Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>O1CCCC1.CN(C)C=O>[OH:36][C:28]1([CH2:27][NH:26][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[N:3]=2)=[O:13])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCC2(O)CN3CCC2CC3)c2ccccc21
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2×30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH:12]=O)[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)(=O)C>O1CCCC1.C(OCC)C.CCCCCC>[CH:12]1([N:7]2[CH2:6][C:5]([CH3:15])([CH3:14])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH2:8]2)[CH2:17][CH2:16]1
Reactant: CC[Mg]Br
Reactant: CC1(C)CN(C=O)Cc2ccc(O)cc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CN(C2CC2)Cc2ccc(O)cc21
Temperature: 55 °C
Yield: 63 %

Procedure:
A stirred, cooled (0° C.) solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuran (40 mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL, 28 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (18.7 mL) and the reaction mixture was then heated at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid. Flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow solid (1.55 g, 63%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[NH:6][C:5](=[O:18])[NH:4]1)[CH3:2]>C(OC(=O)C)(=O)C>[C:12]([N:6]1[CH:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]([CH2:1][CH3:2])[N:4]([C:8](=[O:17])[CH3:7])[C:5]1=[O:18])(=[O:15])[CH3:11]
Reactant: CCC1NC(=O)NC1C(=O)c1ccc(OC)cc1
Solvent: CC(=O)OC(C)=O
Product: CCC1C(C(=O)c2ccc(OC)cc2)N(C(C)=O)C(=O)N1C(C)=O

Procedure:
A solution of 10 g of 4-ethyl-5-(4-methoxybenzoyl)-2-imidazolidinone in 100 ml acetic anhydride is stirred at reflux for 5 hours after which the excess solvent is evaporated. The residue is purified by chromatography.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.[CH3:18][C:19]1([CH3:27])[CH2:25][CH2:24][C:23](=[O:26])[O:22][C:20]1=[O:21]>C(N(CC)CC)C>[C:23]([CH2:24][CH2:25][C:19]([CH3:27])([CH3:18])[C:20]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])=[O:21])([OH:26])=[O:22]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: CC(C)(CCC(=O)O)C(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of triclosan (29.0 g.), triethylamine (15 ml.) and 2,2-dimethylglutaric anhydride (20 g.) was heated at 80° C. for 5 hours. A further quantity (2.0 g.) of anhydride and triethylamine (1 ml.) were added and heating continued for 24 hours. The mixture was cooled to ambient temperature, washed with 2M hydrochloric acid (100 ml.), then with water (3×80 ml.) and dried (MgSO4). The solution obtained was evaporated. The brown residual oil was dissolved in hot cyclohexane. The solution on cooling gave white crystals which were recrystallised from cyclohexane/petrol 60-80 to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 4-carboxy-2,2-dimethylbutyrate (C') (12.7 g.), m.p. 125°-128° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)=[CH:16][Si](C)(C)C)=[CH:4][C:5]2[C:6](=[O:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:15]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=2)=[CH2:16])=[CH:4][C:5]2[C:6](=[O:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(C(=C[Si](C)(C)C)c2cc3c(cc2C)C(C)(C)CCC3=O)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCC2=O
Reaction time: 18 h

Procedure:
A solution of ethyl 4-[1-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2naphthalenyl)-2-trimethylsilyl-ethenyl]benzoate (12.0 g, 27.6 mmol) in dichloromethane (900 mL) was treated with trifluoroacetic acid (100 mL) at 0° C. The mixture was stirred for 18 hours and allowed to reach room temperature. The mixture was diluted with toluene (˜100 mL) and concentrated. The residue was purified by silica gel chromatography (8×15 cm, 0 to 5% ethyl acetate/toluene) to afford the title material as a yellowish solid which was triturated in hexane (9.7 g, 97%). An analytical sample was recrystallized in hexane.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.S(O)(O)(=O)=O.[NH2:24][CH2:25][CH3:26].C1(C)C=CC=CC=1>O.CO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]2[O:18][CH2:26][CH2:25][NH:24][CH2:4]2)=[CH:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CCN
Reactant: O[C@@H](CCl)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Fc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Powdered sodium hydroxide (3.36 g, 84 mmol) was dissolved in water (5.6 mL) and cooled to room temperature. Intermediate (d) (R)-1-chloro-3-(4-fluoro-3-trifluoromethylphenyl)-2-propanol (assumed 13 mmol) was added as a solution in methanol (13.3 mL in total) and the mixture stirred for 5 minutes at room temperature. 2-aminoethane hydrogen sulfate (7.90 g, 56 mmol) was added in one portion and the resultant mixture warmed to 40° C. (bath temperature) for 2 hrs. Toluene (35 mL) and sodium hydroxide (powdered 3.36 g, 84 mmol) were added and the reaction heated at 65° C. (bath temperature) for 18 hrs, with vigorous stirring. The reaction was allowed to cool to room temperature and poured into water (80 mL), layers separated and the aqueous layer extracted with ethyl acetate (40 mL×2). Combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; triethylamine/ethanol ethanol/ethyl acetate, 1/20/79 ratio) yielded the desired intermediate (c), (R)-2-(4-fluoro-3-trifluoromethylbenzyl)morpholine, as yellow oil (2.34 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I-].C[O:9][CH:10]1[O:14][C:13](=[O:15])[CH2:12][CH:11]1[C:16]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:18])[CH3:17]>O.CO>[CH:10]([C:11](=[C:16]([CH3:18])[CH3:17])[CH2:12][C:13]([OH:15])=[O:14])=[O:9]
Reactant: COC1OC(=O)CC1C(C)(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 0.700 g of sodium carbonate in 8 ml of water was added to a solution of 0.700 g of the product of Step A in 1 ml of methanol and the mixture was stirred for 2 hours at 20° C. and was filtered. The filtrate was adjusted to a pH of 2 and was saturated with sodium chloride. The mixture was extracted with chloroform and the organic phase was evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 0.095 g of 3-formyl-4-methyl-pent-3-ene-1-oic acid melting at 102° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][C:6]([O:9]C)=[C:5]2[N:11]([C:19]3[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:22][CH:23]=3)[N:12]=[C:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=12)#[N:2].[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[C:1]([C:3]1[C:4]2[C:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:12][N:11]([C:19]3[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)cnc(OC)c32)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)c[nH]c(=O)c32)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of methyl 4-(4-cyano-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (40 mg) in acetonitrile (5 mL) were added sodium iodide (31.4 mg) and chloro(trimethyl)silane (0.066 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 566.9 (M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:24])[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:13][C:14]([OH:16])=[O:15].Cl>C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[O:24][C:10]([CH2:11][CH:12]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:3]=2[CH:4]=1
Reactant: O=C(O)CC(CC(=O)Nc1cc(Cl)ccc1O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)CC(Cc1nc2cc(Cl)ccc2o1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 11.2 %

Procedure:
Neat N-(2-hydroxy-5-chlorophenyl)-3-(4-chlorophenyl)glutaramic acid (1.5 g) was kept under vacuum (membrane pump) and placed in a preheated (230° C.) oil bath. The resulting melt was stirred at this temperature under vacuum for 1 h. The melt was cooled and close to the point of solidification diethyl ether was added to give a cloudy solution. The traces of solid were removed by filtration and the filtrate was shaken with 20% NaOH solution (20 ml). The sodium salt of the product separates as ether and water insoluble brownish oil. The neat oil is isolated and treated with 10% HCl (2 ml). The desired product separates as slowly solidifying oil which is triturated with methanol/water 1:2 and with acetone to afford 0.16 g of 4-(5-chloro-2-benzoxazolyl)-3-(4-chlorophenyl)butanoic acid as almost colourless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[OH:1][C:2]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Yield: 80 %

Procedure:
Obtained in 80% yield by an analogous method to Example 323, preparation of starting materials, starting from tert-butyl 4-oxo-1-piperidinecarboxylate and 2-bromothiazole.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:27]Br>C(O)(=O)C>[Br:27][C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:25][CH3:26])=[CH:20][C:21]=1[CH:23]=[O:24]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Reactant: BrBr
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.0 g (8.51 mmol) of 2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde is dissolved in 90 ml acetic acid. Bromine (437 ul, 8.51 mmol) is added dropwise and the reaction is stirred for 5 h at RT. Ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water (3×) and brine (2×), dried (Na2SO4) and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexanes/EtOAc) to give 2:08 g of colorless crystals.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.C(Cl)Cl.O=C1CCC(=O)N1[O:24][C:25](=O)[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:25](=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(C=CC=Cc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=CC=Cc1ccccc1)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (1.09 g, 5.0 mmol) in anhydrous methylene chloride triethylamine (0.61 g, 6.0 mmol) was added and the mixture was stirred at ambient temperature for 30 min. The mixture was cooled in the ice bath and a solution of 5-phenyl-penta-2,4-dienoic acid 2,5-dioxo-pyrrolidin-1-yl ester (10) (1.35 g, 5.0 mol) in methylene chloride (20 ml) was added. The reaction mixture was stirred at ice bath temperature for 1.5 hours and at ambient temperature for 2 hours. The solvent was removed and the residue was suspended in water. The precipitate was filtered and washed with water and hexane to give the title compound 11 (1.0 g, 68%). 1H NMR (CDCl3, HMDSO) δ: 1.92-2.32 (2H, m); 3.31-3.67 (4H, m); 6.00 (1H, d, J=15.0 Hz); 6.07 (1H, br s); 6.78-6.96 (2H, m); 7.22-7.61 (6H, m).
Reaction SMILES: CO.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:22](#[N:25])[CH:23]=[CH2:24].O>O1CCOCC1>[C:22]([CH2:23][CH2:24][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:25]
Reactant: C=CC#N
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC#N)c2c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A 40% solution of Triton B in methanol (0.50 mL, 1.1 mmol) is added to a suspension of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 2.6 g, 10.0 mmol) and acrylonitrile (2.2 mL, 33.4 mmol) in 1,4-dioxane (25 mL). The reaction mixture is warmed to 55° C. for 30 min and then it is stirred at room temperature for 18 h. Water (30 mL) is added and the mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title crude compound (3.0 g, 96%) as a yellow solid which is used in the next step without purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl.C([NH:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>C(O)(C)C>[O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:23][CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(CCNCc1ccccc1)NCc1ccccc1
Reactant: c1cc(OCC2CO2)c2ccoc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(CCNCC(O)COc1cccc2occc12)NCc1ccccc1

Procedure:
In a similar manner to that described above but using a mixture of 1-(benzo[b]furan-4-yloxy)-2,3-epoxypropane (1.9 g.), β-benzylamino-N-benzylpropionamide hydrochloride (3.05 g.), sodium hydrogen carbonate (0.84 g.), water (5 ml.) and isopropanol (40 ml.) there is obtained 1-(benzo[b]furan-4-yloxy)-3-β-(N-benzylcarbamoyl)ethylamino-2-propanol, m.p. 109°-110° C. The β-benzylamino-N-benzylpropionamide hydrochloride used as starting material may also be prepared in the manner described above, m.p. 237°-239° C.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([CH3:41])[CH:34]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: Cc1cc(B(O)O)ccc1Cl
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+]
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C

Procedure:
The following compounds were made via method 65. A vial was charged with 1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.300 g, 0.587 mmol), (4-chloro-3-methylphenyl)boronic acid (0.150 g, 0.881 mmol), potassium carbonate (0.244 g, 1.762 mmol), and Pd(Ph3P)4 (0.068 g, 0.059 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2.2 mL) and water (0.73 mL) were added. The vial was sealed and heated to 90° C. for 2 h. The mixture was cooled, quenched with NH4Cl and extracted with EtOAc (5×). The combined organic extracts were concentrated, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give 1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. This material was purified by chiral SFC on Chiralpak AS-H column (25% MeOH/75% CO2) to give (P)-1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 2, both as off-white solids. Data for peak 1: 1H NMR (400 MHz, DMSO-d6) δ=11.68 (br. s., 1H), 8.66 (s, 1H), 8.35 (d, J=1.96 Hz, 1H), 8.23 (d, J=9.68 Hz, 1H), 7.86 (dd, J=2.10, 8.95 Hz, 1H), 7.67 (s, 1H), 7.55-7.61 (m, 2H), 7.44 (dd, J=1.71, 8.27 Hz, 1H), 7.32 (s, 1H), 6.77-6.88 (m, 2H), 6.41 (d, J=1.66 Hz, 1H), 3.73 (s, 3H), 2.44 (s, 3H). m/z (ESI) 557.1 (M+H)+. Data for peak 2: 1H NMR (400 MHz, DMSO-d6) δ=11.68 (br. s., 1H), 8.63 (br. s., 1H), 8.33 (d, J=1.86 Hz, 1H), 8.22 (d, J=9.68 Hz, 1H), 7.82-7.88 (m, 1H), 7.67 (s, 1H), 7.57-7.60 (m, 2H), 7.41-7.47 (m, 1H), 7.32 (s, 1H), 6.77-6.85 (m, 2H), 6.39 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H). m/z (ESI) 557.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1)([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: CCc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCc1cc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.079 g, 0.22 mmol) in 1.5 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-2-ethylaniline (0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (43 mg, 40% yield). MS/ES+: m/z=507.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:53](=[O:54])[C@@H:49]([CH:50]([CH3:51])[CH3:52])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (1.27 g) and N-(9-fluorenylmethoxycarbonyl)-D-valine (1.00 g) were treated in the same manner as in Preparation Example 9 to obtain the title compound. Since impurities were unable to be removed from this compound, the compound was provided to the next step without purifying it.