Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH:25][CH3:26])=[O:24])[CH:18]=1>CN(C)C(=O)C>[CH3:26][NH:25][C:23]([C:19]1[CH:18]=[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:9])[CH:4]=2)[CH:22]=[CH:21][N:20]=1)=[O:24]
Reactant: Nc1ccc(O)cc1F
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1

Procedure:
In the first step 4-amino-3-fluorophenol was treated with potassium tert-butoxide and 4-chloro-N-methyl-2-pyridinecarboxamide was added in N,N-dimethylacetamide to form 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide which after extraction was finally treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate in toluene to form 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide which is the compound of formula (I).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH2:32][OH:33]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][CH2:32][OH:33])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: NCCO
Product: CCCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 43 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.050 mmol) and 2-aminoethanol (0.05 mL), was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (9 mg, 43% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.48 (br s, 1 H), 8.55 (s, 1 H), 7.27 (s, 1 H), 7.18-7.15 (m, 2 H), 7.05-7.01 (m, 2 H), 4.14 (s, 2 H), 4.07 (m, 2 H), 3.85 (m, 2 H), 3.63 (m, 2 H), 1.51 (m, 2 H), 1.33 (m, 2 H), 0.90 (m, 3 H); MS m/z 414 (M+1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(Cl)(Cl)Cl.Cl.[CH2:19]([OH:21])C>C1(C)C=CC=CC=1>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH:19]=[O:21])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Oc1cccc2c1CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(O)c2c1CCCC2
Reaction time: 0.25 h

Procedure:
5, 6,7,8-Tetrahydro-naphthalen-1-ol (108, 20 g, 135 mmol) was stirred in 100 mL of ethanol, and potassium hydroxide (7.57 g, 135 mmol) as an aqueous solution was added. The mixture was stirred for 15 minutes and went clear. Solvents were removed and dried. PEG (MW 380-420, 53 mL) was added, followed by chloroform (32.3 mL, 405 mmol) and toluene (34 mL). An aqueous potassium hydroxide solution (50% by weight, 54.4 mL) was introduced dropwise with stirring over 15 minutes. The stirring was continued for another 30 minutes. 1M HCl was added to acidify the reaction mixture and it was extracted with EtOAc three times. The combined organic layers were washed with water and brine The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by flash chromatography (0-40% EtOAc/hexane) to give 4-hydroxy-5,6,7, 8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]>ClCCl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(I)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1ccc(I)cc1C=O
Reaction time: 6 h

Procedure:
Manganese dioxide (0.044 g) was added to a stirred solution of 2-amino-5-iodobenzyl alcohol (0.125 g) in dichloromethane (10 cm3) and the mixture was stirred for 6 hours. A further portion of manganese dioxide (0.044 g) was then added and stirring was continued for 16 hours. The mixture was then filtered, the filtrate evaporated in vacuo, and the residue chromatographed on silica (Merck "MK 60.9385") eluting with ethyl acetate. The requisite fractions were combined and concentrated in vacuo to afford 2-amino-5-iodobenzaldehyde. 0.5H2O as a solid, m.p. 105°, (0.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Br[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: OC(CBr)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OC1CCN(c2cc(Br)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (4.83 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (5.6 g, yield 22%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:31][CH3:32])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=23)[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-1-(4-methylphenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (100 g, 284.7 mmol) and (5-fluoro-2-methoxyphenyl)boronic acid (58.05 g, 341.6 mmol) in dimethoxyethane (1600 mL) and water (440 mL) was added potassium carbonate (106.2 g, 768.6 mmol). The mixture was purged with nitrogen and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (13.95 g, 17.08 mmol) was added. The mixture was purged with nitrogen for 10 minutes and stirred at 100° C. for 1 hour. After concentration, the residue was diluted with ethyl acetate (1500 mL) and washed with aqueous sodium bicarbonate (twice) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30-60% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH3:14]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:13][CH3:14])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CCBr
Product: CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 50 %

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and ethyl bromide to provide 2-nitro-6-ethoxybenzonitrile (192 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1>ClCCl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:4]2[C:5]([F:8])=[CH:6][CH:7]=[C:2]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:3]=2[F:24])[O:22][CH3:23])=[CH:15][CH:16]=1)#[N:21]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(N)c1F
Solvent: ClCCl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(Nc2ccccc2)c1F
Temperature: 25 °C
Yield: 153.9 %

Procedure:
To a stirred solution of (RS)-2-(3-amino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (130 mg) at rt in dichloromethane were added sucessively dry 4A molecular sieves (50 mg), phenyl boronic acid (96 mg), triethylamine (0.11 ml), copper (II) acetate (71 mg) and TEMPO (67 mg). A “CaCl2 trap” was placed over the flask and stirring at rt was continued over the week-end. Then the solids were filtered off and washed with EtOAc. The dark brown filtrate was concentrated to leave a dark brown residue. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 3:2) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-phenylamino-phenyl)-2-methoxy-acetamide (123 mg) as light grey gum. MS 408.3 ([M+H]+)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(C)=O>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCc4ccccc4)nc32)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and benzylamine (0.14 ml) in dry 1,4-dioxane (3 ml) were heated at 60° C. for 36 h. After this time benzylamine (0.14 ml) and dry dimethylsulphoxide (2 ml) were added and the mixture was heated at 60° C. for a further 72 h. The solvent was removed under reduced pressure. Purification was by trituration with diethyl ether and water.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[Br:7][C:5]1[N:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2nc(Br)cs2)cc1
Yield: 91.8 %

Procedure:
Following a modified procedure (Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707), a mixture of 2,4-dibromothiazole (486 mg, 2.0 mmol), 4-fluorophenyl boronic acid (266 mg, 1.9 mmol), and aqueous 2.0 M Na2CO3 solution (2.3 mL, 4.6 mmol) in DME (6.8 mL) was sparged with Ar for 3 min. Tetrakis(triphenylphosphine)palladium(0) (150 mg) was added and the reaction mixture was sparged with Ar for 1 min. The reaction was sealed and irradiated at 105° C. for 12 min in a microwave reactor. The reaction mixture was partitioned with EtOAc (50 mL) and saturated aqueous NaHCO3 solution (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 solution (10 mL), brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The crude material was purified by column chromatography over silica gel to provide 450 mg of 4-bromo-2-(4-fluorophenyl)thiazole which was directly used in the next step without further purification: LCMS (m/z): 259.9 (MH+), tR=1.08 min.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)=[CH:26][CH:25]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2)c2ncccc2c1=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(-c2cccc(-c3ccc(N4CCNCC4)cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-isopropyl-1-{3-[4-(4-tertbutyloxycarbonylpiperazin-1-yl)phenyl]-phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 11 in methylene chloride (10 ml/mmol) was added trifluororacetic acid (6 ml/mmol) and the resulting mixture was stirred at room temperature for 2 hours, then warmed gently for 15 minutes. The mixture was evaporated and the crude product was chromatographed on silica gel eluting with a 9:0.9:0.1 mixture of methylene chloride, methanol and 28% aqueous ammonium hydroxide to afford the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH3:16][NH:17][NH2:18]>ClCCl>[CH3:16][N:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[NH2:18]
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Reactant: CNN
Solvent: ClCCl
Product: CN(N)c1nc(C(F)(F)F)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 4-chloro-2-(trifluoromethyl)quinazoline (8 g, 0.0344 mol) in dry dichloromethane (100 ml) under nitrogen was added methyl hydrazine (1.74 g, 0.037 mol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was washed with water (2×100 ml), brine and dried. The solvent was removed under vacuum to afford 8 g (96%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Cl.[CH2:13]([OH:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14]
Reactant: COc1ccccc1CC#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 500 mL round-bottomed flask was added 2-(2-methoxyphenyl)acetonitrile (50.45 g, 343 mmol) in ethanol (101 mL). HCl (10.42 mL, 343 mmol) gas was bubbled through the suspension for 15 minutes. The HCl bubbler was removed and the reaction was stirred at ambient temperature for 48 hours. The reaction was diluted with 200 mL ether, and the suspension was filtered. The collected solid was washed with ether and dried under vacuum to provide the title compound as the hydrochloride salt. MS (DCI+) m/e 194.0 (M+H)+.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2(O)[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:51])[CH:29]=1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:51])[CH:29]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (98%): 1H NMR (300 MHz, CDCl3) δ 7.46-7.19 (m, 3H), 7.03-6.68 (m, 3H), 5.03 (s, 1H), 3.76-3.67 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 332 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[N+:26]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (10 g, 26 mmol) in dioxane (50 mL) was added hydrogen chloride in dioxane (4 M, 50 mL, 200 mmol), and the mixture was stirred at rt for 16 h. The volatile materials were then removed to provide 2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline dihydrochloride in quantitative yield. MS (EI) for C15H15N3O3: 286 (MH+).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].CC(C)([O-])C.[K+].Br[C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:4]
Reactant: COC(=O)C(C)(C)Br
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(C#N)C#N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A 12 liter 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen bubbler, was charged with malononitrile (251 g, 3.802 moles) and THF (2 liters). Potassium t-butoxide (1M THF, 3.802 L, 3.802 moles) was then added. The mixture was stirred at 50° C. for 30 min. Methyl 2-bromoisobutyrate (688 g, 3.80 moles) was added and the reaction mixture was stirred overnight at 50° C. The reaction was partitioned between aqueous 1N HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.35 (s, 1H); 3.73 (s, 3H); 1.43 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>ClCCl.O>[CH:21]([NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: CC(C)N=C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (0.20 g, 0.70 mmol, 1.0 equiv.) in dichloromethane (4 mL) was added isopropyl isocyanate (0.07 mL, 0.83 mmol, 1.2 equiv.) and TEA (0.19 mL, 1.37 mmol) at 0° C. The reaction was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give tert-butyl (2-(3-isopropylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.18 g, 70% yield).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:6].ClN1C(=[O:21])CCC1=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][SH:2]1(=[O:21])[CH2:3][C:4]2[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[NH:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSCc1cc(C(F)(F)F)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[SH]1(=O)Cc2cc(C(F)(F)F)ccc2N1
Temperature: 5 °C
Reaction time: 0.13 h

Procedure:
To 10.2 g. of α-methylthio-4-trifluoromethyl-o-toluidine predissolved in 50 ml. of methylene chloride and cooled to -38° C. is added dropwise, over 40 minutes, a solution of 6.2 g. of N-chlorosuccinimide predissolved in 250 ml. of methylene chloride, while the temperature is maintained between -28° and -38° C. After an additional 8 minutes, 13.3 ml. of a 15% aqueous sodium hydroxide solution is added, the cold bath is removed and the reaction mixture allowed to warm to 5° C. To the reaction mixture is added 100 ml. of water, the mixture is shaken, and the phases are separated. The methylene chloride layer is cooled to -20° C. and treated with a solution of 9.7 g. of m-chloroperoxybenzoic acid predissolved in 150 ml. of methylene chloride, added dropwise over 10 minutes. The cold bath is removed and the reaction mixture stirred for 20 minutes, after which time, it is washed successively with an aqueous solution of sodium sulfite and sodium bicarbonate and a saturated aqueous solution of sodium bicarbonate. The phases are separated and the methylene chloride layer is dried, evaporated in vacuo to dryness, and the residue recrystallized from chloroform/petroleum ether to yield 2-methyl-5-trifluoromethyl-2H,3H-2,1-benzisothiazole-S-oxide, m.p. 151°-154° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C([O:19][P:20]([O:24]CC)[O:21]CC)C>>[P:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][P:20]([OH:24])([OH:21])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)([OH:24])([OH:21])=[O:19]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(-c2ccc(CBr)cc2)cc1
Product: O=P(O)(O)Cc1ccc(-c2ccc(CP(=O)(O)O)cc2)cc1
Temperature: 140 °C
Yield: 123.1 %

Procedure:
16.97 g (49.9 mmoles) of 4,4'-bis (bromomethyl) biphenyl and 52.04 ml (299.4 mmoles) of triethyl-phosphite are placed in a 250 ml flask which has a cooler and oil heating bath. The mixture is heated to 140° C. under magnetic agitation for 5 hours. On completion the excess triethyl-phosphite is separated by distillation and the white solid residue, redissolved in 50 ml of ethanol, is evaporated to dryness under vacuum, this operation being repeated twice. The residue is dissolved in 30 ml of ethanol and poured slowly into a beaker containing water and ice. The precipitate obtained is filtered on porous septum G3, washed with iced water (1 l) and under vacuum dried in an oven at 40° C., obtaining 21.02 g of 4,4'-bis (phosphonomethyl) biphenyl acid tetra-ethyl ester with a molar yield of 92.8%.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([OH:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Na+].Cl>CO.CCOCC>[CH:20]1([CH2:19][CH:18]([OH:26])[CH:17]=[CH:16][C@@H:11]2[CH2:12][CH2:13][C:14](=[O:15])[C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-2-(4-cyclohexyl-3-hydroxy-1-butenyl)-5-oxocyclopentaneheptanoic acid methyl ester, Isomer A (11.56 g), described in Example 10, in 53 ml of methanol is added 10% NaOH (18.3 ml). The mixture is stirred at room temperature for 2 hr then rendered acidic with 10% HCl and diluted with ether. The ether solution is washed with water, dried and evaporated to yield Isomer A of the title compound, νmaxCHCl3 1730, 1710 cm-1.