Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[C:30]([Cl:31])=[C:29]([Cl:32])N=[C:27]([Cl:33])[C:26]=1[Cl:34])([O-])=O>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:29]([Cl:32])=[C:30]([Cl:31])[C:25]([NH2:22])=[C:26]([Cl:34])[CH:27]2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC1=C(Cl)C(Cl)N(C2CCN(Cc3ccccc3)CC2)C(Cl)=C1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
8.7 g 1-benzyl-4-aminopiperidine, 4.6 g triethylamine and 10 g 4-nitro-2,3,5,6-tetrachloropyridine was added to 100 ml absolute dioxane and stirred for 5 hours at room temperature. After removing dioxane by distillation, the residue was taken up in methylene chloride, admixed with 2 normal hydrochloric acid and stirred vigorously for 30 min. The precipitated precipitate was separated, taken up in a small amount of water, made alkaline with 2 normal ammonia and the aqueous solution was extracted several times with dichloromethane. 13.9 g N-(1-benzylpiperidin-4-yl)-4-amino-2,3,5,6-tetrachloropyridine is obtained as an oil. TLC (mobile solvent: toluene/dioxane/water 9:4.5:0.5), Rf=0.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Br[CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCCOC1CCCCO1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.97 g (10 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 160 ml THF was treated at −78° C. with 13.13 ml (21 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h. 11 ml DMPU were added and 10 min later 4.60 g (20 mmol) of 1-bromo-3-tetrahydropyranyloxypropane in 15 ml THF were added over a period of 20 min. The reaction mixture was warmed up to RT for 16 h, cooled, poured into cooled aqueous saturated NH4Cl and extracted (Et2O 3×). The organic phase was washed with aqueous 10% NaCl, water, dried over Na2SO4, evaporated and purified by flash silica gel column (Hexane/EtOAc 98:2 to 90:10) to yield 1.61 g (42%) of trans-Methyl-{4-[5-(tetrahydro-pyran-2-yloxy)-pent-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 378 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24]CC)=[O:23].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 0.33 h

Procedure:
A solution of 5.3 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in 30 ml of dimethylformamide is added dropwise to a suspension of 0.65 g of sodium hydride (50% suspension in oil) in 30 ml of dimethylformamide. After stirring for 20 min, 1.4 ml of ethyl bromoacetate is added. The reaction mixture is stirred for 1 hr, poured into water and the precipitate is collected. The precipitate is added to 30 ml of 15% sodium hydroxide solution and 30 ml methanol and heated at reflux for 3 hr. The mixture is poured into water, acidified and filtered. Recrystallization from toluene and acetonitrile gives {[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid, mp 207° C.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27](N)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]>>[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]
Reactant: N=C1NC(=O)c2ccccc21
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared from 3-imino-2,3-dihydro-isoindol-1-one and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 86. MS, m/z 424.5=M+1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:23][CH2:22]1)=[O:42]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 225 (502 mg, 1.02 mmol) is treated with acid chloride 8 (301 mg, 1.13 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[C:25]([CH3:24])=[N:26][O:27][C:28]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: CC(=O)N(C)C
Product: Cc1noc(C)c1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 72.5 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (160 mg, 0.52 mmol), N,N-dimethylacetamide (3.2 mL) and 3,5-dimethylisoxazole-4-carbonyl chloride (99 mg, 0.62 mmol) and in the same manner as in Example 120, the title compound (163 mg, 73%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(NN)c1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(OC)c2)n1
Yield: 85 %

Procedure:
Starting from 1.5 g (5.2 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoro-methyl)phenyl]but-1-en-1-olate from example 1A and 1 g (5.73 mmol) of 3-methoxyphenylhydrazine hydrochloride, 1.73 g (4.4 mmol, 85% yield of theory) of product are obtained according to the method described in example 4A and after purification on silica gel (flash chromatography).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2ccncc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7-isoquinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was partitioned between dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.83 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless solid, mp 144°-145° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20].[NH:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:21][C@H:22]([C:27](=[O:28])[NH:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20])[CH2:23][CH:24]([CH3:25])[CH3:26])([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-Amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt (0.21 g, 0.59 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.88 mmol) and HBTU (0.34 g, 0.90 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at RT overnight. DMF was removed under high vacuum. The residue was diluted in EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave the title compound (0.2 g, 68% yield). MS (M+H+): 499.1; 1H-NMR (400 Hz, CDCl3): 8.75(d, 1H), 8.0-7.75(m, 2H), 7.5 5(m, 1H) 5.10(m, 1H), 4.15-2.90(m, 10H), 2.10-1.48(m, 14H), 1.00(m, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][NH2:13].[CH2:14](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][N:6]3[CH:14]=[N:13][N:12]=[C:5]3[C:4]=2[CH:3]=1
Reactant: NNc1ncnc2ccc(Cl)cc12
Reactant: CCOC(OCC)OCC
Product: Clc1ccc2ncn3cnnc3c2c1
Reaction time: 48 h

Procedure:
A mixture of 155.7 gms. of 6-chloro-4-hydrazinoquinazoline and 3000 ml. of triethoxy methane is refluxed with stirring for 48 hours, and after filtering off the insoluble material, the filtrate is evaporated in vacuo to dryness and the residue recrystallized from ether to obtain 9-chloro-1,2,4-triazolo[4,3-c]quinazoline, m.p. 179°-182° C.
Reaction SMILES: C([O:6][C:7]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:10]([OH:11])=[C:9]([Cl:16])[C:8]=1[Cl:17])CCCC.Cl[C:19]1[C:20](=O)[C:21](C#N)=C(C#N)[C:23](=O)[C:24]=1Cl>CO>[CH2:23]([C:13]1([Cl:14])[CH:12]([Cl:15])[C:10](=[O:11])[C:9]([Cl:16])=[C:8]([Cl:17])[C:7]1=[O:6])[CH2:24][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: CCCCCC1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C1Cl
Reaction time: 2 h

Procedure:
To a solution of 110 mg (0.388 mmol) of 3 in methanol, 880 mg (10 eq) of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added. The reaction mixture was stirred for 2 hr, and then the solvent was removed. Silicagel chromatography (hexane: EA=20:1) gave 4 as an orange solid with quantitative yield.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][N:4]=1.[O:11]1CCOCC1>O>[F:10][C:6]1[C:7]([I:9])=[CH:8][C:3](=[O:11])[NH:4][CH:5]=1
Reactant: C1COCCO1
Reactant: Fc1cc(I)c(F)cn1
Agent: Cl
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 50 %

Procedure:
Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness and the residue was triturated in water (20 mL). The solids were collected via filtration and washed with water (2×30 mL) and hexanes (3×30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.68 (d, J=2.34 Hz, 1 H) 11.50 (br. s., 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][OH:18]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][OH:18]
Reactant: OCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromophenol (36.38 g, 210.3 mmol) in acetone (175 ml) was added K2CO3 (0.033 g, 237 mmol) and 2-bromoethanol (20 ml, 283.3 mmol). The reaction mixture was heated at reflux under argon for 4 days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (150 ml) and the solution was washed successively with water, 10% aqueous NaOH, 5% aqueous NaOH, water, and brine. The solution was dried over MgSO4 and concentrated under reduced pressure to give 2-(3-bromophenoxy)ethanol (106) as a light brown oil. Yield (21.07 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 6.85 (ddd, J=7.8, 2.4, 1.3 Hz, 1H), 4.05-4.07 (m, 2H), 3.93-3.97 (m, 2H), 2.11 (t, J=12.3 Hz. 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:10][CH2:9]2)[N:7]=1.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH2:26])[CH3:25])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]>C(O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH:26][CH2:9][CH:8]([OH:10])[C:6]2[N:7]=[C:3]([C:2]([F:12])([F:11])[F:1])[S:4][CH:5]=2)[CH3:25])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: FC(F)(F)c1nc(C2CO2)cs1
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
0.54 g (0.030 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)ethylene oxide is dissolved in 5 ml of ethanol, and the solution is added dropwise within 10 minutes to a boiling solution of 0.58 g (0.0030 mol) of 2-(4-carbomethoxyphenyl)-1-methylethylamine in 13 ml ethanol. The mixture is then boiled under reflux for 5 hours, the solvent is removed by distillation, and the base is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:13]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)C2C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-1,3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53) in THF (20 mL) is added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise addition of 2.5M n-BuLi (4.16 mL, 10.4 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (405 μL, 6.5 mmol) and let stir for 20 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 45% ethyl acetate/hexanes) to give 679 mg of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[C:42]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Temperature: 85 °C
Yield: 61.3 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (2.0 g, 3.82 mmol), 3-fluorophenyl boronic acid (1.07 g, 7.64 mmol), trans-dichlorobis(triphenylphosphine)palladium II (536 mg, 0.76 mmol) and cesium fluoride (5.2 g, 34.4 mmol) along with 100 mL degassed acetonitrile and heat at 85° C. for 4 hours or until all the starting triflate is consumed. Cool the reaction, filter and purify on an SCX column eluting with 2N ammonia/methanol. The crude yield is 1.5 g (83%). Further purify the crude material on a silica column, eluting with 3% methanol/methylene chloride to give 1.1 g of the title compound (63%): 1H-NMR (CDCl3, 400 MHz) δ 7.81 (d, J=9.6 Hz, 1H); 7.73 (d, J=8.4 Hz, 1H); 7.39 (d, J=8.4 Hz, 1H); 7.28-7.25 (m, 1H); 7.19 (d, J=2.4 Hz, 1H); 7.11-7.06 (m, 2H); 7.04-7.01 (m, 2H); 6.88 (d, J=9.2 Hz, 2H); 6.75 (dd, J=6.4, 2.4 Hz, 2H); 4.34 (s, 2H); 4.07 (t, J=6.0 Hz, 2H); 3.93 (s, 3H); 2.81 (t, J=6.0 Hz, 2H); 2.57-2.57 (m, 4H); 1.67-1.61 (m, 4H); 1.48-1.46 (m, 2H).
Reaction SMILES: CO.[C:3]1([P:9](=S)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[OH:24].[Na+].Cl[O-].[Na+]>O>[C:3]1([P:9](=[O:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of methanol (125 ml), triphenylphosphine sulfide (7.5 g) and aqueous 2.5% sodium hydrogen carbonate (25 ml) is added aqueous 14.3% sodium hypochlorite (125 ml) at 10° C. to 15° C., and the mixture is stirred for 1 hour at the same temperature. The reaction mixture is diluted with water (500 ml), and the separated crystals are collected by filtration, washed with water and dried to give triphenylphosphine oxide (6.5 g). m.p. 154°-157° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[N:30]=[CH:29][N:28]=3)[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.8 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-amino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (˜3.4 mmol) in isopropanol (10 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (0.97 g, 1.2 eq) and diisopropylethylamine (0.88 g, 2 eq). The mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography eluting with 1% and 5% MeOH in dichloromethane to provide tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexylcarbamate (2.0 g, ˜100%). LC/MS found [M+H]+=551.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[CH:40][CH:39]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1ccc(CCCCCCCCO)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154 %

Procedure:
A solution of Intermediate 7 (182 mg, 0.6 mmol), 4-(8-hydroxyoctyl)benzoic acid (100 mg, 0.4 mmol, e.g. preparable according to K. Fukai JP11174621), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP, 208 mg, 0.4 mmol, e.g. available from Aldrich) and N,N-diisopropylethylamine (0.276 ml, 1.6 mmol) in dry N,N-dimethylformamide (3 ml) was allowed to stir at room temperature for 4 hours. The solvent was evaporated and the residue partitioned between chloroform (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml); the organic fraction was collected by passing through a hydrophobic frit and evaporated. The residue was dissolved in chloroform (20 ml), and the solution passed through a 10 g aminopropyl SPE cartridge under gravity. The cartridge was further eluted with 10% methanol in chloroform, and product containing fractions evaporated to give the title compound (330 mg). LCMS showed MH+=536; TRET=2.92 min.