Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[S:8](=[O:15])(=[O:14])[NH:7][CH2:6]1)(=O)[CH3:2].CO>O1CCCC1>[CH2:1]([NH:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[S:8](=[O:14])(=[O:15])[NH:7][CH2:6]1)[CH3:2]
Reactant: CC(=O)NC1CNS(=O)(=O)c2sccc21
Solvent: C1CCOC1
Solvent: CO
Product: CCNC1CNS(=O)(=O)c2sccc21
Temperature: 70 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A suspension of 4-acetamido-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (4.93 g, 0.02 mol) in tetrahydrofuran (50 ml) was heated in an oil bath at 70° C. Borane-dimethyl sulfide complex (20.0 ml of 10.0M, 0.20 mol) was added dropwise over 1/2 hour and the mixture was stirred at 70° C. for 4 hrs. The mixture was cooled in ice and methanol was added (50 ml) dropwise. The volatile solvents were removed in vacuo and the residual oil was heated with 6N hydrochloric acid (50 ml) on the steam bath for 1/2 hr. Ethyl acetate (200 ml) was added and the mixture was basified with sodium bicarbonate. Methanol (20 ml), was added, the mixture filtered and the aqueous layer was re-extracted with ethyl acetate (100 ml) -methanol (10 ml). The organic solutions were combined, dried and concentrated in vacuo. A colorless viscous oil (4.47 g) was recovered. Yield 96%.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:6][CH2:7][CH:8]([NH:15][C:16]([CH:18]2[N:22]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:21][CH2:20][S:19]2)=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1CCCNCC1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCN1CCCCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and azepane, the title compound was obtained in 99.1% purity by HPLC.
Reaction SMILES: [C:1]([C@:8]([NH2:17])([CH2:13][CH2:14][CH2:15]O)[C:9]([O:11][CH3:12])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>>[C:1]([C@:8]([NH2:17])([CH2:13][CH2:14][CH2:15][Br:38])[C:9]([O:11][CH3:12])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@](N)(CCCO)C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)[C@@](N)(CCCBr)C(=O)OC(C)(C)C

Procedure:
The crude residue of methyl (S)2-BOC-amino-5-hydroxy-pentanoate is treated with triphenylphosphine and CBr4 to obtain a crude sample of methyl (S)2-BOC-amino-5-bromo-pentanoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH2:6][CH2:7][NH:8]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCc1ccsc1
Product: Clc1ccc(C2NCCc3ccsc32)cc1

Procedure:
2-(3-Thienyl)ethanamine (3.15 g) and 4-chlorobenzaldehyde (3.5 g) were mixed without solvent resulting in dissolution af the crystals of the amine followed by precipitation of slightly yellow crystals. The mixture was left at RT for 4 h. Trifluoroacetic acid (20 ml) was added and the mixture stirred overnight at RT.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([OH:11])=[O:10])/[O:3]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of pure (Z)-2,2 dimethyl-5-(t-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) was treated at 22° C. with acetic acid (2 ml) followed by 6.8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). The solvent was concentrated under reduced pressure and the residue was triturated with toluene to give 1.00 g (85%) of the title compound as a white crystalline material: mp 203-204° C. (dec.). IR (KBr) v max (cm −1): 1805, 1707 and 1662. 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 6), 5.89 (s, 1). Anal. calcd for C7H8O5: C, 48.84; H, 4.68. found: C, 48.84; H, 4.65.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:19][C:16]1[O:15][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=2)=[N:18][N:17]=1
Reactant: Cc1nnc(-c2ccnc(NC(=O)OC(C)(C)C)c2)o1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2ccnc(N)c2)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
A mixture of tert-butyl[4-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]carbamate (440 mg, 1.59 mmol) and trifluoroacetic acid (10 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (257 mg, yield 92%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[C:18]([NH:21][CH3:22])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([NH:20][CH2:24][C:25]#[C:26][CH3:27])=[C:18]([NH:21][CH3:22])[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1N
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCNc1c(NC)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(5-Amino-6-methylamino-pyrimidin-4-yl)piperazine-1-carboxylic acid t-butyl ester (200 mg) was dissolved in N,N-dimethylformamide (5.0 mL), and then 1-bromo-2-butyne (57 μL) and anhydrous potassium carbonate (107 mg) were added to this solution. The reaction solution was stirred at room temperature for 20 hours, and then poured into a saturated aqueous ammonium chloride solution. It was then extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (118 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+].S([NH:27][N:28]=[CH:29][CH:30](Cl)[Cl:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])O.[Na+]>O.CO.C1(C)C=CC=CC=1>[ClH:31].[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[CH:30]=[CH:29][N:28]=[N:27]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Reactant: COc1ccc(CCCCN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27 mmol) was dissolved in water (10 ml). Toluene (20 ml) and 2N-sodium hydroxide (10 ml) were added and the mixture was partitioned. The mixture was washed 20% brine (10 ml) twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methanol (5 ml) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). This methanol solution was added dropwise to a slurry of 2,2-dichloroacetaldehyde tosylhydrazone (5213 mg, 18.54 mmol) in methanol (30 ml) at 20-25° C. and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of toluene (19 ml) and saturated aqueous sodium hydrogen carbonate (57 ml) and the mixture was stirred at room temperature for 50 min. The organic solvent was evaporated by concentration under reduced pressure and the residue was extracted with toluene (40 ml). 4N-Sodium hydroxide (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. Water (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. Water (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. The organic layer was washed with 20% citric acid (15 ml), and then 3 times with water (20 ml), with saturated aqueous sodium hydrogen carbonate (30 ml) and with water (30 ml), and concentrated under reduced pressure. The residue was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (2.5 ml) was added. The mixture was concentrated under reduced pressure and 2-propanol was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added, and the mixture was concentrated under reduced pressure. Ethyl acetate (10 ml) was added and triturated. The mixture was stirred at room temperature for 40 min. The precipitated crystals were collected by filtration and dried under reduced pressure to give 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole hydrochloride (1.61 g, yield 68%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]([F:20])([F:19])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(OCC)C>O1CCCC1>[CH:16]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]([F:19])([F:20])[F:5])=[CH:13][CH:12]=2)([OH:15])[CH:1]=[CH2:2])[CH2:18][CH2:17]1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: C=C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 550 ml (0.55 mole) of 1M vinylmagnesium bromide in tetrahydrofuran was cooled to 10°-15° C., and a solution of 115.0 grams (0.5 mole) of cyclopropyl 4-trifluoromethoxyphenyl ketone in 100 ml of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition the reaction mixture temperature was maintained at less than 20° C. where it was stirred for one hour. The reaction mixture was poured into a mixture of 2000 ml of pH5 buffer in 1000 ml of ice. To this was added 1000 ml of diethyl ether. The mixture was stirred until the ice melted. The aqueous layer was separated and was washed with two 500 ml portions of diethyl ether. The ether washes were combined with the original organic layer, and the combination was washed in turn with two 500 ml portions of the pH5 buffer solution, two 500 ml portions of water, and one 300 ml portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with ground sodium carbonate and filtered. The filtrate was concentrated under reduced pressure yielding 130.0 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-2-propen-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Methyl ester (16) (500 mg, 1.48 mmol) was coupled to phenylboronic acid (150 mg, 1.23 mmol) using Method E. The crude compound was purified by column chromatography, eluting with a stepped gradient of 20-25% EtOAc in heptane to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21](=[O:33])[NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[N:10](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21]([NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[O:33])[NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (S)-tert-butyl 7-nitro-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound C of Example 20, 4.45 g, 9.86 mmol) in CH2Cl2 (49 mL) was added TFA (11.4 mL, 148 mmol). The resulting solution was stirred at room temperature for 1 h and then quenched carefully with sat. NaHCO3 until bubbling ceased. The aqueous layer was extracted with CH2Cl2 (3×), and the combined organic extracts were washed with sat. NaHCO3, water and sat. NaCl. The extracts were dried over Na2SO4, filtered and concentrated in vacuo to give 3.38 g of the title compound as a pale yellow solid. 1H NMR (CDCl3, mixture of amide rotamers) δ 8.05 (d, J=6.6 Hz, 1H), 7.97-7.88 (m, 1H), 7.53-7.32 (m, 2H), 7.22-6.94 (m, 4H), 5.25-5.03 (m, 1H), 4.18-3.94 (m, 2H), 3.83-3.65 (m, 1H), 3.35 (dd, J=16.7, 5.1 Hz, 1H), 3.09 (dd, J=17.1, 9.1 Hz, 1H), 2.90-2.70 (m, 2H), 2.18-1.96 (m, 1H), 1.93-1.44 (m, 3H); MS (ESI+) m/z 352.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:20]=1)CC(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:40]1C=C(C=CC=1)CN(C)C(=O)OCC1C=CC=CC=1.BrC1C=CC(CCO)=C(C)C=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:12][C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH3:40])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cccc(N)c1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Agent: Cc1cc(Br)ccc1CCO
Product: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(CN(C)C(=O)OCc2ccccc2)c1
Yield: 69 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 60B (1.6 g, 5.9 mmol) was reacted with 30B to give 60C (2.0 g, 69%) as an oil. MS (ESI) m/z 512.2 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH2:35])=[N:29][C:30]=3[NH2:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OCC)C>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH2:35])=[N:29][C:30]=3[NH2:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(N)nc(N)nc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c2ncn(C3CC[C@@H](CO)S3)c2n1
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 16 (50 mg, 0.1 mmol), acetic acid (7 μL, 0.12 mmol), and 0.17 mL of 1 M tetrabutylammonium fluoride in THF (0.17 mmol) was stirred in 10 mL tetrahydrofuran overnight. Water (2 mL) and 15 mL ethyl ether were added followed by stirring for 5 minutes. The organic phase was extracted with 2 mL water and then the combined aqueous solution was washed with 15 mL ethyl ether. The aqueous extract was concentrated in vacuo to 1 mL and then applied to a 4-mL Dowex 1×4 100-200 (-3OH) column to remove tetrabutylammonium salts by eluting with water followed by 20% aqueous methanol. The solvent was removed in vacuo and the product was recrystallized from ethanol/ethyl acetate to afford 19.5 mg (54%) of 17; mp. 187°-90° C. dec; FAB MS 267 (M+H)+ ; 1H NMR (DMSO-d6 ) δ 8.0 (s, 1, H-8), 6.68 (br, s, 2, NH2), 5.95 (m, 1, 1'-H), 5.71 (brs, 2, NH2), 5.22 (m, 1, 5'-OH), 3.73 (m, 1, 5'-H), 3.57 (m, 2, 4'-H, 5'-H), 2.4 (m, 1, 2'-H), 2.32 (m, 1, 2'-H), 2.12 (m, 1, 3'-H), 1.98 (m, 1, 3'-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[Cl:44])[C@H:12]([CH3:36])[CH2:13][CH2:14][CH2:15][O:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[Cl:44])[C@H:12]([CH3:36])[CH2:13][CH2:14][CH2:15][OH:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@H](CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CO
Product: C[C@H](CCCO)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 110.9 %

Procedure:
4-Chloro-N-(2,5-dichlorophenyl)-N-(1R)(1-methyl-4-trityloxybutyl)benzenesulfonamide (5.25 g, 8.0 mmol) was treated with amberlyst 15 (excess, 50 g) in MeOH (150 mL) at room temperature. After 18 h the amberlyst was removed by filtration and the filtrate was concentrated in vacuo. Silica gel chromatography (20% EtOAc/hexanes) of the concentrate afforded 4-chloro-N-(2,5-dichlorophenyl)-N-(1R)(4-hydroxy-1-methylbutyl)benzenesulfonamide (3.75 g, 63% yield): 1H NMR (CDCl3) δ 7.74 (d, 2H, J=8.2 Hz), 7.34–7.52 (m, 5H), 4.18–4.41 (m, 1H), 3.35–3.61 (m, 2H), 1.61–1.72 (m, 2H), 1.77 (s, br, 1H), 1.05–1.09 (m, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=3)=[CH:9][N:10]2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: Brc1cccnc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(-c3cccnc3)c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Method K Combine 4-(6-nitro-1H-indol-3-yl)-benzonitrile, 9 (265 mg, 1.0 mmol), potassium phosphate tribasic (513 mg, 2.4 mmol), copper (I) iodide (38 mg, 0.2 mmol), and 2 mL of DMF in a 4 mL vial. Add 3-bromopyridine (120 μL, 1.2 mmol) and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (127 μL, 0.8 mmol). Warm the solution to 110° C. Let the solution stir overnight. Let the solution cool to RT, isolate the yellow precipitate by filtration, and wash the precipitate sequentially with DMF, 1:1 DMF:H2O, H2O, DMF, EtOAc, and then hexanes. Dry the precipitate under vacuum to yield 301 mg, 0.88 mmol, 88% of the title compound. LRMS (API ES+)=341.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]([CH:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])OC2=O)=[O:5])[CH2:3][CH2:2]1.[C:16](O)(C)(C)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:11]([O:10][C:9]([CH3:13])([CH3:14])[CH3:16])=[O:12])[CH2:2][CH2:3]1
Reactant: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC(=O)C1CC1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan-4,6-dione (23.9 g) and t-butanol (25 g) in dry toluene (80 ml) was stirred and heated at 80° C. for 4 hours. The cooled mixture was washed with water (3×30 ml), dried (anhydrous sodium sulphate), treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-cyclopropyl-3-oxopropionate (20.2 g) as a clear oil bp 80°-84° C./8 mmHg.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:48])([F:47])[C:10]1[CH:11]=[C:12]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:13][N:14]([C:34]1[N:35]=[N:36][N:37]([CH3:39])[N:38]=1)[C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:23]=2)[N:18]([C:29](Cl)=[O:30])[C@H:17]([CH2:32][CH3:33])[CH2:16]1.[CH2:49]([OH:51])[CH3:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:49]([O:51][C:29]([N:18]1[C:19]2[C:24](=[N:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)[C@@H:15]([N:14]([CH2:13][C:12]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:10]([C:9]([F:48])([F:47])[F:8])[CH:11]=2)[C:34]2[N:35]=[N:36][N:37]([CH3:39])[N:38]=2)[CH2:16][C@H:17]1[CH2:32][CH3:33])=[O:30])[CH3:50]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(C(F)(F)F)nc2[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Add triethylamine (25 μL) and 4-dimethylaminopyridine (10 mg, 80 μmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carbonyl chloride (100 mg, 0.16 mmol) and ethanol (28 μL) in dichloromethane (0.9 mL). Stir the mixture at room temperature for 8 h. Evaporate the solvent and purify the crude material by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (51 mg, 51%). MS (ES+): 626 (M+H).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:12].C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>ClCCl.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:12][C@@H:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[O:26])=[CH:23][CH:22]=1
Reactant: N[C@@H]1CCc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (0.9 g) in dichloromethane (15 ml) were added in turn triethylamine (1.71 ml) and 4-fluorobenzoyl chloride (0.58 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give (R)-4-fluoro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)benzamide (1.26 g).