Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCBr
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (lo g, 0.041 mol), sodium hydride (2.4 g, 1.5 eq), bromopentane (7.6 ml, 1.5 eq.) in DMSO (90 ml) were reacted as per the procedure of Example 71, Step 1 to yield the 2' and 3' isomers as a foam (7.6 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([N:13]2[CH2:17][C@H:16]([OH:18])[C@H:15]([NH:19][C:20](=[O:29])[O:21]CC3C=CC=CC=3)[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I[Si](C)(C)C.Cl.[NH2:36][NH2:37]>C(#N)C.C(O)C(C)C>[OH:18][C@H:16]1[CH2:17][N:13]([C@H:8]([C:5]2[CH:6]=[N:7][C:2]([NH:36][NH2:37])=[CH:3][CH:4]=2)[C:9]([F:12])([F:10])[F:11])[CH2:14][C@H:15]1[NH:19][C:20](=[O:29])[O:21][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: NN
Reactant: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC#N
Solvent: CC(C)CO
Product: CC(C)(C)OC(=O)N[C@@H]1CN([C@H](c2ccc(NN)nc2)C(F)(F)F)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
To a solution of benzyl (3R,4S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-4-hydroxypyrrolidin-3-ylcarbamate (1.16 g, 2.7 mmol) in acetonitrile (2 mL) cooled to 0° C. in an ice bath was added iodotrimethylsilane (1.22 mL, 8.10 mmol) and the mixture allowed to warm to ambient temperature for 1 hour. The reaction mixture was poured into aqueous 1N HCl (15 mL) and stirred for 10 minutes and extracted with diethyl ether. The aqueous layer was pH adjusted to 10 with a 5N sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated under reduced pressure. The residue (0.512 g, 1.29 mmol) was combined with anhydrous hydrazine (0.81 mL, 25.87 mmol) in i-BuOH (3 mL) in a sealed tube and heated with stirring at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford tert-butyl (3R,4S)-4-hydroxy-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.44 g, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[CH:18]=[C:17]2[CH3:25].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:19]1[CH:18]=[C:17]([CH3:25])[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])[CH:15]=2)[N:20]=1
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Reactant: O=C1NCCN1c1cccnc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)nc2ccc(N3CCN(c4cccnc4)C3=O)cc12
Yield: 35.1 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 95.8 mg, 0.5882 mmol) was reacted with 6-bromo-2-chloro-4-methyl-quinoline (150 mg, 0.5882 mmol), 1,4-dioxane (5 mL), copper iodide (11.2 mg, 0.05882 mmol), trans-1,2-diamino cyclohexane (20.20 mg, 0.1764 mmol) and potassium carbonate (162.6 mg, 1.1764 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 70 mg of the product (35.17% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.F[C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH:39]=[O:40].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1)[C@@H:20]1[CH2:21][N:22]([C:37]2[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:41][C:38]=2[CH:39]=[O:40])[C@H:23]([CH2:25][CH3:26])[CH2:24]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of [3,5-bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (75 mg, 0.15 mmol), 2-fluoro-5-trifluoromethyl-benzaldehyde (44 mg, 0.23 mmol) and K2CO3 (42 mg, 0.30 mmol) in DMF (1.5 mL) is heated at 130° C. and stirred for 2 hours. After the mixture is cooled down until room temperature, H2O and EtOAc is added and then extracted with EtOAc. The combined organic layer is dried over MgSO4, then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give 2-((2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-benzaldehyde as a colorless oil (77 mg, 74%). ESI-MS m/z: 670 [M+1]+, Retention time 2.75 min (condition A).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 133.5 %

Procedure:
4-Bromophenol (30.0 g), 33.5 g of tert-butyl acrylate, 50 mg of palladium acetate, and 27.9 g of potassium carbonate were dissolved in 300 mL of N-methylpyrrolidone, followed by stirring at 120° C. for 3 hours. The reaction solution was cooled to room temperature and 900 mL of water and 300 mL of dichloromethane were added thereto. The organic layer was separated and the water layer was extracted with 100 mL of dichloromethane twice. The organic layer was collected, washed with a 10% hydrochloric acid, saturated sodium bicarbonate water, and saturated saline, and dried by adding sodium sulfate. Sodium sulfate was removed and the mixture was purified by column chromatography (alumina/silica gel, dichloromethane), and the solvent was distilled away under a reduced pressure. As a result, tert-butyl 4-hydroxycinnamate (51 g) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:8]([CH3:13])[CH:9]=1
Reactant: CCCC(=O)Nc1ccccc1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(Br)cc1C
Reaction time: 1 h
Yield: 98 %

Procedure:
30 g of N-butyryl-o-toluidine and 150 g of glacial acetic acid were initially charged at 30° C. A solution of 33 g of bromine in 66 g of glacial acetic acid was added with stirring and then stirring was continued at from 25 to 30° C. for 1 hour. 300 ml of water were then added to the reaction mixture which, after continued stirring for a short time, was filtered, the crystals were washed with water and dried under reduced pressure. 42.5 g (98% yield) of N-(4-bromo-2-methylphenyl)butanamide were obtained in 99.4% purity.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([C:16]2[N:21]=[C:20]3[N:22]([CH2:25][C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[N:23]=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:15]=[C:14]([C:16]2[N:21]=[C:20]3[N:22]([CH2:25][C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[N:23]=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a solution of Example 50 (0.055 g, 0.113 mmol) in methanol (0.5 ml), lithium hydroxide (0.045 g, 1.05 mmol) in water (0.5 ml) was added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale green solid (0.050 g, 96%). M.P.: 252-254° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.70 (s, 1H), 9.01 (d, J=3.9 Hz, 1H), 8.73 (d, J=8.7 Hz, 1H), 8.64 (m, 2H), 8.25 (d, J=8.8 Hz, 1H), 8.20 (m, 4H), 7.97 (d, J=8.9 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.71 (dd, J=7.8, 4.2 Hz, 1H), 6.27 (s, 2H), 3.96 (d, J=5.8 Hz, 2H). MS (m/z): 456.85 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[CH:5]=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:3]=1.[Mg].Cl[P:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[P:33](Cl)Cl>C1COCC1>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[CH:7]=[C:2]([P:26]([C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[P:33]([C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[CH:3]=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:5]=1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Reactant: Cc1cccc(C)c1-c1cc(Br)cc(-c2c(C)cccc2C)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(-c2c(C)cccc2C)cc(P(c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c2ccccc2P(c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-3,5-bis(2,6-dimethylphenyl)benzene (2.74 g, 7.50 mmol) was added dropwise to magnesium (0.28 g, 11.52 mmol) and THF (10 mL) in an argon atmosphere. After the dropwise addition, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature and filtered, and the thus-obtained THF solution of 1-(3,5-bis(2,6-dimethylphenyl))magnesium bromide, and 1,2-bis(dichlorophosphino)benzene (0.28 g, 1.00 mmol) were reacted as in Production Example 1. The reaction was allowed to proceed overnight at 60° C. After purification, the title compound was obtained as a yellow powder (0.70 g, yield 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([OH:18])=O)[CH2:11][C:12](O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OC)=O.C([N:26](CC)CC)C.N.CC([O-])=O.[Na+].C(OC(=O)C)(=O)C>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:16](=[O:18])[NH:26][C:12](=[O:13])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: COC(=O)Cl
Agent: N
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Temperature: 10 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
Alternatively, the title compound can be obtained in the following manner: A solution of 500 mg (1.97 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step) in 50 mL dioxane was cooled to 10° C. and treated with 229 μL (2.96 mmol) of methyl chloroformate and 936 μL (6.71 mmol) of triethylamine for 7.2 h. A solution of 0.5 M ammonia in dioxane (15.8 mL, 7.90 mmol) was added at 10° C. and the mixture stirred at RT for 72 h. The mixture was filtered through Celite, the filter cake washed with EtOAc, and the solvents were evaporated in vacuo. The residue was treated with solid 1.30 g (15.8 mmol) of NaOAc and acetic anhydride (4 mL) and heated to 100° C. for 1 h. The mixture was cooled to RT and concentrated to half the original volume. The residue was taken up in EtOAc (100 mL), washed with saturated aqueous NaHCO3 (1×75 mL), brine (1×75 mL), and water (1×75 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50-60% EtOAc-hexane afforded 197 mg (43%) of the title compound as an off-white solid (see spectrum above).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:7]([O:18][CH3:19])=[C:8]([C:12]([O:16][CH3:17])=[C:13]([Cl:15])[CH:14]=1)[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[NH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH3:35]>C(C(C)=O)C.CCOCC>[CH2:34]([N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][NH:27][C:9](=[O:11])[C:8]1[C:12]([O:16][CH3:17])=[C:13]([Cl:15])[CH:14]=[C:6]([Br:5])[C:7]=1[O:18][CH3:19])[CH3:35]
Reactant: CCN1CCCC1CN
Reactant: COc1c(Cl)cc(Br)c(OC)c1C(=O)O
Solvent: CCC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCN1CCCC1CNC(=O)c1c(OC)c(Cl)cc(Br)c1OC

Procedure:
20 ml of thionyl chloride is added to 11.82 g (0.04 mol) of 3-bromo-5-chloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for 1 hour. To the solution is added 50 ml of toluene. The solvent and excess thionyl chloride is evaporated at reduced pressure. The residue is dissolved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise while stirring to 5.13 g (0.04 mol) 2-(aminomethyl)-1-ethylpyrrolidine in 50 ml methyl ethyl ketone. After stirring for 30 minutes at room temperature 300 ml of ether is added. The obtained semisolid product is separated and dissolved in 300 ml of water. Sodium hydroxide solution is added while stirring and cooling in ice. The precipitate is collected and washed with water. Yield: 12.0 g, m.p. 124°-25° C.
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[CH:36][C:7]([C:8]([N:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=1)([O-])=O.Cl.[Sn].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[O:9])=[CH:36][CH:37]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
4-Nitro-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (264.0 mg, 0.52 mmol) was dissolved in methanol (5 ml) to which were subsequently added concentrated hydrochloric acid (2.0 ml) and tin (powder, 186.0 mg, 1.57 mmol) while cooling in an ice bath. After 1 hour of stirring at room temperature, the reaction solution was poured in ice water, adjusted to pH 9 to 10 with 10% sodium hydroxide aqueous solution, mixed with chloroform and then passed through cerite to remove insoluble materials. The resulting residue was washed with chloroform, the filtrate was extracted with chloroform, and the resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain 243.0 mg (97.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.CN(C)C=O.[CH2:27]([O:30][CH3:31])[C:28]#[CH:29]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:28][CH2:27][O:30][CH3:31]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (200 mg, the compound of Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) at room temperature was added methyl propargyl ether (0.5 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium(II) chloride (30 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (50 ml) and aqueous citric acid solution (50 ml, 20%). The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane to provide the title compound as a pale yellow solid m.p. 210° C. decomp.
Reaction SMILES: [OH-].[Li+].[C:3]12([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:26]4[CH2:31][CH2:30][CH2:29][C@@H:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:27]4)=[N:20][C:21]=3[S:22][CH2:23][CH2:24][CH3:25])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Cl>O.CO.C1COCC1.CCOC(C)=O>[C:3]12([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:26]4[CH2:31][CH2:30][CH2:29][C@@H:28]([CH2:32][C:33]([OH:35])=[O:34])[CH2:27]4)=[N:20][C:21]=3[S:22][CH2:23][CH2:24][CH3:25])=[O:15])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)O)C2)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 18 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
A solution of lithium hydroxide (0.053 g, 1.26 mmol) in water (1 mL) was added dropwise to a stirred solution of methyl {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl}acetate (Intermediate 73, 204 mg, 0.42 mmol) in MeOH (3 mL) and THF (2 mL) at 18° C., over a period of 1 minute. The resulting solution was stirred at 18° C. for 20 hours. The reaction mixture was adjusted to pH 4.5 with 2M HCl and the reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl}acetic acid (180 mg, 91%), as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36])[CH3:39]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]([CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+]#N)=[C:14]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[N:25]=[CH:24]3)[CH:13]=1)=[O:9].O.[F:32][C:33]([F:46])([F:45])[C:34]1[CH:44]=[CH:43][C:37](/[CH:38]=[CH:39]/B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[CH3:18][C:17]1[CH:16]=[C:15](/[CH:39]=[CH:38]/[C:37]2[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:45])[F:46])=[CH:44][CH:43]=2)[C:14]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[N:25]=[CH:24]3)=[CH:13][C:12]=1[CH2:11][CH2:10][C:8]([O:7][CH3:6])=[O:9]
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c([N+]#N)cc1C
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(/C=C/c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
Example Compound 2-N1-1 (324 mg) was dissolved in a 50% aqueous solution of HBF4 (0.5 ml), and this solution was added dropwise with an aqueous solution (0.5 ml) of sodium nitrite (83 mg) under ice cooling. The reaction mixture was stirred for 30 minutes, and then the precipitates were collected by filtration to obtain 4-(2-methoxycarbonylethyl)-5-methyl-2-(1-methyl-1H-indazol-5-yl)benzenediazonium tetrafluoroborate (Intermediate 16, yield: 200 mg). A solution of this Intermediate 16 (200 mg) in 1,4-dioxane (1 ml) was successively added with water (1 ml), (E)-4-(trifluoromethyl)styrylboronic acid (200 mg, Ald), and Pd(OAc)2 (20 mg, Ald), and stirred at room temperature for 3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (15 ml) and ethyl acetate to extract the organic layer, and washed with saturated brine (30 ml), and then solvent was evaporated. The residue was purified by silica gel column chromatography (Yamazen, n-hexane:ethyl acetate=3:1) to obtain the title compound (30 mg).