Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([N:12]2[C:16]3=[C:17]4[S:23][CH:22]=[CH:21][C:18]4=[N:19][CH:20]=[C:15]3[N:14]=[CH:13]2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]#[N:11])[CH2:5][CH2:4]1.O.C(O)(C(F)(F)F)=O.C(#N)C>[Pd].CO>[OH:1][CH2:2][C:3]1([N:12]2[C:16]3=[C:17]4[S:23][CH:22]=[CH:21][C:18]4=[N:19][CH:20]=[C:15]3[N:14]=[CH:13]2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]#[N:11])[CH2:5][CH2:4]1
Reactant: N#CC=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: N#CCC1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Reaction time: 4.5 h

Procedure:
A mixture of [4-(hydroxymethyl)-4-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexylidene]acetonitrile (18 mg, 0.055 mmol) and 10% palladium on carbon (5.9 mg) in methanol (0.6 mL) was stirred under an atmosphere of H2 (balloon) for 4.5 h. The mixture was filtered through a pad of Celite and concentrated. The crude residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two isomers. On analytic HPLC (Waters SunFire C18, 2.1×50 mm, 5 μM; flow rate 3 mL/min; Injection volume 2 μL; at gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=acetonitrile)): First peak retention time 1.05 min, LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.0. Second peak retention time 1.13 min, LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13](=[N:15][OH:16])[NH2:14])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].[C:19](OCC)(=O)[CH3:20].[Na]>C(O)C>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13]3[N:14]=[C:19]([CH3:20])[O:16][N:15]=3)[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CCC(N)=NO
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: CCO
Product: Cc1nc(CCn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Reaction time: 5 h

Procedure:
A mixture of 2.52 g of 3-(3-methyl-xanthine-7-yl)propionic acid amide oxime, 4.0 ml of ethyl acetate and a solution of 0.46 g of metallic sodium in 25 ml of ethanol is heated to boiling under stirring for 5 hours. The hot reaction mixture is filtered and the filtrate is evaporated. The residue is treated with 20 ml of water, the pH is adjusted to 7 and the precipitated product is crystallized from water. Thus 1.7 g of 3.7-dihydro-3-methyl-7-(2-[5-methyl-1,2,4-oxadiazole-3-yl]-ethane-1-yl)-1H-purine-2,6-dione are obtained, m.p.: 258°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc(OC)c2c3c(c(=O)oc2c1)CNCC3
Product: COc1cc(OC)c2c3c(c(=O)oc2c1)CN(CCN1CCCCC1)CC3

Procedure:
In the same way as described in Example 5, 0.02 m of 1,2,3,4-tetrahydro-8,10-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one was alkylated with N-(2-chloroethyl)-piperidine to give, after crystallization from MeOH, 3.0 g of product; mp 190°-224° C.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:21][C:22]([C:24]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:21][C:22]([C:24]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′-(methylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 23, step (i), 320 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (280 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture was purified by chromatography on silica eluting with 1:1 ethyl acetate/isohexane as eluent to afford the sub-titled compound (230 mg).
Reaction SMILES: FC1C(C2(C)OC=CO2)=CC=C(OC)C=1C=O.C([O:20][C:21](=[O:39])[CH:22]=[CH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([C:32]2([CH3:37])[O:36][CH:35]=[CH:34][O:33]2)[C:25]=1[F:38])C.[OH-].[K+]>O1CCOCC1.O>[F:38][C:25]1[C:26]([C:32]2([CH3:37])[O:33][CH:34]=[CH:35][O:36]2)=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=1[CH:23]=[CH:22][C:21]([OH:39])=[O:20]
Reactant: CCOC(=O)C=Cc1c(OC)ccc(C2(C)OC=CO2)c1F
Agent: COc1ccc(C2(C)OC=CO2)c(F)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2(C)OC=CO2)c(F)c1C=CC(=O)O

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenetyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g) (Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenetyl)-N'-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (g, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[O-]CC.[Na+].[C:9]1(=[O:13])[CH2:12][CH2:11][CH2:10]1>C(O)C>[N+:1]([CH2:4][C:9]1([OH:13])[CH2:12][CH2:11][CH2:10]1)([O-:3])=[O:2]
Reactant: O=C1CCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.3 %

Procedure:
Under a nitrogen atmosphere, nitromethane (116 mL, 2.14 mol) and sodium ethoxide (2.6 g of 96% pure material, 36 mmol) were sequentially added to a solution of cyclobutanone (50.0 g, 713 mmol) in ethanol (71 mL), and the resulting solution was stirred at room temperature for 4 days. Some of the ethanol was removed under reduced pressure, and water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were washed sequentially with water (2×80 mL) and brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by vacuum distillation under high vacuum at 70° C. to provide 46.1 g of 1-(nitromethyl)cyclobutanol as an orange liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CO)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
In ethanol (100 ml) was dissolved 7.531 g of 2-(3-nitrophenyl)propanal. Under ice-cooling, sodium borohydride (1.9 g) was added thereto, followed by stirring at room temperature for 1 hour. To the mixture was added brine, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by silica gel column, to give the title compound (6.275 g, 57.19% in 3 steps) as a brown oil.
Reaction SMILES: [C:1]12[CH2:15][CH2:14][CH:13]=[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2>C1(C)C=CC=CC=1.[Pd]>[C:1]12[CH2:15][CH2:14][CH2:13][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: C1=C2CCC=C2CCCCCCCCC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: C1CCCCCC2=C(CCCC1)CCC2
Reaction time: 1 h
Yield: 85 %

Procedure:
6.06 g of bicyclo[10.3.0]pentadec-1,12-diene--crude material; see Example 1--in 40 ml of toluene were hydrogenated at 100°, under atmospheric pressure, in the presence of 0.6 g of 10% palladium on charcoal. After 60 min. of hydrogenation, the reaction mixture was cooled, filtered on CELITE and finally distilled (0.02 Torr--bath temperature: 140°) to afford 5.2 g (84% yield) of the desired title compound having a purity of 93% according to vapour phase chromatography analysis (CARBOWAX 10%--1.6 m--140°). The compound thus prepared was found identical with a sample prepared according to J. Amer. Chem. Soc. 79, 5558 (1957).
Reaction SMILES: FC1C=CC=CC=1C1C2C=C(N[C:20](NCCO)=[O:21])C=CC=2N2C=NN=C2CN=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[N:39]3[C:40]([CH3:43])=[N:41][N:42]=[C:38]3[CH2:37][N:36]=[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:50])[C:34]=2[CH:51]=1>C(Cl)Cl>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:35]1[C:34]2[CH:51]=[C:30]([N:29]=[C:20]=[O:21])[CH:31]=[CH:32][C:33]=2[N:39]2[C:40]([CH3:43])=[N:41][N:42]=[C:38]2[CH2:37][N:36]=1
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Reactant: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(N=C=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
A solution of [6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate is prepared as described in paragraph (a) of Example 1 from 7.0 g (21.6 mmol) of 8-amino-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH:20]([CH:24]4[CH2:26][CH2:25]4)[CH2:21][C:22]#[N:23])[CH:19]=3)[C:12]([O:27][CH3:28])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>>[Cl:42][CH2:43][CH2:44][CH2:45][S:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH:20]([CH:24]4[CH2:26][CH2:25]4)[CH2:21][C:22]#[N:23])[CH:19]=3)[C:12]([O:27][CH3:28])=[CH:11][N:10]=2)[CH:3]=1)(=[O:48])=[O:47]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1cnc(Nc2cccc(N)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cnc(Nc2cccc(NS(=O)(=O)CCCCl)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-{2-[(3-aminophenyl)amino]-5-methoxypyrimidin-4-yl}-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (prepared according to Example 345, 8.0 mg, 0.000021 mol) in 1,4-dioxane (0.1 mL, 0.002 mol) was added triethylamine (0.02 mL, 0.0001 mol), followed by 3-chloropropane-1-sulfonyl chloride (0.0039 mL, 0.000032 mol). The reaction was stirred at room temperature for 1 h, quenched with 1 N HCl. The mixture was extracted with EtOAc and the organic layer was separated. The combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to provide the desired sulfonylated intermediate.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]2=[O:28])[CH2:12][CH2:11]1.O.[OH-].[Li+].Cl>C1COCC1>[O:28]=[C:19]1[N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:29])=[O:2])[CH2:11][CH2:12]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: COC(=O)c1ccccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Temperature: 40 °C
Yield: 98 %

Procedure:
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzoic acid methyl ester Compound 93 (1.2 g, 3.0 mmol) was dissolved in THF (10 mL) and treated with lithium hydroxide monohydrate (864 mg, 21 mmol). The reaction mixture was heated to 40° C. for 24 hrs, cooled to rt, adjusted to pH 3 with 1N HCl, and concentrated in vacuo. Purification by Gilson HPLC (elution with 10 to 90 gradient of H2O 0.2% TFA buffer/acetonitrile with 0.1% TFA buffer) afforded Compound 3-1 as a white solid (1.45 g, 2.93 mmol, 98%). 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=5 Hz, 1H), 7.92 (m, 1H), 7.59-7.43 (m, 2H), 7.32-7.22 (m, 1H), 7.14-6.89 (m, 3H), 4.62 (s, 2H), 3.97-3.68 (m, 2H), 3.45-2.94 (m, 4H), 2.71-2.33 (m, 3H), 2.13-1.96 (m, 2H), 1.80-1.65 (m, 2H); MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7](O)(=[O:27])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.[OH-].[Na+]>C1COCC1>[CH2:7]([OH:27])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a suspension of LiAlH4 (0.499 g, 13.14 mmol) in dry THF (50 mL) was added arachidonic acid (1.00 g, 3.28 g) in dry THF (40 mL) at 0° C. (ice-bath) under argon and the reaction mixture was stirred for 1 h at 0° C. and then for 1 h at room temperature. After a slow addition of water (0.2 mL), the white gelatinious precipitate was dissolved by adding 10% aq NaOH (0.2 mL) and water (0.6 mL) and the mixture was allowed to stir for 1 h. The mixture was then dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure to furnish a crude, which was purified over silica-gel column chromatography using 20% ethyl acetate/hexane to give the product as a clear oil (0.945 g, 99%). 1H NMR (CDCl3): δ5.37 (m, 8H), 3.64 (t, 2H, J=6.4 Hz), 2.81 (m, 6H), 2.09 (m, 4H), 1.61 (m, 2H), 1.50-1.30 (m, 8H), 1.04 (t, 3H, J=6.8 Hz). m/z (APCI) 291.43 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCCC2=O)c1cc(Cl)ccc1Cl
Yield: 96 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in presence of triethylamine (90 μL, 0.65 mmol) in THF (6 mL) according to method B gave 2,5-dichloro-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (150 mg, 0.48 mmol, 76% yield) as a grey powder after purification by crystallisation in DCM.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:17]>O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[Ag:17]
Reactant: [Ag+]
Agent: Cc1ccc2[nH]nnc2c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Ag]
Reaction time: 0.08 h

Procedure:
The mixture thus obtained was stirred for 5 minutes, and then mixed with a solution of 3.8 g of 5-methylbenzotriazole and 1.2 g of sodium hydroxide in 150 ml of water and a solution of 5 g of silver nitrate in 150 ml of water simultaneously over 6 minutes, to prepare an emulsion.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:24]1([C:30]([NH:32][CH:33]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[C:34](O)=[O:35])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:34]([C@@H:33]([NH:32][C:30]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:31])[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[O:35])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1
Yield: 32 %

Procedure:
This material was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using 2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (step A). The final product was obtained in 32% yield (33 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty g. of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene was dissolved in 400 ml. of pyridine, together with 23.4 g. of methanesulfonyl chloride and 50 mg. of 4-dimethylaminopyridine. The mixture was stirred under a nitrogen blanket overnight at ambient temperature, and was then poured into 2 liters of water and stirred vigorously. The solids were collected by filtration, and washed successively with water, methanol and diethyl ether. The washed solids were then vacuum dried at 60° to obtain 32.5 g. of the desired intermediate product, m.p. 195°-197°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1([F:17])[CH2:16][NH:15][CH2:14]1>>[F:12][C:13]1([F:17])[CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: FC1(F)CNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1nc(N2CC(F)(F)C2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and 3,3-difluoroazetidine following the method used to prepare Intermediate 49. LCMS (ES+) 230 (M+H)+, RT 2.57 minutes (method 1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][CH:16]([OH:30])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][CH:16]([O:30][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: OC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution (0° C.) of 1-(3,5-bis(trifluoromethyl) phenyl)methyloxy-3,3-diphenyl-2-hydroxypropane (Example 1; 0.49 g) in a mixture of tetrahydrofuran (4 ml) and dimethylformamide (1 ml) was added 80% sodium hydride (0.039 g; suspension in oil). After 0.5 hours methyl bromoacetate (0.121 ml) was added and the solution stirred at room temperature for 16 hours. Water (0 ml) and ethyl acetate (50 ml) were added and the organic phase washed with water (5 times), saturated brine and dried (MgSO4). After removal of the solvent in vacuo the residue was purified by silica gel chromatography (eluting with 10% ethyl acetate in hexane) to give 1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(carbomethoxy) methyloxy-3,3-diphenylpropane m/e CI+ =544 (M+NH4+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:30])=[O:29]
Reactant: CCOC(=O)C(=O)N(CCO)N=Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCOS(C)(=O)=O)N=Cc1ccccc1
Reaction time: 2 h

Procedure:
26.4 g. of the ethyl ester product from part (a) and 10 g. of triethylamine are dissolved in 200 ml. of methylene chloride. 11.4 g. of methylsulfonyl chloride dissolved in a small amount of methylene chloride are added dropwise at -20°. After two hours, 300 ml. of water are added to the reaction solution and this mixture is stirred for 10 minutes. The organic phase is dried (Na2SO4) and, after distilling off the solvent, a colorless oil is obtained which crystallizes upon scratching. Recrystallization from ethanol yields as a white powder [1-[2-[(methylsulfonyl)oxy]ethyl]-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 93°-95°.
Reaction SMILES: [C:1]([CH:9]([CH3:13])C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:15]1CCC[CH2:16]1>>[C:2]1([CH:1]([OH:8])[CH2:9][CH2:13][CH2:16][OH:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C(=O)O)C(=O)c1ccccc1
Agent: Cl
Product: OCCCC(O)c1ccccc1
Reaction time: 60 h

Procedure:
A solution of 35.6 g (0.20 mole) of benzoylpropionic acid in 100 ml of tetrahydrofuran was added dropwise to 300 ml of a 1 molar solution of borane tetrahydrofuran complex in tetrahydrofuran. The mixture was stirred at ambient temperatures for 60 hr, giving a gel. This was treated with 100 ml of 2N hydrochloric acid solution and the mixture stirred for 15 min. Most of the tetrahydrofuran was removed on a rotary evaporator and the residue partitioned between methylene chloride and water. The aqueous layer was extracted again with methylene chloride. The combined extract was washed with water, dried (sodium sulfate), and concentrated to yield 24.30 g of 1-phenyl-1,4-butanediol. This intermediate was dissolved in acetone and heated at reflux temperature for 5 hr while 30 g of manganese dioxide was added in five portions. The reaction mixture was filtered and concentrated to a brown oil that was chromatographed on silica gel using 15% ethyl acetate-85% methylene chloride to elute the fraction identified by 1H nmr as the title compound. The fraction weighed 11.20 g, after concentration and was shown to have a purity greater than 90%.