Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].[C:3]1([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.Cl>CN(C=O)C>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:17]3)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 120 °C

Procedure:
Potassium fluoride (225 mg) was added into a solution of 2-phenylchroman-6-ol (300 mg) in dry DMF (3 ml). After stirring the resulting mixture at 120° C. for 30 minutes 2-chloro-5-nitropyridine (195 mg) was added. The reaction mixture was stirred for a further 6½ hours at 120° C. After cooling into room temperature 1 M HCl-solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water then with saturated NaCl-solution and dried with Na2SO4. 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine was recrystallised from acetone-2-propanol (1:5). 1H NMR (400 MHz, d6-DMSO) δ: 9.00 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.47-7.32 (m, 5H), 7.20 (d, 1H, J 9.2 Hz), 7.00-6.89 (m, 3H), 5.15 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (ddd, 1H, J −16.8, 11.3, 6.2 Hz), 2.75 (ddd, 1H, J −16.8, 5.4, 3.3 Hz), 2.18 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl.[CH3:23][N:24](C)[CH2:25][CH2:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:23])[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]2=3)=[O:19])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CN(C)CCCCl
Reactant: O=C(Nc1cccnc1Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Temperature: 0 °C
Yield: 20.7 %

Procedure:
To a solution of 2-chloro-3-(4-nitrobenzoyl)aminopyridine (1.93 g) in N,N-dimethylformamide (13 ml) was added sodium hydride (60 % in oil, 585 mg) and the solution was stirred at 0° C. for ten minutes. 3-Dimethylaminopropyl chloride hydrochloride (1.16 g) was added to the solution and the mixture was stirred for 3 hours at 150° C. The solution was diluted with ethyl acetate and the solution was washed with successively with water, saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (80 g, ethyl acetate:n-hexane =1:3) to give 1-(4-nitrobenzoyl)-5-methyl-2,3,4,5-tetrahydropyrido [3,2 -b][1,4]diazepine (450 mg).
Reaction SMILES: [NH2:1][C:2](N)=[S:3].ClC1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8]N=1.[OH-].[K+].[OH-].[Na+]>C(O)C.O.C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:2]([SH:3])=[N:1][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NC(N)=S
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: FC(F)(F)c1ccc(S)nc1
Temperature: 25 °C
Yield: 60 %

Procedure:
Thiourea (684 mg, 8.80 mmol) was added to a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.45 g, 8.00 mmol) in ethanol (4 ml), and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, subsequently a solution of potassium hydroxide (792 mg, 12.0 mmol) in water (4 ml) was added thereto, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled again to room temperature, and 1 N sodium hydroxide and methylene chloride were added thereto. After the aqueous layer was separated, acetic acid added to the aqueous layer, which was then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of to hexane and diethyl ether, and was collected by filtration to obtain the title compound (860 mg, 4.80 mmol, 60%) as a pale yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1.COC(=O)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([F:32])[CH:26]=1>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:19](=[O:21])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)=[CH:26][C:27]=1[F:32]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)c(F)c1
Temperature: -78 °C

Procedure:
Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 4 L, 4000 mmol) was added over 1 hour to a solution of 3-chlorophenyl acetic acid (250.0 g, 1465 mmol) in anhydrous tetrahydrofuran (1.75 L) at −78° C. under nitrogen. The resulting reaction mixture was stirred for an additional hour at −78° C. Then, a solution of methyl-4-chloro-3-fluorobenzoate (221.0 g, 1175 mmol, Example 4, Step A) in tetrahydrofuran (500 mL) was added over 1 hour at −78° C., and the resulting reaction mixture was stirred at the same temperature for 2 hours. The reaction was monitored by TLC. On completion, reaction mixture was quenched with 2 N hydrochloric acid (2.5 L) and aqueous phase was extracted with ethyl acetate (2×2.5 L). The combined organic layer was washed with brine (2.5 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude material which was purified by flash column chromatography (silica gel: 100 to 200 mesh, product eluted in 2% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[N-:46]=[C:47]=[O:48].[K+]>O.C(O)(=O)C>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:47]([NH2:46])=[O:48])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: [N-]=C=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NC(N)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 35 °C
Yield: 33.8 %

Procedure:
To a suspension of (S)-2-(1-((5-(3-amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (10 mg, 0.12 mmol) The mixture was heated 35° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 18 mg (33% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CNC(=O)c1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
To a solution of 2-fluoro-4-formyl-N-methylbenzamide (0.62 g) in methanol (17 mL) was added sodium borohydride (0.16 g) in small portions, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.44 g).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([N:15]3[C:23]4[C:18](=[CH:19][C:20]([CH:24]5[CH2:27][N:26]([CH2:28][CH2:29][CH3:30])[CH2:25]5)=[CH:21][CH:22]=4)[CH:17]=[CH:16]3)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[ClH:31].C1(S(N2C3C(=CC(C4CN(CCC)C4)=CC=3)CC2)(=O)=O)C=CC=CC=1>>[ClH:31].[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([S:12]([N:15]3[C:23]4[C:18](=[CH:19][C:20]([CH:24]5[CH2:27][N:26]([CH2:28][CH2:29][CH3:30])[CH2:25]5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(-c4cnco4)cc3)c2)C1
Agent: CCCN1CC(c2ccc3c(c2)CCN3S(=O)(=O)c2ccccc2)C1
Agent: Cl
Product: CCCN1CC(c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(-c3cnco3)cc2)C1

Procedure:
This compound was prepared from 1-(4-oxazol-5-yl-benzensulfonyl)-5-(1-propyl-azetidin-3-yl)-1H-indole by the method outlined for compound 9. ESI-MS [m/z]: 424.15 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)CC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-isobutylpiperidine (0.63 g, 2.5 mmole) and 20% palladium hydroxide (0.1 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-isobutylpiperidine as oil. Yield 0.35 g (91%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][C@@H:9]([CH2:25][NH:26][CH3:27])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C)(C)C.C[O-].[Na+]>CO>[CH3:16][C:13]1([CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@@H:11]([CH2:10][C@H:9]2[CH2:8][CH2:7][C:6](=[O:5])[N:26]([CH3:27])[CH2:25]2)[CH2:15][O:14]1
Reactant: CNC[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CCC1=O
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((methylamino)methyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (212 mg, 0.53 mmol) in absolute MeOH was added a NaOMe solution in MeOH (33%, 0.4 mL). The resulting solution was stirred for 24 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (50 mL), washed with 1 M HCl, sat. aq. NaHCO3, brine, and dried over Na2SO4, filtered and evaporated to give (S)-tert-butyl 2,2-dimethyl-4-(((R)-1-methyl-6-oxopiperidin-3-yl)methyl)oxazolidine-3-carboxylate (160 mg, 92%). MS ESI +ve m/z 564 (M+Na).
Reaction SMILES: [BH4-].[Li+].[I:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[N:6]([C:13]([CH3:19])([CH3:18])[C:14](OC)=[O:15])[CH:5]=1.O>C(O)C>[I:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[N:6]([C:13]([CH3:19])([CH3:18])[CH2:14][OH:15])[CH:5]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cncnc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CC(C)(CO)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
Lithium borohydride (32.3 mL, 64.6 mmol, 2.0 M in THF) was added to methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (8.92 g, 25.9 mmol) (see Preparation 21) in ethanol (70 mL). The mixture was stirred at room temperature for 17 hours then water (70 mL) was added. The mixture was evaporated in vacuo then the residue was partitioned between DCM (250 mL) and water (50 mL). The aqueous phase was extracted with DCM:MeOH (90:10, 2×250 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford the title compound as an off-white solid in 100% yield, 8.20 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH2:29](Br)[C:30]#[CH:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[CH:10][C:11]([O:18][CH2:31][C:30]#[CH:29])=[N:12][C:13]=2[C:14]([F:15])([F:17])[F:16])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c(C(F)(F)F)n1
Reaction time: 60 h
Yield: 46.6 %

Procedure:
A mixture of 0.11 g of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-oxo-pyridine (step 5 of Example 1), 2.5 g of propargyl bromide, 0.3 g of potassium carbonate, and 5 mL of DMF was stirred for 60 hours and concentrated in vacuo. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and filtered through silica gel. The filtrate was reconcentrated in vacuo and the residue was crystallized from ether/hexane to give 56 mg of white solid: mp 138°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
365 mg (1.02 mmol) 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol in 7 ml CH2Cl2 were treated with 94 μl (1.21 mmol) methane sulfonic acid chloride, 0.13 ml (1.53 mmol) pyridine and 135 mg (1.2 mmol) DMAP at 0° C. The solution was stirred at RT over night, was diluted with water and acidified with 10% aq. KHSO4. The inorganic phase was extracted with CH2Cl2. The combined organic phases were washed with NaHCO3 solution, brine and dried over Na2SO4. Evaporation gave 446 mg crude Methanesulfonic acid 4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester, MS: 436 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:12])[CH:9]=2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CC(N(C)C)=O>[OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:9]=2)[CH2:4]1
Reactant: OCC1Cc2ccc(O)cc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(CO)C3)nc1
Reaction time: 5 h
Yield: 44 %

Procedure:
Combine in a round bottom flask equipped with a stir, Dean Stark Trap filled with toluene, and reflux condenser 2-Hydroxymethyl-indan-5-ol (630.2 mg, 3.84 mmol), K2CO3 (690.0 mg, 5.0 mmol), 6-Chloronicotinamide (600.0 mg, 3.84 mmol) and a solution of DMA:Toluene (15:5 mL). After the reaction refluxes under nitrogen atmosphere for 5 hours, concentrate under reduced pressure and then add ethyl acetate. Wash the organic layer several times with water, then brine, and dry over Na2SO4. After concentrating the reaction mixture under reduced pressure, flash chromatograph using 20% THF, 7% 1N NH3-MeOH, 73% DCM eluent to afforded 481.1 mg, 1.69 mmol (44% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.8-2.2 (4H, m), 2.6-2.8 (3H, m), 3.6-3.8 (2H, br d), 3.9-4.0 (1H, m), 6.1-6.6 (2H, br d), 6.8-7.0 (3H, m), 7.2-7.3 (1H, m), 8.1-8.2 (1H, m), 8.6 (1H, s); MS m/z 285 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[Br:23][C:11]1[CH:10]=[C:9]([C:6]2[CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CON1CCC(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CON1CC=C(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.9 %

Procedure:
To a solution of 4-(1-methoxy-piperidin-4-yl)-phenylamine (as prepared above, 42 mg, 0.20 mmol) in DCM (2 mL) was added NBS (36.2 mg, 0.20 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to obtain 2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (43 mg, 74.5%) which was used in the next step without purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][N:10]=[CH:11][CH2:12]Cl)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:14][C:15]([F:45])([F:44])[C:16]1[CH:17]=[C:18]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]1[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:20].C(N(C(C)C)CC)(C)C>C(#N)C>[N:1]1([CH2:7][CH2:8][O:9][N:10]=[CH:11][CH2:12][N:24]2[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]3[CH:17]=[C:16]([C:15]([F:14])([F:45])[F:44])[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=3)[C@H:22]([CH2:27][C:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][CH:29]=3)[CH2:23]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCC=NOCCN1CCOCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC=NOCCN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture of 2-chloroethanal O-[2-(morpholin-4-yl)ethyl]oxime (0.13 g), (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.29 g), diisopropylethylamine (0.11 mL), and acetonitrile (10 mL) was heated under reflux overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichloromethane and K2CO3 (aq). The layers were separated, the organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford 2-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-ethanal O-[2-(morpholin-4-yl)ethyl]oxime 0.38 g (95%) as an E/Z mixture. MH+ 626, Rf 0.53+0.66 (E+Z isomer) (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 71.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:28]([OH:30])=O)[O:3]1.[NH4+].[OH-].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:37]=1.O>C(O)(C)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:25])([F:26])[F:27])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:28]([NH2:37])=[O:30])[O:3]1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: O=C(O)C1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)C1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.3 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-carboxylic acid (12.5 mg, 0.03 mmol) obtained in Example 2-4 and a 25% ammonia aqueous solution (3.06 μl, 0.045 mmol) were dissolved in isopropanol (0.3 ml). Thereafter, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (13.3 mg, 0.045 mmol) was added to the solution, and the obtained mixture was then stirred at a room temperature for 3.5 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1), so as to obtain 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-carboxylic amide (9.8 mg, 78%) in the form of a colorless amorphous substance.