Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(OC)C=C2OC(C)(C)CC=12)=O.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)c2c(c1)OC(C)(C)C2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)cc2c1CC(C)(C)O2
Solvent: ClCCl
Product: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To the mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (3d) (1.74 g, 7.36 mmol) in CH2Cl2 (10 mL) at 0° C. was added BBr3 (22.0 mL, 22 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at 0° C. for 6 hr, quenched with H2O (100 mL), extracted with CH2Cl2(2×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 10% EtOAc in hexanes to give an pale yellow solid (171 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1 H) 6.99 (s, 1 H) 5.87 (s, 1 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C12H14O4 m/z 223.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:10](=[O:28])[NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2)([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](O)=[O:4].[CH:29]1([CH2:32]N)[CH2:31][CH2:30]1.C([N:36](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:29]1([CH2:32][N:11]([C@@H:12]2[C:18](=[O:19])[NH:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]2=3)[C:10](=[O:28])[C:2]([OH:1])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([NH2:36])=[O:4])[CH2:31][CH2:30]1
Reactant: CC(C)CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCC1CC1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CC(O)(C(N)=O)C(=O)N(CC1CC1)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 17.7 %

Procedure:
A solution of 50.0 mg (0.13 mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 18.6 mg (0.26 mmol) cyclopropanmethylamine in 1.5 ml dimethylformamid were cooled to 0° C. and 20 μl (0.14 mmol) triethylamine and 54.5 mg (0.14 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) were added. Stirring was continued over the weekend at room temperature. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 19:1 to 1:1) yielded 10.0 mg (18%) (R/S)-N-cyclopropylmethyl-2-hydroxy-2-isobutyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide MS (m/e): 436.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13]CC)=O)[C:8]([N+:16]([O-])=O)=[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[N:6]=1.ClC1N=C([C:35](OCC)=[O:36])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.C(C[NH2:55])O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]2[C:8]([NH:16][C:35](=[O:36])[N:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:9]([C:11]([NH2:55])=[O:13])[N:10]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(NCCO)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NCCO)nc21
Yield: 95 %

Procedure:
Ethyl 2-(2-hydroxyethylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.250 g, 0.710 mmol), ethanolamine (0.052 g, 0.852 mmol) and diisopropylethylamine (0.137 g, 1.06 mmol) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 mL). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.250 g, 95%). MS (ESI) m/z 378.5 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.FC1C=CC([N+]([O-])=O)=CC=1C(F)(F)F.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[N:28]=1>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[N:28]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: Fc1cccc(F)n1
Reactant: COc1cc(Br)c(F)cc1O
Agent: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: COc1cc(Br)c(F)cc1Oc1cccc(F)n1

Procedure:
According to the procedure of example 20(a) except substituting 2-methoxy-4-propylphenol for 4-bromo-5-fluoro-2-methoxyphenol (441 mg; 2 mmol), and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 2,6-Difluoropyridine (0.18 mL; 2 mmol), the title compound was prepared as a yellow oil (246 mg; 39%), after purification on silica gel (cyclohexane/ethyl acetate: 95/5).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1Cl)C.[CH2:21](C(CC)CN)C>>[CH2:1]([NH:8][C:14]1[N:15]=[C:16]([CH3:21])[CH:17]=[CH:18][C:13]=1[C:12]([O-:11])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:2]1([CH2:1][NH3+:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)CN
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cccnc1Cl
Product: Cc1ccc(C(=O)[O-])c(NCc2ccccc2)n1
Product: [NH3+]Cc1ccccc1

Procedure:
The title compound was prepared as a benzylamine salt according to the procedure of Example 3A substituting 2-chloro-6-methyl-nicotinic acid for 2-chloro-nicotinic acid ethyl ester and benzyl amine for 2-ethylbutylamine (0.480 g, 46%). MS (ESI+) m/z 243.03 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H), 3.67 (s, 2H), 4.65 (s, 2H), 5.73 (br s, 3H), 6.16 (d, J=7.72 Hz, 1H), 7.17 (m, 10H), 7.76 (d, J=7.35 Hz, 1H), 8.66 (br s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[NH:31][CH2:30][CH:27]([NH:28][CH2:29]1)[CH2:26][CH2:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH:23]5[NH:31][CH2:30][CH:27]4[CH2:26][CH2:25][CH2:24]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 0.71 g (2.5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.54 g (2.7 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.13 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for 1.5 hr. The reaction mixture was stirred overnight at room temperature and filtered to obtain 0.40 g of the title compound, mp 268°-271° dec.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4]1)[CH3:2].Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([NH:18][CH2:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:19])=[O:10])=[CH:4]1)[CH3:2]
Reactant: CCn1ccc(C(=O)O)c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccn(CC)c1

Procedure:
Into a suspension of 3.33 g (23.9 mmol) of 1-ethyl-3-pyrrolecarboxylic acid, 4.41 g (28.7 mmol) of β-alanine ethyl ester hydrochloride and 5.50 g (28.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 40 ml of methylene chloride, 4.0 ml (28.7 mmol) of triethylamine were added dropwise under ice cooling and stirring. The reaction mixture was stirred at room temperature for 2.5 hours.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].S(O[CH2:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)(=O)(=O)C.C(OCC)(=O)C>O1CCCC1>[CH3:34][O:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH3:30])[C:26]=1[O:31][CH3:32])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine 2-pyrrolidinone (2.85 g, 33.5 mmol) and tetrahydrofuran (70 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (67 mL, 0.5 M in toluene, 33.5 mol). After 45 minutes, add a solution of 3,4,5-trimethoxybenzyl mesylate (8.8 g, 32.02 mmol) in tetrahydrofuran (60 mL). After the addition of 3,4,5-trimethoxybenzyl mesylate is complete, heat to reflux. After 18 hours, cool the reaction mixture and partition between water and ethyl acetate. Separate the aqueous layer and extract 4 times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])(=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(C2C=CC=CC=2N)(=O)=O)C=CC=CC=1.C(#N)CC#N.[OH2:44].[NH2:45][NH2:46]>>[NH2:22][C:21]1[C:18](=[N:17][NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:44])[C:19]([NH2:20])=[N:46][N:45]=1
Reactant: NN
Reactant: O
Reactant: N#CC(C#N)=NNc1ccccc1S(=O)(=O)c1ccccc1
Agent: Nc1ccccc1S(=O)(=O)c1ccccc1
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccccc1S(=O)(=O)c1ccccc1
Yield: 20 %

Procedure:
This compound was prepared using 94 mg (0.5 mmol) of 2-[(2-benzenesulfonylphenyl)-hydrazono]malononitrile, which was derived from 2-(phenylsulfonyl)aniline (233 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 20 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 68 mg (20%) of the title compound as an orange coloured solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][CH:7]=1.[ClH:18].Cl.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C@H:21]12>>[ClH:1].[ClH:18].[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:25]3[CH2:24][CH2:23][N:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:21]4[CH2:20]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OC
Reactant: C1CCN2CCNC[C@H]2C1
Agent: Cl
Product: COc1ccc(-c2ccc(N3CCN4CCCC[C@@H]4C3)nn2)cc1OC

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(3,4-dimethoxy-phenyl)-pyridazine and (R)-octahydro-pyrido[1,2-a]-pyrazine, dihydrochloride.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4,4-diphenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield. mp 198°-199°. FDMS m/e=426 (M+ of free base). α[D]589 =-17.80 (c=0.66, methanol).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:8]1[CH2:12][CH2:11][CH:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:9]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:7].[CH3:29][CH2:30][CH2:31]CCC>C1(C)C=CC=CC=1.CCOCC>[OH:7][CH:6]([CH:8]1[CH2:12][CH2:11][CH:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:9]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:4]#[C:3][CH2:2][CH2:1][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC
Reactant: O=CC1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC#CC(O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere at -40° C, a solution of 70.4 ml of n-butyl lithium in hexane (2.3 molar) is added dropwise to a solution of 1-heptane (14.78 g, 2.2 equivalents) in 50 ml of toluene. The mixture is stirred at the same temperature for 10 minutes. The solution is transferred carefully to an additional funnel and added at to a solution of 2-formyl-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid (22.82 g, 1 equivalent), described in Example 1, in 50 ml of toluene cooled to -70° C. The reaction is stirred at the same temperature for 2 hr. The mixture then is diluted with ether and washed with water. The aqueous layer is acidified with acetic acid and extracted with ether. The ether extract is washed with water, dried and concentrated to give the title compound, nmr (CDCl3) δ 0.89 (t, 3H), 3.90 (broad, 1H), 4.33 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][O:10]C.Cl>CC(C)=O.O.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1ccc(C(C)(C)O)cc1F
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(CC=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a room temperature solution of 2-{3-fluoro-4-[2-methoxyvinyl]phenyl}propan-2-ol (100 mg, 0.48 mmol) in acetone (5 mL) was added dropwise 4 M aqueous hydrochloric acid (5 mL, 20 mmol). The reaction was stirred at room temperature for two hours. The mixture was then diluted with 25 mL of water and 50 mL of diethyl ether. The water phase was extracted with diethyl ether (2×) and the combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCSc1ccc(F)cc1
Temperature: 80 °C

Procedure:
4-Fluorobenzenethiol (0.50 ml, 4.69 mmol) and 2-bromoethanol (0.345 ml, 4.87 mmol) was dissolved in tetrahydrofuran (12 ml). The solution was added with 1N aqueous solution of sodium hydroxide (4.8 ml,4.8 mmol) and heated at 80° C. for 80 minutes with stirring. The reaction mixture was diluted with a mixed solvent of ethyl acetate-hexane, and washed with diluted aqueous solution of sodium hydroxide, water, and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration and the filtrate was concentrated under reduced pressure to obtain 2-(4-fluorophenylthio)ethanol as crude product. By using the resulting product, 2-(4-fluorophenylthio)ethanol ethanesulfonate was obtained as crude product by similar procedures to those of Example 26a. By using the resulting product, the title compound was obtained as colorless solid by similar procedures to those of Example 26b (yield: 64%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1[C:62]2[CH:61]([CH2:63][CH2:64]O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[O:54][C:53]=2[CH:52]=[CH:51][CH:50]=1>C1COCC1>[CH2:28]([O:27][CH:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:64][CH2:63][CH:61]2[C:62]3[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=3[O:54][C:55]3[C:60]2=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:19][CH:18]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:29]
Reactant: OCCC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3Oc3ccccc32)cc1)OCC
Reaction time: 0.25 h

Procedure:
Diethyl azodicarboxylate (40% solution in toluene, 1.61 g, 9.3 mmol) was added dropwise, under argon, over 10 min to a solution of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropionate (2.23 g, 9.3 mmol) and triphenylphosphine (2.43 g, 9.3 mmol) in THF (45 ml). The mixture was stirred for 15 min, then a solution of 2-(9H-xanthen-9-yl)ethanol (2.0 g, 9.3 mmol) in THF (10 ml) was added dropwise over 10 min. The resulting mixture was stirred at room temperature for 60 h. The solvent was evaporated, the residue stirred with benzene (20 ml) and the resulting crystalline solid filtered off. The filtrate was evaporated and the residue purified by column chromatography on silica gel (benzene eluent) to give the title compound as an oil: (1.9 g, 45.8%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=O.[N:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>O1CCOCC1>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[C:25]([N:24]([CH2:23][CH2:22][CH2:21][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)=[O:43])[S:26][CH:2]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2csc(N(CCCN3CCOCC3)C(=O)c3cccs3)n2)c(OC)c1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A mixture of 2-bromo-2′,4′-dimethoxyacetophenone (156 mg, 0.6 mmol) and (3-morpholin-4-yl-propyl)-thiourea (122 mg, 0.6 mmol) in dry dioxane (5 ml) was heated at 80° C. for 2 h, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5 mL) followed by the addition of N,N-diisopropylethylamine (209 μL, 1.2 mmol) and thiophene-2-carbonyl chloride (96 μL, 0.9 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 2M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (207 mg) as an yellow solid as the hydrochloride salt. LC/MS (ESI) m/z 474.3 [M+H]. HPLC retention time (Method A)=2.81 min.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[C:15]([OH:17])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[NH:32][CH3:33]>C(Cl)Cl>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[N:32]([CH3:33])[C:15]([C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1nc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
To a suspension of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (1 eq, 0.38 mmol, 101 mg) in anhydrous DCM (3 ml), I drop of DMF was added, followed by 2M oxalyl chloride in DCM (1.7 eq, 0.65 mmol, 330 ul) dropwise. Effervescence was seen and the reaction was stirred at room temperature for 40 mins before evaporating in vacuo. The crude material was dissolved in DCM (3 ml) and 2-chloro-N-methyl aniline (2 eq, 0.76 mmol, 94 ul) was added. The reaction was stirred at room temperature for 16 hr and extracted into DCM, washed with aq K2CO3, the organic layer dried over MgSO4, filtered, and purified on silica (ISCO, gradient 0% ethyl acetate/petrol to 25% ethyl acetate/petrol) to give 326 as a white solid (42 mg, yield 30%). 1H NMR DMSO, 2.89-2.92 (2H, m), 3.43 (3H, s), 4.23 (2H, br. m), 7.02 (1H, d, J=8.4), 7.08 (1H, t, J=7.6), 7.26 (1H, t, J=8), 7.38-7.41 (2H, m), 7.48-7.51 (2H, m), 7.58 (1H, d, J=8.4). MS: (ESI+): MH+ 371, purity >95%.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33]O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(C=O)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Diisopropylazodicarboxylate (2.0 mL, 10 mmol) was added to a solution of 3-hydroxybenzaldehyde (1.23 g, 10 mmol), 2-(t-butyloxycarbonylamino) ethanol (1.6 g, 10 mmol), and triphenylphosphine 2.7 g, 10 mmol) with stirring in dry THF (50 mL) in an ice bath. After allowing the reaction mixture to warm to room temperature overnight, the solvent was evaporated under vacuum. The mixture was diluted with EtOAc (300 mL) and extracted with 1M NaOH (20 mL), water (2×20 mL), and brine (10 mL). After drying (MgSO4), and evaporation, the product was purified by chromatography on silica gel, eluting with 0% to 50% EtOAc in hexane. Evaporation of solvent yielded a pale yellow viscous oil (1.6 g), which was only about 80% pure. 1H NMR(300 MHz, CDCl3): major component 9.97 (s, 1H), 7.48-7.13 (m, 4H), 4.97 (br, 1H), 4.09-4.05 (m, 2H), 3.58-3.53 (m, 2H), 1.45 (s, 9H). IR(neat): cm-1 3353 (s, br), 1694 (s). MS(NH3): 283 (base, M+NH4).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[ClH:19].Cl.Cl.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:25][CH2:24]1.N1CCCCC1>C(N(CC)CC)C.C1COCC1>[ClH:19].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:13]([C:11]3[S:12][C:8]([C:5]4[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:30]2)[CH2:25][CH2:24]1
Reactant: CN1CCN(C2CCCNC2)CC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(N4CCN(C)CC4)C3)s2)noc1C(F)(F)F
Yield: 53 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-Methyl-4-piperidin-3-yl-piperazine, tri-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. An additional 3 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCO3 solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (47 mg, 53%). LC/MS 4.62 min, [M+1]+ 443.