Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:27]#[N:28])=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:20](=[C:27]([NH2:28])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1
Reactant: COc1ccc(Br)c(C#N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-methoxypicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 3-methoxybenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (acetone d-6): δ 8.91 (d, 1H), 8.34 (d, 1H), 7.63 (d, 1H), 7.51-7.53 (dd, 1H), 7.27-7.33 (m, 2H), 6.65 (br, 2H), 4.11 (s, 3H). LRMS [M+H]=226.1
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])=O)=[CH:5][CH:4]=1.CCOCC.C(Cl)(Cl)[Cl:22]>CCCCCC.CCOCC>[Cl:22][C:12]1[NH:13][C:8]([C:6]2[S:7][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:10][C:11]=1[C:14]#[N:15]
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)s1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: N#Cc1cc(-c2ccc(Cl)s2)[nH]c1Cl
Temperature: 0 °C

Procedure:
Hydrogen chloride gas is bubbled through a mixture of [(5-chloro-2-thenoyl)methyl]malononitrile (4.60 g, 20.5 mmol), ether and chloroform at a moderate rate for 20 minutes. The reaction mixture is poured into an ice-water mixture and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to give a brown solid. The solid is mixed with a hexane/ether solution and filtered to obtain the title product as a brown solid, mp >200° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cn2nc(I)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50-mL round bottom flask was added 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq), anhydrous dichloromethane (10 mL), acetic anhydride (0.071 mL, 1.5 eq), pyridine (0.073 mL, 1.8 eq), and 4-(dimethylamino)pyridine (0.61 mg, 0.01 eq). After the mixture was stirred at room temperature for four hours, it was quenched with saturated aqueous sodium bicarbonate and extracted with i-PrOH—CHCl3 (1:4). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to yield N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide as a white solid in amount of 67 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18](B(O)O)=[C:17]([O:27][CH3:28])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1C=CC=CC=1.CCO.O.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>[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH2:12][OH:13])=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: OCc1cc(C(F)(F)F)ccc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
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: CCO
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C

Procedure:
A mixture of [2-iodo-5-(trifluoromethyl)phenyl]methanol (Intermediate 11, 3.09 g, 10.2 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Intermediate 6, 4.34 g, 20.5 mmol), (Ph3P)4Pd (1.42 g, 1.23 mmol) and Na2CO3 (9.11 g, 85.9 mmol) in benzene/EtOH/H2O (7:1:3, 250 mL) was heated at reflux for 24 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (65×200 mm, 0-20% EtOAc in hexanes gradient) to afford 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol. Rf=0.50 (20% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.68 (d, J=12.0 Hz, 1H), 4.52 (br s, 1H), 4.46 (br s, 1H), 3.73 (s, 3H), 3.25-3.17 (m, 1H), 1.82 (br s, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([Cl:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>CCOC(C)=O>[Cl:40][C:34]1[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=[C:32]([NH:31][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:33]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 52.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.89 min (HPLC 1); tR: 1.12 min (LC-MS 2); ESI-MS: 573/575 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26]
Reactant: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(OCCN)cc2NC1=O
Reaction time: 18 h
Yield: 100.4 %

Procedure:
[7-(2-tert-Butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester (2.5 g, 6.6 mmol) and trifluoroacetic acid (5.1 mL, 66 mmol) were combined in methylene chloride (25 mL) at 25° C. After 18 h, the solution was concentrated in vacuo to give the title compound as a tan solid (2.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:14][C:15]1[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=1.O>CO>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:14][C:15]1[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=1)[NH2:1]
Reactant: Cc1cc(N)ccc1S
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(N)ccc1SCc1nccn1C
Yield: 90.3 %

Procedure:
To a solution of 4-amino-2-methylthiophenol (500 mg) in methanol (10 ml) was added 1N aqueous solution of sodium hydroxide (12 ml), and a solution of 2-chloromethyl-1-methylimidazole hydrochloride (660 mg) in methanol (10 ml) was added at 0° C. Water was added to the mixture, and the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate, to give 3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]aniline (757 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](F)=[O:7])=[CH:4][C:3]=1[Br:11].[CH3:12][OH:13]>N1C=CC=CC=1>[CH3:12][O:13][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([Br:11])[CH:4]=1
Reactant: O=C(F)c1ccc(F)c(Br)c1
Reactant: CO
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)c(Br)c1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
221 g (1 mole) of 4-fluoro-3-bromobenzoyl fluoride were added dropwise to a mixture of 96 g (3 moles) of methanol and 1 g of pyridine. The reaction mixture was then boiled for a further 2 hours under reflux and was subsequently worked up by distillation. 217 g (93% of theory) of 4-fluoro-3-bromobenzoic acid methyl ester were thus obtained in the form of a colorless oil which solidified when cold and had a boiling point of 124° C./22 mm Hg (melting point 29° to 30° C.).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[F:6][C:7]1[CH:28]=[CH:27][C:10]([C:11]([CH2:13][CH2:14][CH2:15][N+:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)=[CH:18][CH:17]=2)=[O:12])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[F:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]([OH:12])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH:18]=[C:19]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: O=C(CCC[n+]1ccc(-c2ncco2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: OC(CCCN1CC=C(c2ncco2)CC1)c1ccc(F)cc1

Procedure:
To a 1.75 g. portion of 1-(3-p-fluorobenzoylpropyl)- 4-(2-oxazolyl)pyridinium perchlorate, prepared as described in Example 9, in 75 ml. of methanol, is added portionwise with stirring 1.75 g. of sodium borohydride. The mixture is stirred for 1 1/2 hours, allowed to stand, some of the methanol is evaporated and the mixture is poured into ice water causing the formation of a tan solid which is recovered by filtration, m.p. 100°-103° C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:10](=[O:23])[C@@:11]([CH3:22])([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH2:13])(C)C.OO.O.[OH-].[Li+].S(S([O-])=O)([O-])(=O)=[O:30].[Na+].[Na+].Cl>O1CCCC1.O>[CH3:22][C@:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])([CH:12]=[CH2:13])[C:10]([OH:23])=[O:30]
Reactant: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1C(C)C
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A cooled (0° C.) solution of (R)-4-isopropyl-3-[(R)-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoyl]-oxazolidin-2-one (543.3 mg, 1.591 mmol) in tetrahydrofuran/water (15 mL, 2:1) was subsequently treated with hydrogen peroxide (30%, 820 μL, 7.955 mmol) and lithium hydroxide monohydrate (133.5 mg, 3.181 mmol). After stirring at 0° C. for 2 h, the reaction was quenched with solid sodium metabisulfite (3 g, 16 mmol). After stirring at room temperature for 30 min, the mixture was acidified with hydrochloric acid (1 M) to pH 2, the aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (322.3 mg, 88%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 0.98 (app t, J=8.5 Hz, 2H), 1.34 (s, 3H), 3.46 (d, J=8.9 Hz, 1H), 3.57-3.67 (m, 3H), 5.19-5.29 (m, 2H), 6.00 (dd, J=17.4, 10.7 Hz, 1H), 10.80 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 4-formylphenylboronic acid. Colorless crystals (170 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH3:17][N:18]([CH3:28])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>Cl>[ClH:8].[CH3:28][N:18]([CH3:17])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][C:24]2([NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH2:23][CH2:22]1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: CN(C)CCC1CCC(=O)CC1
Agent: Cl
Product: CN(C)CCC1CCC2(CC1)Nc1cc(Cl)c(S(N)(=O)=O)cc1S(=O)(=O)N2

Procedure:
A mixture of 4-amino-6-chloro-1,3-benzenedisulfonamide (4.3 g., 0.015 mole) and 4-(2-dimethylaminoethyl) cyclohexanone (3.0 g., 0.018 mole) in 3 N ethanolic HCl (50 ml.) is refluxed for one and one half hours and cooled to give 4'-(2-dimethylaminoethyl)-6-chlorospiro-[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride (m.p. 279°-81° C.) which is dissolved in warm water (300 ml.) and treated with aqueous ammonia (1 ml.) to give 4'-(2-dimethylaminoethyl)-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide which melts at 238°-9° C. after recrystallization from dimethylformamide-water.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][CH3:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:16](N)[CH2:17][NH2:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]([C:10]2[NH:18][CH2:17][CH2:16][N:11]=2)[CH2:12][CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(C(F)(F)F)c1
Product: CCC(C1=NCCN1)c1cccc(C(F)(F)F)c1

Procedure:
rac-2-[1-(3-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 257.0 ((M+H)+.).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([CH3:10])[CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:9]
Reactant: CCOC(=O)C(C)CCBr
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCCCC1
Temperature: 60 °C

Procedure:
10.5 g. (0.05 mole) of ethyl 4-bromo-2-methylbutyrate was combined with 17.0 g. (0.20 mole) of piperidine and 100 ml. of benzene and stirred for 16 hours at room temperature and then heated at 60°C. for 4 hours. The reaction mixture was cooled and the colorless solid which appeared was removed by filtration. The mother liquor was concentrated to give a mobile yellow liquid which distilled (b.p. 78°C. at 0.25 mm) as 6.7 g. (63%) of colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:40])[CH3:39])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:39])[CH3:40])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-19 (0.165 g) and lithium hydroxide (45 mg) were added to tetrahydrofuran (4 ml) and water (2 ml). The same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 80 mg (51%); mp 175-176° C., MS APC−ve 604 (M−H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC.CON(C)[C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].Cl>O1CCCC1>[C:40]([C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7])(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CON(C)C(=O)C(C)(C)C
Reactant: O=C(O)c1ccoc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1occc1C(=O)O
Temperature: -20 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
A solution of 3-furoic acid (8.97 g, 0.08 mol) in tetrahydrofuran (200 ml) was cooled to -70° C. and a 2.0M solution of lithium diisopropylamide in THF-ethylbenzene-heptane (80 ml, 0.16 mol) was added dropwise over 3/4 hr at -70° to -20° C. under nitrogen to give a tan suspension. A red solution formed after stirring for 113/4 hours at -20° C. To this solution was added N-methoxy-N-methylpivalamide (11.67 g, 0.08 mol) in tetrahydrofuran (10 ml) at -40° C. The reaction mixture was left at ambient temperature overnight. Then ,it was cooled in ice and neutralized with 6N ethanolic hydrogen chloride (50 ml). The neutralized solution was acidified with 1.5N HCl (150 ml) and was extracted with ether (300 ml). The ether extracts were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated in vacuo to a brown solid (15.4 g). Chromatography on silica gel using hexane-THF-acetic acid (10-2-0.2) gave a yellow solid (9.8 g), mp 85°-89° C.
Reaction SMILES: C([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:14][NH:15][C:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9][CH2:8]1)=[O:6])CC.[Li+].[OH-].[OH-].[Na+].Cl>C1COCC1.O.CO>[C:32]([O:31][C:29]([NH:28][CH:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]1)[CH2:14][NH:15][C:16]([C:18]1([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCOC(=O)[C@H]1CC[C@H](C(CNC(=O)C2(c3ccc(Cl)cc3)CC2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CNC(=O)C1(c2ccc(Cl)cc2)CC1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-/trans-4-(1-tert-Butoxycarbonylamino-2-{[1-(4-chloro-phenyl)-cyclopropane-carbonyl]-amino}-ethyl)-cyclohexanecarboxylic acid propyl ester (1-9) (1.26 g, 0.00248 mol, 1 eq) was dissolved in THF (20 mL) and MeOH (10 mL) in a 250 mL RB flask LiOH (0.12 g, 0.00497 mol, 2 eq) in H2O (5 mL) was added to this solution. The reaction mixture was stirred at RT for 1 hour. NaOH (MW 40, 0.0075 mol, 3 eq) in H2O (5 mL) was added to the above reaction mixture. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with H2O. The pH was adjusted to 2˜3 with 5% HCl while cooling with an ice-H2O bath. THF and MeOH were removed under vacuum. The residue was extracted with EtOAc (3×80 mL). The combined EtOAc extracts were washed with brine (1×80 mL), dried over Na2SO4 and solvent evaporated to dryness. The crude product was purified on silica gel column, eluting with MeOH/CH2Cl2 (1.25˜10%) to afford 0.28 g plus 0.23 g (less pure) (46% yield) of 1-10. The 1H NMR (DMSO-d6) data is depicted in FIG. 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].C1(S(O[CH2:25][CH2:26][Cl:27])(=O)=O)C=CC=CC=1>[Na].CO>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH2:25][CH2:26][Cl:27])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc2cc(OCCCl)ccc2s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5-Hydroxybenzo[b]thiophene-2-carboxylic acid methyl ester (1.47 g.) was dissolved in a solution of sodium (0.163 g.) in methanol (15 ml.) and 2-(benzenesulphonyloxy)ethyl chloride (1.57 g.) was added. The resulting solution was heated under reflux for 8 hours and then allowed to cool and stood overnight. The solution was then evaporated and the residue was partitioned between water and ether. The aqueous layer was separated and washed several times with ether. The combined organic layer and ethereal extracts were washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-(2-chloroethoxy)benzo[b]-thiophene-2-carboxylic acid methyl ester, (0.74 g.), m.p. 116°-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+].[Cl-].[NH4+]>CO>[CH2:30]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2NCc2ccccc2)c1
Yield: 59.1 %

Procedure:
A solution of 200 mg (0.5 mmol, 1 eq) of methyl 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate (prepared in Example 52c) and 72 μL (0.70 mmol, 1.4 eq) of benzaldehyde in 4 ml of methanol in the presence of 63 mg (1.0 mmol, 2 eq) of sodium cyanoborohydride is stirred at room temperature for 16 hours. The reaction medium is hydrolyzed with ammonium chloride solution and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 144 mg of methyl 3-[2-benzylamino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in the form of a colorless oil. Yield=59%