and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase was extracted with water and the combined aqueous phases extracted with methylene chloride, dried (magnesium sulfate), filtered and evaporated to give the crude product. This was washed with a small amount of ethyl acetate and dried to give 1.3 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH:34]([F:38])[C:35](O)=[O:36].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>CN(C)C=O>[F:33][CH:34]([F:38])[C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: O=C(O)C(F)F
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1)C(F)F
Reaction time: 6 h
Yield: 18.5 %

Procedure:
A solution of 103 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.5 ml of N,N-dimethylformamide is treated successively with 180 μl (1.0 mmol) of N-ethyl-diisopropylamine, 20 μl (0.3 mmol) of difluoroacetic acid, and 102 mg (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) at RT, and thereafter, stirred for 6 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in 3 ml of dichloromethane and the solution is washed with 1.5 ml of a saturated solution of sodium hydrogenate and with 1.5 ml of hydrochloric acid (0.1 N). The organic phase is dried over sodium sulfate and evaporated. For purification, the crude material is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 21 mg (18% of theory) of (S)-2,2-difluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=396 (M+NH4)+.
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>[Zn]>[OH:17][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CCCCCCCCCCCCCCCC=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Zn]
Product: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C

Procedure:
The reaction of hexadecanal (1.2 g) and tertbutyl bromoacetate (1.56 g) was carried out under the presence of activated zinc (0.59 g) according to similar manner to that of Preparation 1-(1) to afford an oil of tert-butyl 3-hydroxyoctadecanoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCn1ccc2ccccc21
Temperature: 60 °C

Procedure:
A solution of indole (1.0 g) in dry DMSO (1 ml) is dropped into a suspension of sodium hydride (60% mineral oil suspension; 0.37 g) in dry DMSO (20 ml). The mixture is heated at 60° C. for 1 h. After cooling to room temperature, the resulting solution is added dropwise with a solution of n-octyl bromide (2.82 ml) in dry DMSO (2.8 ml). After a night at room temperature, the reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases are washed with a NaCl saturated solution, dried and evaporated to dryness. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane), to obtain 1.86 g of 1-(n-octyl)indole as oil. The compound is characterized through its 1H-NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[N:27]=[CH:28][N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:30]=4)[N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1COCC1.O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[N:27]=[CH:28][NH:29][CH:30]=4)[N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2c[nH]cn2)no1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
Into a flask containing (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide (0.148 g, 0.223 mmol) a solution of THF (9 ml), formic acid (1 ml, 0.223 mmol) and water (0.1 ml) was added. The resulting mixture was stirred at RT. During the next 2 days 7 ml of formic acid was added. The solvents were evaporated, acetonitrile was added and evaporated, repeating this procedure twice. The product was purified with LC/MS-trigger. Yield 42.4%. 1H-NMR (400 MHz; MeOD): δ 1.33 (d, 3H), 4.36 (dd, 1H), 4.45 (dd, 1H), 4.55-4.66 (m, 1H), 6.77 (s, 1H), 7.68-7.75 (m, 2H), 7.78-7.92 (m, 3H), 8.00 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: C([Mg]Cl)CCC.[Li]CCCC.Br[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH:29]=[O:30]>CCOCC.C1(C)C=CC=CC=1>[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH:29]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2)[OH:30]
Reactant: O=CCCC(F)(F)F
Reactant: COc1ccc2cc(Br)cnc2c1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(O)CCC(F)(F)F)cnc2c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
BuMgCl (0.16 mL of a 2 M solution in ether, 0.32 mmol) was added to 1 mL of toluene at −10° C. n-BuLi (0.26 mL of a 2.5 M solution in hexanes, 0.64 mmol) was added dropwise and the reaction mixture was allowed to age at −10° C. for 45 min. A solution of 3-bromo-7-methoxyquinoline (200 mg,) in 1 mL of toluene was added at −20° C. After 1 h, the reaction mixture was cooled to −78° C. and 4,4,4-trifluorobutyraldehyde (0.16 mL, 1 mmol) was added and the reaction mixture was slowly allowed to warm to ambient temperature. The procedure was repeated proportionally using 440 mg (1.8 mmol) of 3-bromo-7-methoxyquinoline. The two reactions were combined and partitioned between water and hexanes-EtOAc. The organic phase was concentrated and purified by flash chromatography on silica gel (25% to 66% EtOAc/hexanes) to provide the title compound as a racemic mixture. 1H NMR (500 MHz, CD2Cl2): δ (ppm) 8.71 (d, J=2.1 Hz, 1H), 8.06 (s, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.9, 2.2 Hz, 1H), 4.93 (m, 1H), 3.93 (s, 3H), 2.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][N:13]([CH3:30])[C:14](=[O:29])/[CH:15]=[CH:16]/[C:17]1[CH:18]=[N:19][C:20]([NH:23][CH2:24][C:25]([O:27]C)=O)=[CH:21][CH:22]=1.COC([CH2:35][NH:36]C1N=CC(/C=C/C(N(C)CC2C3C(=CC=CC=3)NC=2C)=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][N:13]([CH3:30])[C:14](=[O:29])/[CH:15]=[CH:16]/[C:17]1[CH:18]=[N:19][C:20]([NH:23][CH2:24][C:25]([NH:36][CH3:35])=[O:27])=[CH:21][CH:22]=1
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3c(Cl)cccc23)cn1
Product: CNC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3c(Cl)cccc23)cn1
Yield: 94 %

Procedure:
According to the procedure of Example 21, except substituting (E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide (0.75 g, 1.8 mmole) for the (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide, the title compound (0.721 g, 94%) was prepared as a white solid: MS (ES) m/e 426.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cccs1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1cccs1)C(=O)N2
Yield: 19 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2-thiophene carboxaldehyde and following the method described in Example 10, the desired compound was obtained.