Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Temperature: 207 °C

Procedure:
5.11 g of of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile and 30.74 g of pyridine hydrochloride were intimately mixed and then heated under nitrogen at 207° C. for an hour. On cooling the reaction was treated with about 100 ml of water and the solid was filtered. This solid was digested with methyl cellusolve and washed with ether to give 3.00 g of 4-[(3-bromophenyl)amino]-6,7-dihydroxy-3-quinolinecarbonitrile: mass spectrum (electrospray, m/e): M+H 356, 358.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH3:22])[C:3]=1[F:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[C:4]([CH3:22])[C:3]([F:23])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])(=[O:26])[CH3:25]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
2.68 g (8.38 mmol) of Compound 1 obtained in Example 80 (3) was dissolved in 30 mL of pyridine, 0.88 mL (9.2 mmol) of acetic anhydride was added under ice-cooling and the mixture was stirred at 50° C. for 18 hours. The reaction solution was poured into ice water and the precipitated crystals were collected by filtration to give 3.03 g of 2-(4-acetylamino-3-fluorophenyl)-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].O1CCCC1.C([Li])(CC)C.[C:56](#[N:59])[CH:57]=[CH2:58]>CO.O>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:58][CH2:57][C:56]#[N:59])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: C=CC#N
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCC#N)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (0.145 g, 0.23 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (0.22 mL, 1.3 M in hexane, 0.28 mmol). After 30 minutes, add acrylonitrile (0.015 g, 0.28 mmol). Allow to warm to ambient temperature and then heat to reflux. After 12 hours, add water and separate the layers. Extract the aqueous layer three times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/0.5/96.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.61 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane).
Reaction SMILES: Br[C:2]1[C:26]([F:27])=[C:25]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]2[C:6](=[O:24])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=3)[O:9][C:4]=2[C:3]=1[F:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][Si:56]([C:59]#[CH:60])([CH3:58])[CH3:57].O>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:27][C:26]1[C:2]([C:60]#[C:59][Si:56]([CH3:58])([CH3:57])[CH3:55])=[C:3]([F:35])[C:4]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=3)=[CH:7][C:6](=[O:24])[C:5]=2[C:25]=1[NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(Br)c(F)c3o2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(C#C[Si](C)(C)C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
30 mg (0.054mmol) of 7-bromo-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 84 (2) was dissolved in a mixed solvent of 0.5 mL of dimethylformamide and 0.5 mL of triethylamine, 1 mg (0.004 mmol) of palladium (II) acetate, 2 mg (0.008 mmol) of triphenylphosphine and 38 μL (0.27 mmol) of trimethylsilylacetylene were added and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled to room temperature, water was added thereto and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with 2N hydrochloric acid, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (chloroform:acetonitrile=19:1) to give 12 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-7-(2-trimethylsilylethynyl)-4H-1-benzopyran-4-one (yield: 39%).
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:25])[CH3:26])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[S:29][CH2:30][C:31]([OH:33])([CH3:34])[CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CS
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(C)(C)O)cc(C(C)(C)C)n1C
Yield: 25.7 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 1-mercapto-2-methylpropan-2-ol (213 mg, 2 mmol) and potassium tert-butoxide (225 mg, 2 mmol) in dimethylacetamide (10 mL) was heated at 100° C. for 12 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, eluant: EtOAc-MeOH 9:1) afforded 125 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 6H), 1.31-1.42 (m, 11H), 1.58-1.81 (m, 2H), 2.95 (s, 2H), 3.87 (s, 3H), 4.30-4.43 (m, 2H), 4.70 (s, 1H), 6.84 (s, 1H), 7.40-7.65 (m, 2H), 8.21 (d, J=2.0 Hz, 1H). MS (ESI+) m/z 486 (M+H)+. Anal. calculated for C24H34F3N3O2S: C, 59.36; H, 7.06; N, 8.65. Found: C, 59.27; H, 6.74; N, 8.40.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[C:42]([C:43](Cl)=[O:44])=[CH:41][N:40]=[C:39]2[CH:46]=[CH:47][S:48][C:38]=12.O>ClCCl>[Cl:36][C:37]1[C:42]([C:43]([N:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[C@H:5]2[CH2:10][C@@H:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:6]2)=[O:44])=[CH:41][N:40]=[C:39]2[CH:46]=[CH:47][S:48][C:38]=12
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(C(=O)c1cnc2ccsc2c1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
tert-Butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) and diisopropylethylamine (0.095 ml) were dissolved in dichloromethane (3 ml), a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonyl chloride (70 mg) in dichloromethane (2 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (120 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH3:25][NH:26][CH3:27]>O>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Reactant: CNC
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 97 %

Procedure:
4-Fluoro-2-nitro-N-quinolin-8-yl-benzenesulfonamide 145 (0.13 g, 0.36 mmol) was dissolved in dimethyl amine (2M in THF; 1.77 ml, 3.59 mmol) and the mixture was heated at 90° C. in a sealed tube for 5 h. After cooling, water was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (0.13 g, 97%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>S(=O)(=O)(O)O.CC(C)=O>[OH:21][C:14]1[C:13]2[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19][C:18]=2[C:17]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:16][CH:15]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=S(=O)=O
Solvent: CC(C)=O
Product: Cc1ccc2c(S(=O)(=O)O)ccc(O)c2n1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Oleum (18-24% SO3, 20 ml) was added to a solution of 2-methyl-quinolin-8-ol (10 g, 62.8 mmol) in concentrated sulfuric acid (40 ml). After warming to 65° C. for 2 hours, the reaction mixture was poured onto 200 g of crushed ice. The suspension was diluted with acetone (60 ml) and stirred for 10 minutes, whereupon solids were filtered off. After washing with acetone (3×60 ml) and drying under high vacuum, the title compound (14.13 g, 94%) was obtained as a slightly yellowish solid. 1H NMR (400 MHz, d6-DMSO): δ=9.60 (d, J=8.3 Hz, 1H), 8.02-7.94 (m, 2H), 7.29 (d, J=7.7 Hz, 1H), 2.94 (s, 3H). MS (ES+): 240.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C=O)C.O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:19][CH:18]=1)[CH3:43]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
DIPEA (1.4 g, 10.86 mmol) was added drop wise to 4-hydroxy benzoic acid (500 mg, 3.62 mmol) in DMF (10 mL). EDCI (1.7 g, 9.05 mmol) and HOBT (586 mg, 4.34 mmol) were added consecutively and, after 15 minutes, glycine ethyl ester HCl (603 mg, 4.344 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (4-hydroxy-benzoyl amino)-acetic acid ethyl ester in 91% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:56])[C:35]=1[CH:36]=[O:37].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:52]([C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:56])[N:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH:36]=[O:37])[N:51]=[CH:50]2)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
149 mg (0.338 mmol) of 1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one and 116 mg (0.301 mmol) of 2-bromo-6-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-benzaldehyde were weighed into a 4 mL reaction vial fitted with a stir bar and septum cap. Added 2.5 mL of dioxane. Added 0.33 mL (0.92 mmol) of an 0.91 g/mL solution of cesium carbonate in water. The mixture was sparged with nitrogen for 10 min. Added 13 mg (0.016 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane. The mixture was sparged with nitrogen for 5 min. Sealed the vial with a cap and stirred at 95° for 90 min. Cooled the reaction to room temperature, diluted with 15 mL CH2Cl2 and dried over Na2SO4. Filtered through a 0.45 μM syringe filter and removed the solvent on rotavap. Purified the crude by flash chromatography on silica gel to obtain 129 mg of the title compound as a light yellow solid. MS (ESI) 619 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cnc(CN[C@@H]2CCCc3cccnc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
(R)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.40 g, 1.50 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.40 g, 1.57 mmol) and K2CO3 (0.58 g, 4.50 mmol) in CH3CN (10 mL) were reacted according to General Procedure A. The crude 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoic acid methyl ester was isolated as an orange-brown oil (0.68 g, 100%) and used without purification in the next step of the synthesis.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][C:6]([CH:9]1[CH2:11][CH2:10]1)([CH3:8])[CH3:7])C.O.[OH-].[Li+]>C1COCC1.O.CO.O>[CH:9]1([C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([OH:12])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(C)(C)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-3-methylbutyric acid ethyl ester (3.0 g, 17.6 mmol) and lithium hydroxide monohydrate (3.5 g, 105 mmol) in THF/H2O/MeOH (24 mL, 2:1:1 v/v) was stirred at rt overnight. The reaction mixture was diluted with water (100 mL), and washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give 3-cyclopropyl-3-methylbutyric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([CH:14]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=1)[CH2:7][N+:8]([O-:10])=[O:9])[C:13]([O:20][CH3:21])=[O:19])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
[(S,S)-N-(4-tert-butylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (12.9 mg, 0.02 mmol, S/C=50), 4-methyl-β-nitrostyrene (184 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 30° C. for 24 hours. 1HNMR determination of the solution showed that the yield of the product was 51%. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 82% ee.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH:9]1[CH2:10][N:11]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC(N(C)C(=O)OC(C)(C)C)C2)nc1C
Yield: 70.9 %

Procedure:
The same operation as in Example (217a) was performed using 3-[(tert-butoxycarbonyl)(methyl)amino]azetidine (1.31 g, 7.03 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (134 mg, 0.54 mmol) and diisopropylethylamine (0.19 mL, 1.07 mmol), to obtain 136 mg of the title compound as a colorless oily substance (72%).
Reaction SMILES: C(OC([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][O:14][C:13]=2[C:12]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][N:32]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:33](=[O:52])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH2:50][CH3:51])[CH:49]=3)[CH:40]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60]>C(Cl)Cl>[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60].[CH:53]1([N:32]([CH2:31][CH2:30][NH:22][CH2:21][CH2:20][C:12]2[C:13]3[O:14][CH2:15][C:16](=[O:19])[NH:17][C:18]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[C:33](=[O:52])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH2:50][CH3:51])[CH:49]=3)[CH:40]=2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl(2-(N-cyclohexyl-3-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanamido)ethyl)carbamate [Example 4, Step vi)] (245 mg), DCM (5 mL) and TFA (2.5 mL) was stirred at 25° C. for 30 min. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (62.3 mg). MS [M+H]+=605.3 (calc=605.3451) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.70 (s, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 4.46 (q, J=7.3 Hz, 2H), 3.76-3.62 (m, 5H), 3.48 (t, J=5.7 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.92-2.83 (m, 4H), 2.62 (t, J=6.0 Hz, 2H), 1.80-1.56 (m, 4H), 1.55 (t, J=7.3 Hz, 3H), 1.44-1.24 (m, 5H), 1.17-1.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.[NH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1.CC(C)N=C=NC(C)C.C(#N)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:24]([F:26])([F:27])[F:25])[CH2:22][CH2:23]3)[C:17]([NH:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:34][CH:33]=3)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
188 mg (426 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (racemate), 82.4 mg (426 μmol) of tert-butyl 4-aminobenzoate, 6.1 mg (43 μmol) of Oxima and 66 μl (0.43 mmol) of DIC in 4 ml of dimethylformamide were reacted according to General Method 5B. Following preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)], the title compound was obtained. Yield: 157 mg (59% of theory)
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH:3]([S:10]C(=O)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[OH-].[Na+]>[SH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2](=[O:1])[CH3:14]
Reactant: CC(=O)SC(C(C)=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
Under nitrogen a mixture of 10.6 g (0.05 mol) of ethanethioic acid S-(2-oxo-1-phenylpropyl)ester and 130 ml of 5% sodium hydroxide was stirred rapidly at room temperature for 45 minutes, then extracted with ether. The aqueous mixture was chilled in an ice-bath, acidified with 6N HCl and extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and the solvent was removed to give 6.9 g (82%) of crude rac.-1-mercapto-1-phenyl-2-propanone. This compound is sensitive to air and therefore the crude product was used immediately for the condensation reaction.