Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Na].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][N:12]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C1NCCN1Cc1ccc(OCC(F)(F)F)nc1
Temperature: 80 °C

Procedure:
2,2,2-Trifluoroethanol (3.6 g) was dissolved in toluene (20 ml), and sodium hydride (0.7 g) was added to prepare a sodium salt of 2,2,2-trifluoroethanol. Then, 3 g of 1-(2-bromo-5-pyridylmethyl)-2-(nitromethylene)imidazolidine (the known compound described in Japanese Patent Application No. 132,943/1984) was added, and the mixture was heated at 80° C. for 8 hours. Toluene was distilled off under reduced pressure, and the residue was poured into 20 ml of ice water and then neutralized. The aqueous solution was extracted with dichloromethane, and the extract was purified by silica gel column chromatography to give 1-[2-(2,2,2-trifluoroethoxy)-5-pyridylmethyl]-2-(nitromethylene)-imidazolidine. mp. 132°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Br)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated with oxalyl chloride (3 mL, 33.98 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 15 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and slowly added to a cooled solution (0° C.) of 2-aminothiazole (680.6 mg, 6.79 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.79 mmol) in methylene chloride (17 mL). The resulting reaction mixture was stirred at 0° C. for 10 min and then at 25° C. for 15 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a 10% aqueous hydrochloric acid solution (2×100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), and washed with a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (1.23 g, 95%) as an orange solid which was used in subsequent reactions without further purification. An analytical sample was recrystallized from ethyl acetate to provide a cream solid: mp 201-202° C.; EI-HRMS m/e calcd for C17H19BrN2OS (M+) 378.0401, found 378.0405.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][O:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[CH3:13][O:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH:19]=1
Reactant: COc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Temperature: 90 °C
Yield: 54.2 %

Procedure:
1-Fluoro-2-methoxy-4-nitrobenzene (0.785 g, 4.59 mmol), 4-methoxy-1H-imidazole (0.45 g, 4.59 mmol) and potassium carbonate (0.697 g, 5.05 mmol) were mixed in dry acetonitrile (10 mL) and heated at 90° C. for 4 days. DCM was added and the mixture was filtrated through a pad of silica eluting with 5% MeOH in DCM. The solvents were evaporated and mixture was purified by column chromatography in silica eluting with a gradient of MeOH and DCM to give the title compound as a gum 0.62 g (54%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[S].[NH2:19][CH2:20][CH:21]([NH2:23])C.[CH3:24]OCCO>>[ClH:1].[CH3:24][N:23]1[CH2:21][CH2:20][N:19]=[C:2]1[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COCCO
Reactant: ClCc1ccc(-c2nsc3ccccc23)cc1
Reactant: CC(N)CN
Agent: [S]
Product: CN1CCN=C1c1ccc(-c2nsc3ccccc23)cc1
Product: Cl

Procedure:
26 g of 3-(4'-chloromethylphenyl)-1,2-benzisothiazole, 6.4 g of sulfur and 15 g of 1,2-diaminopropane in 400 ml of glycol monomethyl ether are heated for 15 hours at 110° C. After distilling off the solvent, the residue is dissolved in 50 g of methanol and this solution is stirred into 400 g of ethereal hydrochloric acid (15 g of HCl in diethyl ether), whilst cooling. The crystals formed are filtered off and dissolved in 300 parts of water, the solution is filtered and the filtrate is rendered alkaline with concentrated NaOH and extracted with methylene chloride. The methylene chloride phase is dried and 20 g of hydrogen chloride gas are passed in. 17 g of the desired end product are obtained as colorless crystals, melting at 243° C. The yield corresponds to 52% of theory.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CS(C)=O>[C:29]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([OH:31])=[O:30]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-tryptophan in DMSO to provide the title compound in good yield.
Reaction SMILES: CO[C:3](=[O:14])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[CH3:15][NH2:16].[K+].[Br-]>C(O)C>[CH3:15][NH:16][C:3]([CH2:4][NH:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1)=[O:14]
Reactant: CN
Reactant: COC(=O)CNC(=O)c1cccnc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)CNC(=O)c1cccnc1
Temperature: 55 °C

Procedure:
A suspension of [(pyridine-3-carbonyl)-amino]-acetic acid methyl ester (1.5 g, 7.7 mmol) and methylamine (33 wt % in absolute ethanol, 3.86 mL, 38.6 mmol) in ethanol (8 mL) was heated at 55° C. in a Parr reactor for 6 h. The mixture was cooled and then concentrated under reduced pressure to yield the product as a iridescent beige plates (1.41 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 9.05 (d, J=2.2 Hz, 1H), 9.00 (t, J=5.8 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.23 (br d, J=8.1 Hz, 1H), 7.90 (q, J=4.1 Hz, 1H), 7.53 (dd, J=7.7, 4.7 Hz, 1H), 3.86 (d, J=5.8 Hz, 2H), 2.61 (d, J=4.4 Hz, 3H); IR (KBr) 3314, 1641 cm−1; ESIMS m/z 194 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27 mmol) and dichloromethane (40.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid. ESI-MS m/z calc. 323.99. found 325.1 (M+1)+; Retention time: 1.37 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].C[O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24]C)[CH2:20][C:19](=O)[CH2:18][CH2:17]2.C([BH3-])#N.[Na+].C1([CH2:37][OH:38])C=CC=CC=1.B(Br)(Br)Br>CO.C(Cl)Cl.O>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:37](=[O:38])[N:1]([CH:18]3[CH2:19][CH2:20][C:21]4[C:16](=[CH:15][C:14]([OH:13])=[C:23]([OH:24])[CH:22]=4)[CH2:17]3)[CH2:2]2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: OCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Agent: BrB(Br)Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C1OC(c2cccc(Cl)c2)CN1C1CCc2cc(O)c(O)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.83 g of 2-amino-1-(m-chlorophenyl)ethanol, 1.0 g of 6,7-dimethoxy-2-tetralone and 0.85 g of sodium cyanoborohydride in 25 ml of methyl alcohol is stirred at room temperature for 18 hours. The reaction mixture is poured into water and a product residue is isolated. This residue is purified by flash chromatography to give 0.80 g of 3-chloro-α- (1,2,3,4-tetrahydro-6,7-dimethoxy)naphthalen-2-yl)amino!methyl!benzenemethanol, which is in turn converted to 5-(3-chlorophenyl-3-(1,2,3,4-tetrahydro-6,7-dimethoxy)naphthalen-2-yl)-2-oxazolidinone. Subsequent reaction with boron tribromide in methylene chloride as in Example 1, Step A, gives 5-(3-chlorophenyl)-3-(1,2,3,4-tetrahydro-6,7-dihydroxynaphthalen-2-yl)-2-oxazolidinone as a solid, mp 195° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[N:7]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(NS(C)(=O)=O)n2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine was treated with methanesulfonyl chloride (100 mg) and then stirred at 70° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was dissolved in EtOAc and washed with 1N HCl, NaHCO3 (saturated), brine, dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 11.0 (s, 1H), 8.37 (d, 1H), 8.25 (d, 1H), 7.82 (d, 2H), 7.72 (m, 1H), 7.61 (d, 1H), 7.42 (d, 2H), 7.17 (d, 1H), 3.15 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 523.1. found 523.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1N)[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:22]>O>[CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[Br:22])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: Br
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 16.33 g [0.1 mol] of 2,6-diethyl-4-methylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 80° C., of 13.9 g [0.05 mol] of FeSO4×7H2O in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred at 80° C. for another 1 hour, allowed to cool to room temperature and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 21.3 g of an oil which, according to GC, contains 94.6% 2,6-diethyl-4-methylbromobenzene (89% of theory).
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:40])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2O3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3H in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample 1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)=[CH:5][C:3]=1[NH2:4].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].N1C=CC=CC=1>CC#N>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:4][C:3]1[CH:5]=[C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:25])([F:27])[F:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:33]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A 20 mL vial is charged with 2-methyl-5-[6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazin-2-yl]aniline (0.444 g, 1.2 mmol), 3-bromobenzoyl chloride (0.378 mL, 1.8 mol), pyridine (0.292 mL, 3.6 mmol), MeCN (4 mL) and the mixture is stirred at room temperature for 18 hr. The reaction mixture is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (530 mg). LCMS (m/z)=552.3 and 554.3 [M+H]+, tR=3.04 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[C:5]([O:27][CH3:28])[C:4]=1B(O)O.[CH2:32]([O:34][C:35](=[O:56])[C@H:36]([CH2:48][C:49]1[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=1)[NH:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH3:33].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[CH2:32]([O:34][C:35](=[O:56])[C@H:36]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:4]2[C:5]([O:27][CH3:28])=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:51][CH:50]=1)[NH:37][C:38](=[O:47])[C:39]1[C:40]([Cl:46])=[CH:41][CH:42]=[CH:43][C:44]=1[Cl:45])[CH3:33]
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(O)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of 2,6-dimethoxy-4-(tert-butyl-diphenylsilyloxy)benzeneboronic acid (3 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (0.8 g), Pd(PPh3)4 (1 g) and K2CO3 (2.1 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 6 hour under N2. The mixture was diluted with EtOAc and washed with water, dried and evaporated. The residue was dissolved in EtOAc and the solution was filtered through a silica gel column and evaporated. The residue was dissolved in THF, and TBAF (1.6 M in THF, 4 ml) was added. The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with EtOAc. The extract was washed with water, dried and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1/2) to yield 0.5 g of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-4-hydroxyphenyl)-L-phenylalanine ethyl ester. ESMS m/z: 490 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=1>ClCCCl>[O:70]=[C:66]1[CH:65]=[C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[CH:69]=[CH:68][NH:67]1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cc[nH]c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.45 g, 0.78 mmol), was reacted with diisopropylethylamine (0.8 g, 6.2 mmol), diphenylphosphinic chloride (0.74 g, 3.1 mmol), then reacted with 4-aminopyridin-2(1H)-one (Molbridge) (0.086 g, 0.78 mmol) in 1,2-dichloroethane at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a off white solid (Yield 28 mg, 6%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([CH3:26])[CH:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[F:15].[BH4-].[Li+].O.C(OCC)(=O)C>C1COCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:5]([CH3:26])[CH2:4][CH2:3][OH:2])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: COC(=O)CC(C)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CCO)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-trifluoro-phenyl)-butyric acid methyl ester (0.79 g, 1.88 mmol) was dissolved in 10 mL of THF and lithium borohydride (0.5 g, excess) was added. The reaction mixture was stirred at room temperature overnight. 50 mL of water and 50 mL of EtOAc were added. The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was used in next step without further purification (0.71 g, 96%). 1H NMR (CDCl3 400 MHz) δ 7.61 (m, 2H), 7.36 (m, 2H), 7.06 (m, 1H), 6.82 (m, 0.5H), 6.60 (m, 0.5H), 4.79 (m, 0.5H), 4.56 (m, 0.5H), 3.85 (m, 1H), 3.68 (m, 1H), 3.12 (m, 1H), 2.39 (m, 0.5H), 1.95 (m, 0.5H), 1.57 (m, 0.5H), 1.46 (dd, J=4.4 and 5.9 Hz, 1.5H), 1.32 (m, 0.5H), 0.92 (dd, J=7.3 and 9.5 Hz, 1.5H).
Reaction SMILES: C([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1)=O.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[O:13]=[C:5]1[CH2:4][C:3](=[C:18]2[C:19](=[O:20])[O:21][C:14]([CH3:15])=[N:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: O=Cc1cc(=O)[nH]c2ccccc12
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1=NC(=C2CC(=O)Nc3ccccc32)C(=O)O1

Procedure:
17 Grams of 4-formylcarbostyril, 18 g of N-acetylglycine, 7 g of anhydrous sodium acetate and 100 ml of acetic anhydride were heated at 110° C. to make a homogeneous solution, further the solution was refluxed for 1.5 hours. After cooled the reaction mixture, the reaction mixture was poured in a cold water and the crystals precipitated were collected by filtration. The crystals were washed with cold water, then recrystallized from ethanol-chloroform to obtain 10 g of 4-(1,2-dihydro-2-oxo-4-quinolyliden)-2-methyl-5-oxazolone.1/2-hydrate.