Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])[CH:10]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:30])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:33])=[N-]>C(OCC)C>[CH3:33][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:19])[CH2:15][CH2:16][C:17]2=[O:18])[CH:10]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]1=[O:30])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=[N+]=[N-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O

Procedure:
1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one was treated with a diazomethane solution in diethyl ether and after evaporation of the reaction mixture to dryness, the residue was purified by column chromatography on silica gel using a 5:3 (v/v) mixture of toluene and ethyl acetate, and finally only ethyl acetate, as an eluent. The structure of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one so obtained was confirmed by mass-spectrometry and PMR and IR spectroscopy.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)N)#[CH:23]>>[C:22]([C:24]1[CH:30]=[C:29]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:26][CH:25]=1)#[CH:23]
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCN(C(=O)OCC)C4)c1

Procedure:
In analogy to Example 38A, the title compound was prepared from ethyl 3-cyano-2-{[(1E)(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.20 g, 4.14 mmol) and 3-ethynylaniline (968 mg, 8.27 mmol) to yield 443 mg (28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC21
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (100 mg, 0.31 mmol) in dichloromethane (3 mL) at −78° C. was added dropwise boron tribromide (0.79 mL, 0.79 mmol; 1.0M in CH2Cl2). After 5 min, the reaction was warmed to 0° C. and an additional 0.2 mL of boron tribromide (1.0 M in CH2Cl2) was added. After 2 h, the yellow mixture was recooled to −78° C. and quenched with water. The reaction was warmed to room temperature and stirred for 14 h. The mixture was then concentrated, quenched again with aqueous hydrogen chloride (3M), and the resulting yellow solution was concentrated to dryness. The residue was diluted with tetrahydrofuran (10 mL) and saturated aqueous sodium bicarbonate (1 mL). Di-tert-butyl dicarbonate (69 mg, 0.31 mmol) was added, and the mixture was stirred for 1 h. The reaction was then diluted with ethyl acetate and the layers were separated. The organic layer was then dried over sodium sulfate, fitered, and concentrated. The resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) to give the desired product as an off-white solid (86 mg, 90%). MS (ESI) 305.3 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH:4]([C:15]2[CH:16]=[N:17]C=N[CH:20]=2)[N:3]1[CH2:21][CH:22]([CH3:24])[CH3:23].O=C1C2C(=CC(F)=CC=2)C(C(O)=O)C(C2[S:41]C(C#N)=CC=2)N1CC(C)C.O=C1C2C(=CC=C(F)C=2)C(C(O)=O)C(C2C=NN(C)C=2)N1CC(F)(F)F.O=C1C2C(=CC=CC=2)C(C(O)=O)C(C2SC(C#N)=CC=2)N1CC1CC1.O=C1C2C(=CC=CC=2)C(C(O)=O)C(C2SC(C#N)=CC=2)N1CCCC.C(N1C(C2C=NC=CC=2)C(C(O)=O)C2C(=CC(OC)=CC=2)C1=O)C(C)C>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH:4]([C:15]2[CH:16]=[N:17][S:41][CH:20]=2)[N:3]1[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN1C(=O)c2ccccc2C(C(=O)O)C1c1cncnc1
Reactant: CC(C)CN1C(=O)c2ccc(F)cc2C(C(=O)O)C1c1ccc(C#N)s1
Agent: CCCCN1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(C#N)s1
Agent: COc1ccc2c(c1)C(=O)N(CC(C)C)C(c1cccnc1)C2C(=O)O
Agent: Cn1cc(C2C(C(=O)O)c3ccc(F)cc3C(=O)N2CC(F)(F)F)cn1
Product: CC(C)CN1C(=O)c2ccccc2C(C(=O)O)C1c1cnsc1

Procedure:
1-oxo-2-isobutyl-3-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; 1-oxo-2-isobutyl-3-(5-cyanothiophen-2-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; 1-oxo-2-(2,2,2-trifluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; 1-oxo-2-cyclopropylmethyl-3-(5-cyanothiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; 1-oxo-2-(1-butyl)-3-(5-cyanothiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; and 2-isobutyl-7-methoxy-1-oxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([CH:9]=1)[NH2:8].FC(F)(F)C1C=CC(OC)=C([N:22]=[C:23]=[O:24])C=1.[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30]>>[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([N:8]([C:34]2[CH:43]=[CH:44][CH:45]=[C:32]([C:29]([OH:31])=[O:30])[CH:33]=2)[C:23]([NH2:22])=[O:24])[CH:9]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Agent: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Product: COc1ccc(C(F)(F)F)cc1N(C(N)=O)c1cccc(C(=O)O)c1

Procedure:
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N-(3-carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according to Method D1c.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[CH3:13])[CH3:2].Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=2)=[CH:6][C:5]=1[CH3:13])[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1ccc(B(O)O)cc1C
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: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(-c2cccc(N)c2)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
4-ethoxy-3-methylphenyl boronic acid (0.125 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.071 g in 67% yield.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CCCCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](SCCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 106.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (82.6 mg, 0.142 mmol), 6-bromo-2-methyl-2-hexanol (139 mg, 0.710 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to give 87.2 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 6-bromo-2-methyl-2-hexanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[F-:12].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([F:12])(=[O:10])=[O:9]
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=S(=O)(F)c1ccccc1F
Temperature: -5 °C

Procedure:
A 100-L round bottomed flask fitted with overhead stirrer, nitrogen inlet, temperature probe and ice bath was charged with 2-fluorobenzenesulfonyl chloride (50 g) and tetrahydrofuran (220 g). The solution was cooled down to −5° C. with an ice bath. Tetrabutylammonium fluoride (270 mL of 1M in tetrahydrofuran solution) was added slowly to the reactor. The internal temperature was kept less than 8° C. After the addition was completed, HPLC showed the reaction was completed. The reaction was quenched by slowly adding 250 g of water. Then 430 g of toluene was added to the reaction mixture. The layers were separated. The organic layer was washed with 250 g of water twice. The organic layer was distilled down under vacuum with the bath temperature at 48° C. 1H NMR (400 MHz, CDCl3) δ 8.01-7.96 (m, 1H), 7.76-7.83 (m, 1H), 7.32-7.44 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])=[O:12].S(Cl)([Cl:28])=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([Cl:28])=[O:17])(=[O:13])=[O:12]
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 18 h

Procedure:
4 g of (S)-2-(2-naphthylsulonylamino)-3-phenyl-propionic acid are dissolved in 40 ml of anhydrous benzene-anhydrous tetrahydrofuran (3:1), and 3.2 ml of thionyl chloride are added thereto. The mixture is stirred at 40° to 50° C for 18 hours. The reaction mixture is condensed to dryness under reduced pressure, and the residue is recrystallized from a mixture of benzene and n-hexane. 3.2 g of (S)-2-(2-naphthylsulfonylamino)-3-phenyl-propionyl chloride are obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[BH4-].[Na+].O>CO.O1CCCC1>[CH2:17]([CH:3]([CH2:1][CH3:2])[CH:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=2[C:10]=1[CH3:11])[OH:5])[CH3:18]
Reactant: CCC(CC)C(=O)c1oc2ccc(F)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)C(O)c1oc2ccc(F)cc2c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 106.9 %

Procedure:
2-Ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-1-one (15.0 g) synthesized above was dissolved in a mixed solvent of methanol (50 mL)-tetrahydrofuran (250 mL), and sodium tetrahydroborate (90%, 5.1 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (16.17 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:24])[CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CN(CCN)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
1.62 g (10 mmol) of 4-tert-butyl benzaldehyde and 1.85 g (10 mmol) of N-(4-chloro -phenyl)-N-methyl-ethane-1,2-diamine were dissolved in 20 ml methanol and the solution was stirred for 2 h at rt. 567 mg (15 mmol) of sodium borohydride were added in portions under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the solvent was evaporated. The reaction mixture was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the 2.97 g (90%) product as a yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.34 (d, 2H), 7.24 (d, 2H), 7.13 (d, 2H), 6.64 (d, 2H), 3.77 (s, 2H), 3.42 (t, 2H), 2.91 (s, 3H), 2.83 (t, 2H), 1.30 (s, 9H).
Reaction SMILES: C([Mg]Cl)(C)C.Cl[CH2:7][CH2:8][CH2:9][OH:10].[Mg].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19]>O1CCCC1.BrCCBr>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([OH:19])[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCCCCl
Reactant: O=Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OCCCC(O)c1ccccn1
Yield: 54.2 %

Procedure:
i-Propyl magnesium chloride (11.6 ml, 2M in tetrahydrofuran) was added dropwise to a solution of 3-chloropropanol (2.1 g) in tetrahydrofuran (20 ml) at 0° C. Magnesium turnings (0.8 g) and 1,2-dibromoethane (1 drop) were added and the mixture was refluxed for 5hand then added at 0° C. to a solution of pyridine-2-carboxaldehyde (1.3 g) in tetrahydrofuran (10 ml). The mixture was quenched with aqueous ammonium chloride and basified to pH 9 with aqueous potassium carbonate. Extraction with ethyl acetate and then extraction of the residual inorganics with methanol, followed by evaporation and purification by chromatography on silica eluting with dichloromethane—2M ammonia gave the sub-title compound as a brown oil (1.1 g).
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.[OH-].[NH4+:10]>CO>[NH2:10][C@@H:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:8]
Reactant: [NH4+]
Reactant: C1CCC2OC2CC1
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CCCCC[C@H]1O

Procedure:
In a sealed tube, cycloheptene oxide (5.44 g; 48.50 mmol)and ammonium hydroxide solution (10 ml) in 4 ml methanol is heated to 80° C. for 72 hrs. After removal of the heat, the mixture is concentrated in vacuo to obtain trans-2-aminocycloheptanol which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
Methyl 2-(4-fluorophenyl)-2-methylpropanoate (5.08 g, 26.9 mmol) was dissolved in THF (51 ml) and cooled to 0° C. before adding a solution of lithium aluminium hydride (1M in THF) (38.8 ml, 38.8 mmol) dropwise over 30 mins. When the addition was complete, the reaction was warmed to r.t. and stirred for 3 h. After recooling on ice, water (1.35 ml) was added cautiously followed by 15% NaOH in water (1.35 ml) and more water (4.05 ml). The suspension was stirred at r.t. for 30 mins before the solid was filtered off and washed with THF (2×30 ml). The solvent was evaporated and the product purified by chromatography with EtOAc/heptanes to give a clear oil (3.48 g, 80%): MS (ESI+) for C10H13FO m/z 168.2 [M+H]+; LC purity 94% (ret. time, 1.76 min); 1H NMR (500 MHz, CDCl3) δH 7.41-7.32 (m, 2H), 7.15-7.00 (m, 2H), 3.62 (d, J=6.4 Hz, 2H), 1.35 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenol (see example 13) (150 mg, 0.44 mmol, 1.0 eq) in DMF (2 mL) was added Cs2CO3 (214 mg, 0.66 mmol, 1.5 eq) and the reaction mixture was stirred for 1 h. Isopropyl 2-bromoacetate (80 mg, 0.44 mmol, 1.0 eq) was then added and the reaction was stirred for a further 1 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound as a colourless oil (130 mg, 80%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].ClCCl.[NH3:27]>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH2:27])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: N
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(N)=S)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 98.1 %

Procedure:
To a stirred solution of 20 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine in 325 parts of dichloromethane were added 40 parts of methanol, saturated with ammonia. The reaction mixture was stirred for 5 days at room temperature. The precipitated product was filtered off, washed with dichloromethane and dried, yielding 20.5 parts (98.1%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 265.2° C. (int. 1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([NH:40][C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C(=O)O)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
3-(Acetylamino)-2-[4-(tert-butoxycarbonyl)phenyl]propanoic acid (222 mg, 0.72 mmol), EDCI (207 mg, 1.08 mmol), and HOBT (127 mg, 0.94 mmol) were dissolved in DMF (7 mL) and stirred for 5 minutes before adding aniline (99 μL, 1.08 mmol). After stirring at room temperature for 18 h, the solution was concentrated. The resulting residue was taken up in EtOAc, washed (water, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica (0-4% MeOH/DCM) afforded tert-butyl 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoate as an off-white solid. 1H NMR (DMSO-d6) δ10.18 (s, 1H), 8.08 (t, J=5.9 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.56 (d, J=7.6 Hz, 2H), 7.46 (d, j=8.2 Hz, 2H), 7.25 (t, J=7.9 Hz, 2H), 7.00 (t, J=7.5 Hz, 1H), 4.03 (dd, J=8.2, 6.3 Hz, 1H), 3.51 (ddd, J=13.2, 8.4, 5.0 Hz, 1H), 3.42 (dt, J=12.9, 6.5 Hz, 1H), 1.74 (s, 3H), 1.50 (s, 9H). MS (ESI) calcd [M+H]+ 383.2, found 383.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])=[O:6].C([C:29]1[C:30]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:31][CH:32]=[CH:33][CH:34]=1)#N.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(NC3C=CC=C(C(F)(F)F)C=3)=O)=NC=NC=2N=1)(C)C.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([S:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:2]([NH:1][C:39]2[C:29]3[CH:34]=[CH:33][CH:32]=[N:31][C:30]=3[N:35]=[CH:36][N:37]=2)[CH:3]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2Br)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccccc1Br)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 60 %

Procedure:
The product of Example 31A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 3 1A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (58 mg, 60%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.48 (d, J=5.88 Hz, 2 H) 6.84 (d, J=8.46 Hz, 2 H) 6.87-7.02 (m, 1 H) 7.13-7.44 (m, 5 H) 7.58-7.64 (m, 1 H) 7.64-7.84 (m, 2 H) 7.93 (s, 1 H) 8.62 (d, J=1.84 Hz, 1 H) 8.82-9.20 (m, 3 H) 9.94 (s, 1 H) 10.30 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.