Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][N:18]3[C:19](=[O:29])[CH2:20][C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:26][C:27]3=[O:28])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Product: Cc1ccc(Cl)cc1N1CCN(CCN2C(=O)CC3(CCCC3)CC2=O)CC1
Temperature: 160 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
A mixture of 1-(5-chloro-2-methylphenyl)piperazine (20 mg, 0.095 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (17.3 mg, 0.043 mmol, 49%): ESI-MS m/z 404 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4nccnc4CC(N)=O)n3)cc2)CC1
Reaction time: 3 h
Yield: 78.2 %

Procedure:
2-(3-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrazin-2-yl)acetamide (26) (42 mg, 0.087 mmol) was dissolved in methanol (4 mL) and 37% formaldehyde (26 μL, 0.35 mmol) was added. After five minutes sodium tri(acetoxy)borohydride (92 mg, 0.44 mmol) was added and the mixture stirred for three hours. The solution was concentrated, and the residue suspended in 10% sodium hydroxide (1 mL). After five minutes brine (2 mL) was added, and the mixture extracted with ethyl acetate (5×3 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (27) (34 mg, 77% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.64 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.38 (d, J=2.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.3 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 4.09 (d, J=4.7 Hz, 1H), 3.77 (s, 2H), 3.17 (d, J=4.3 Hz, 2H), 3.05-2.92 (m, 2H), 2.33 (s, 3H), 2.20 (s, 2H), 1.82-1.61 (m, 4H). LCMS Method C: rt 4.53 min; m/z 500.1 [M+H]+; m/z 498.2 [M−H]−.
Reaction SMILES: [CH2:1]1[CH:3]2[C:4]([O:6][C:7](=[O:8])[CH:2]12)=O.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:7](=[O:8])[CH:2]2[CH:3]([CH2:1]2)[C:4]1=[O:6]
Reactant: O=C1OC(=O)C2CC12
Reactant: NCCCO
Product: O=C1C2CC2C(=O)N1CCCO
Temperature: 180 °C
Yield: 49 %

Procedure:
A mixture of cyclopropane-2,3-dicarboxylic acid anhydride (purchased at Acros, Ref 37012-0010, 500 mg, 1.0 eq.) and 3-amino-1-propanol (340 mL, 1.0 eq.) was heated 6 h at 180° C. The reaction mixture was purified on silica, eluting with a 98:2 to 19:1 gradient of dichloromethane/methanol, to yield 360 mg (49%) of the desired product as light yellow solid. MS (m/e): 168.1 (M−H−, 100%)
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a solution of methyl 2-fluoro-5-nitrobenzoate (1.65 g, 8.29 mmol) and N-(2-fluoro-5-hydroxyphenyl)-2-[3-(trifluoromethyl)phenyl]acetamide (2.60 g, 8.30 mmol) produced in Example 53(i) in N,N-dimethylformamide (17 mL) was added potassium carbonate (1.72 g, 12.5 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (90 mL), washed successively with water (2×90 mL) and saturated brine (90 ml), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.78 g, 93%) as a brown oil.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:4][N:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2cnco2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cnco2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(1,3-oxazol-5-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(1,3-oxazol-5-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 65%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([C:17]2[N:18]=[N:19][N:20]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a suspension of 0.64 g (16 mmol) 50% sodium hydride in 7.5 mL of dry dimethylformamide was added 5.7 g (16 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate and the resultant mixture stirred for 30 minutes. To the resultant solution, 5.7 g (18 mmol) bromotriphenylmethane was added and the mixture stirred for 24 hours. The mixture was diluted to 200 mL with water and the insolubles collected by filtration. The product was recrystallized from ethyl acetate to give 6.1 g of the title compound; m.p.=161°-162° C. (dec.).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH3:26]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:26])=[O:24])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Product: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2

Procedure:
Following the procedure in Example 51, 2-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid was coupled with ammonia to give 115. MS (ESI+): 338.1. 1H NMR (400 MHz, DMSO) δ 8.94 (d, J=2.2, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.5, 2.2, 1H), 7.69 (s, 1H), 7.44 (d, J=1.4, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5, 1H), 6.40 (d, J=1.7, 1H), 5.34 (dt, J=13.0, 6.4, 1H), 4.52 (dd, J=11.0, 5.6, 4H), 1.44 (d, J=6.6, 6H).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:7]1[CH:8]=[N:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1cc(F)cnc1Cl
Product: N#Cc1cc(F)cnc1-c1ccc(F)cc1
Yield: 68 %

Procedure:
Prepared in 68% yield from the product of Example 169A and 4-fluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (DMSO-d6) δ 7.39-7.45 (m, 2H), 7.87-7.92 (m, 2H), 8.58 (dd, J=8.6, 2.9 Hz, 1H), 8.99 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]([O-])=O.[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][N:10]=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Brc1ccc2[nH]nnc2c1
Reaction time: 0.5 h

Procedure:
A mixture of Example 248A (262 mg; 1.4 mmol) in 10% H2SO4 (4 mL) was treated with NaNO2 (120 mg; 1.7 mmol) in water (1 mL), stirred for 30 min., diluted with water, and extracted with EtOAc. The extracts were rinsed with brine, dried (Na2SO4), concentrated and purified by flash chromatography (5% MeOH/CH2Cl2) to provide the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>CN(C)C=O.CCOC(C)=O>[CH:14]1([CH2:13][O:1][CH:2]2[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]2)[CH2:16][CH2:15]1
Reactant: N#CC1=CCCC(O)C1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC1=CCCC(OCC2CC2)C1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To the solution of (R or S)-5-Hydroxycyclohex-1-enecarbonitrile (Intermediate #40, 2.0 g, 16 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (850 mg, 21 mmol, 60% dispersion in oil) at 0° C. The resulting suspension was stirred at ambient temperature for 30 minutes before the addition of bromomethylcyclopropane (3.3 g, 24 mmol). The mixture was then stirred at 75° C. for 6 hours, and diluted with EtOAc (50 mL). The organic solution was washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-5% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.63-6.62 (m, 1H), 3.69-3.66 (m, 1H), 3.34-3.32 (m, 2H), 2.54-2.49 (m, 1H), 2.38-2.30 (m, 1H), 2.29-2.24 (m, 2H), 1.85-1.83 (m, 1H), 1.75-1.72 (m, 1H), 1.08-1.04 (m, 1H), 0.59-0.54 (m, 2H), 0.24-0.20 (1,2H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[F:6])/[CH2:3]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>C1COCC1>[C:38]1(=[O:48])[N:42]([CH2:1]/[C:2](/[CH3:3])=[CH:5]/[F:6])[C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C\F)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(=C\F)CN1C(=O)c2ccccc2C1=O
Yield: 69 %

Procedure:
A solution of (E)-2-methyl-3-fluoroallyl alcohol (prepared in Step D) (17.11 g), triphenylphosphine (49.80 g), diethyl azodicarboxylate (33.06 g) and phthalimide (27.93 g) in THF (500 ml) is stirred at room temperature overnight. The THF is evaporated and the oily residue is extracted three times with hexane giving a powdery solid which is subsequently extracted three times with ether. The combined extracts are evaporated and the residue (63 g) is purified by chromatography on silica gel (950 g) using a mixture of 20% diethyl ether/light petroleum. The major fraction is a colorless crystalline mass (28.6 g, 69% yield) which is essentially pure product. A small portion can be crystallized from hexane to give (E)-1-phthalimido-2-methyl-3-fluoro-2-propene as colorless plates: m.p. 57°-58° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:10][C:3]1[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([CH3:8])[C:4]=1[NH2:9]
Reactant: C1CCNC1
Reactant: Cc1ccc(Br)c(C)c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCCC2)c(C)c1N
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 3-bromo-2,6-dimethylphenylamine(0.27 g, 1.35 mmol) dissolved in toluene (5.4 mL) and pyrrolidine (0.56 mL, 6.8 mmol) was added sodium t-butoxide (0.39 g, 4.0 mmol). The suspension was deoxygenated for approximately 10 minutes by passing a stream of nitrogen through the solvent. Solid tris(dibenzilideneacetone)dipalladium(0) (10 mg) and rac-2,2′Bis(diphenylphosphino)-1,1′binaphthyl (25 mg) were combined and added in one portion. Nitrogen bubbling continued for an additional 2 minutes before heat was applied (100° C. overnight). The reaction mixture was cooled to room temperature and diluted with ethyl acetate and HClaq. (2N). The aqueous layer was adjusted basic with sodium bicarbonate solution and re-extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted and concentrated under reduced pressure to give to give the desired 2,6-dimethyl-3-pyrrolidin-1-ylphenylamine as an amber oil.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].O.C(=S)=[S:26]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:26])[N:13]=1
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
16g of adenosine 1-oxide monohydrate (53.3 mmol) was refluxed in 150 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 9.0 using Amberlite IRC-50 (H+-type). Water was then added thereto to make the total volume 400 ml. To this was added 100 ml of carbon disulfide, and the mixture was reacted in an autoclave at a temperature of 120° C for a period of 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance thus formed was recovered followed by concentration to dryness. The residue was dissolved in 125 ml of 2.5N aqueous ammonia, and any impurities contained were filtered out. A mixture of n-butanol and acetic acid (250 ml:125 ml) was added to the filtrate to crystallize the product to obtain 16.5 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 98% yield. UV Absorption Spectrum: maxpH 1 238.5 nm (ε:13800) and 293 nm (ε:18400); maxpH13 243 nm (ε:19100) and 283 nm (ε:14000).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2([CH2:27][CH3:28])[CH2:26][CH2:25]2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1(B(O)O)[CH2:39][CH2:38]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:33]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2([CH2:27][CH3:28])[CH2:26][CH2:25]2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)N(C(=O)OC(C)(C)C)c2cc(Br)ccc23)CC1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)N(C(=O)OC(C)(C)C)c2cc(C4CC4)ccc23)CC1
Temperature: 130 °C
Yield: 38.1 %

Procedure:
Under Argon atmosphere, racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (28 mg, 0.049 mmol), cyclopropylboronic acid (4.5 mg, 0.0524 mmol), Pd(PPh3)4 (5 mg), K3PO4 (50 mg) and a few drops of water were mixed in toluene (3 mL). The mixture was heated under microwave irradiation at 130° C. for 20 min. Then the solution was poured into water and the aqueous layer was extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by Prep-TLC to obtain racemic (2′R,3R,4′S)-6-cyclopropyl-4′-(3-chlorophenyl)-2′-(1-ethyl-cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[F:30][C:31]1[CH:65]=[CH:64][C:34]([C:35](/[N:37]=[C:38]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:36])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:35](/[N:37]=[C:38]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:4][C:3]=3[N:17]\2[C@H:18]2[CH2:23][CH2:22][C@@H:21]([C:24](=[O:25])[NH:26][CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]2)=[O:36])=[CH:64][CH:65]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCOCC3)ccc2N)CC1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(OCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used for (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (19 mg, 35% yield). M/Z calc'd for C30H38FN5O4: 551.65. found 552 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:30])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Yield: 105 %

Procedure:
Reaction of 11.8 g (33.3 mmol) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid with oxalyl chloride according to Cohen et al Helv. Chim. Acta, 1978 61, 837 afforded 13.0 g (105%) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride as a yellow oil. This acid chloride was reacted according to Org. Synth., 1984, 63, 198 with 4.94 g (34.3 mmol) of Meldrum's acid and 6.58 g (6.73 mL, 83.2 mmol) of dry pyridine as described above for the racemic series to afford 16.5 g of crude adduct i.e.(S)-5-[2-[3,4-dihyro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione as a brownish foam. Crystallization attempts from several solvents or solvent mixtures failed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:5].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)([CH3:5])[CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15]
Reactant: COC(CBr)OC
Reactant: COC(=O)C(C)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(CC(OC)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 35 g (150 mmol) 2-(3,4-dichloro-phenyl)-propionic acid methyl ester (Journal of Medicinal Chemistry (2004), 47(23), 5753-5765), 31.7 g (188 mmol) bromoacetaldehyde dimethyl acetal (commercially available and 6.6 g (165 mmol) NaH (55%) in 100 mL DMF was stirred at room temperature and afterwards evaporated to dryness. Ice water and ethyl acetate was added and the organic fraction was washed with sat. NaCl aq., dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica eluting with a mixture of ethyl acetate and hexane. The product containing fractions were evaporated to yield 29.6 g (61%) of the title compound as yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([NH:35][S:32]([CH:29]2[CH2:31][CH2:30]2)(=[O:34])=[O:33])=[O:16])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recrystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9% acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92%). 1H NMR (DMSO-d6) δ 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([F:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:14][NH2:15])=[O:2])=[CH:5][C:6]=1[F:11]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(Br)c(F)c1
Temperature: 70 °C

Procedure:
A mixture of compound 4-bromo-3-fluoro-benzoic acid methyl ester (1 g, 4.29 mmol), hydrazine hydrate (2.2 mL, 42.9 mmol) and MeOH (20 mL) was heated at 70° C. for overnight. Concentrated, diluted with EtOAc (300 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated give the desired product 2AR (0.9 g, 90%).