Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(Cl)cc2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.9 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 13.5 g of 4-chlorobenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0°0 C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 149°-150° C.). 1H NMR (CDCl3) δ 2.83 (dd, 1 H), 2.95 (dd, 1 H), 3.60 (dd, 2 H), 5.67 (dd, 1 H), 7.33-7.44 (m, 4 H).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([SH:9])=[N:7][N:6]=[N:5]1)#[N:2].[N-:10]=[N+:11]=[N-:12].CN(C)C(=[NH2+])N(C)C>O1CCOCC1>[NH:10]1[C:1]([CH2:3][N:4]2[C:8]([SH:9])=[N:7][N:6]=[N:5]2)=[N:2][N:12]=[N:11]1
Reactant: N#CCn1nnnc1S
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: C1COCCO1
Product: Sc1nnnn1Cc1nnn[nH]1
Yield: 55 %

Procedure:
A solution of 6.0 g. (42.5 mmole) of 1-cyanomethyl-1H-tetrazol-5-thiol and 10.0 g. (6.3 mmole) of tetramethylguanidinium azide in 90 ml. of dioxane was heated at the reflux temperature for 3 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo and the residue dissolved in ethyl acetate:water, 1:1. The ethyl acetate layer was separated, and the pH of the aqueous layer was adjusted to pH 1.8 with 20% hydrochloric acid. The acidified aqueous layer was then extracted 3 times with 75 ml. portions of ethyl acetate, and the extracts were combined. The extract was washed with 5% hydrochloric acid, with brine, was dried over sodium sulfate, and then evaporated in vacuo to dryness. The red oil obtained as a residue crystallized on seeding. The crystals were washed with ethyl acetate and with diethyl ether and were dried. There were obtained 3.7 g. of the bis-tetrazolmethyl thiol melting at about 173° C. to about 175° C. The filtrate from the first crop was evaporated to an oil and after seeding the oil, 0.3 g. of a second crop crystalline product were obtained. A third crop of 0.3 g. was obtained in the same manner. Total yield of product was 4.3 g. (55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].O[Li].O>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a stirring solution of ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 0.78 mmol) in 1:1:1 THF/EtOH/H2O (21 ml) at RT was added LiOH—H2O (0.164 g, 3.91 mmol). The resulting reaction mixture was stirred at RT overnight. Solvent was removed under reduced pressure and the residue was diluted with H2O (10 mL). The aqueous solution was acidified to pH˜4 with 3M HCl and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated to afford 5-chloro-2-(quinolin-6-yl)benzoic acid (0.201 g, 91% yield) as a white solid. MS (ESI) m/z: 284.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][S:23][CH:24]([CH3:26])[CH3:25])[CH:7]=1)[CH3:2].C(N(CC)CC)C>CN(C=O)C.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]>[CH3:1][O:3][C:4](=[O:27])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[C:16]([CH2:22][S:23][CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)OC)cc2CSC(C)C)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.5 g, 1.1 mmol) and triethylamine (0.5 mL) were dissolved in DMF (10 mL) and MeOH (10 mL) and degassed for 10 minutes with N2. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09 g, 0.11 mmol) was added, and then carbon monoxide was bubbled through the solution for 10 minutes. The reaction was stirred under a balloon of carbon monoxide at 65° C. overnight, and then concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:21]([C:20]([C:16]1[CH:15]=[C:14]([CH3:40])[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:18]([CH3:19])[CH:17]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:32][CH3:33])([OH:34])[CH2:35][CH3:36])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)O)cc3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.9 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.181 mL, 0.181 mmol) was added to a solution of (E)-(4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2′,6′-dimethyl-biphenyl-4-yl)acetic acid methyl ester (Example 58-(1); 31.8 mg, 0.060 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for 10 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (25.8 mg, 84%).
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.C(OCC)C>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)CN1CCCNCCN(CC(=O)O)CCCNCC1
Yield: 95.5 %

Procedure:
To a solution of compound (4) (0.48 g, 0.96 mmol) in absolute ethanol (40 ml) was added 10% Pd/C (0.12 g). The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 10 hours. The reaction mixture was filtered through a celite pad, and washed with ethanol (2×10 ml). The combined filtrate was evaporated in vacuo to give an oily residue, which was then treated with diethyl ether (Et2O) to obtain an off-white solid (0.29 g, 98% yield). 1H NMR (500 MHz, D2O): δ 3.48 (brs, 2H), 3.01-3.19 (m, 10H), 2.80 (brs, 6H), 2.67 (brs, 2H), 1.84 (brs, 4H); 13C NMR (125 MHz, D2O): δ 179.0, 56.3, 55.7, 48.9, 45.4, 22.8; HRMS (FAB) calculated for C14H28N4O4: 317.2189 [(M+H)+], measured value: 317.2185 [(M+H)+].
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].N.CO>C(OCC)(=O)C>[NH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:9]=[C:8]([C:2]([OH:1])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C)(O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(C)(O)c1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate gradient), gave Example 120 a colorless oil. Yield (0.157 g, 90%): 1H NMR (400 MHz, CDCl3) δ 7.20-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.73 (t, J=7.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.70-1.84 (m, 4H), 1.53 (s, 3H), 1.42 (brs, 3H), 1.18-1.30 (m, 3H), 1.06-1.16 (m, 1H), 0.84 (t, J=7.2 Hz, 3H). ESI MS m/z 236.2 [m+H]+, 218.2 [m+H−H2O].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:51]1([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: C1CCCNCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), and CH2Cl2 (2 mL) were added hexahydro-1H-azepine (4.5 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to yield a white foam.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.O>C1C=CC=CC=1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]1=[O:16]
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCCCC1COCc1ccccc1
Solvent: O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: O=C1C(COCc2ccccc2)CCCC1Cc1ccccc1Br
Reaction time: 3 h

Procedure:
To a solution of the ketone of Example 113 in benzene is added pyrrolidine (4 equivalents). The mixture is heated to reflux for 24 hours removing the water formed by use of a Dean-Stark type apparatus. The reaction mixture is concentrated in vacuo. The organics are dissolved in dioxane followed by addition of 2-bromobenzyl bromide (1.5 equivalents). The mixture is heated to reflux for 6 hours. Water is added and the refluxing continued for 3 hours. The solution is concentrated in vacuo to dryness. The remaining organics are partitioned between ether and water. The ether layer is dried (MgSO4), concentrated in vacuo, then chromatographed to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]([CH2:18][F:19])[O:15][CH2:14][C@:12]2([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O.FC1C=CC=CC=1[C@]12CO[C@@H](COC(C)C)C[C@H]1CSC(N)=N2>>[F:19][CH2:18][C@@H:16]1[O:15][CH2:14][C@:12]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:13]=[C:8]([NH2:7])[S:9][CH2:10][C@@H:11]2[CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CF)C[C@H]2CS1
Agent: CC(C)OC[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)CO1
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CF)C[C@H]2CS1

Procedure:
tert-Butyl[(4aR,6R,8aS)-6-(fluoromethyl)-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C26) was converted to the product according to the general procedure for the synthesis of (4aR,6R,8aS)-8a-(2-fluorophenyl)-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, trifluoroacetate salt (2) in Example 2. In this case, the reversed-phase HPLC purification was carried out using a different system (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 25% to 100% B). Yield: 3 mg, 0.01 mmol, 10%. LCMS m/z 299.1 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 1.43-1.48 (m, 1H), 1.63-1.72 (m, 1H), 2.64-2.72 (m, 2H), 2.75-2.80 (m, 1H), 3.60 (d, J=11.0 Hz, 1H), 3.76-3.85 (m, 1H), 3.96 (dd, J=10.8, 1.5 Hz, 1H), 4.30-4.48 (m, 2H), 6.13 (br s, 2H), 7.14-7.22 (m, 2H), 7.30-7.36 (m, 2H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[Cl:6][CH2:5][CH:7]([OH:9])[CH2:8][O:4][CH2:1][CH2:2][CH3:3]
Reactant: ClCC1CO1
Reactant: CCCO
Product: CCCOCC(O)CCl
Yield: 73.7 %

Procedure:
A mixture of 300 g 1-propanol (5.0 mol), 231 g epichlorohydrin and 10 g ion exchange resin was refluxed for 22 hours. The reaction mixture was then cooled, filtered and distilled to give 281 g of 1-chloro-3-propoxy-2-propanol (74% yield). Reaction of this product with paraformaldehyde (2.8 mol) gave 202 g of product (69% yield) having the following structure: ##STR41##
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC)=O)=[CH:22][CH:21]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:32])[F:33])=[CH:25][CH:24]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(C(F)(F)F)cc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Sodium (622 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl 4-trifluoromethylphenylacetate (6.27 g, 27 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature, and the solvent was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, recrystallized from ether and dried at 110° C. and 0.2 mm Hg to afford 3.03 g of 1-cyclopentyl-3-ethyl-6-(4-trifluoromethylphenylmethyl) pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212°-213° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:29]([CH3:31])[CH3:30]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC(C)C
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.843 mmol) and isobutyl bromide (115 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (15 mg, 15.7%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])[CH:30]=[CH:31][C:32]=1[Cl:33].CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:1][CH:3]3[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][CH2:5][N:4]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:39][CH2:38]2)=[O:36])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-benzyl 4-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (227 mg) in THF (20 ml) were added N-(3,4-dichlorophenyl)piperazine-1-carboxamide (179 mg), DIPEA (319 ul) DMF (1.6 ml) and MgSO4 (30 mg) the mixture stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (277 mg) added and stirring continued for 16 hours at room temperature. Saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic phase was dried (MgSO4) and evaporated to give the title compound as a semi-solid gum (331 mg, 84%).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17](N)=[N:18][CH:19]=1.[OH-:21].[Na+]>S(=O)(=O)(O)O.CCO>[F:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17]([OH:21])=[N:18][CH:19]=1
Reactant: [OH-]
Reactant: CSc1ccc(-c2cnc(N)cn2)c(F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Sodium nitrite (1.73 g, 25.1 mmol) was added portionwise to concentrated sulfuric acid (20 mL) at 0° C. The mixture was stirred at 45° C. until homogeneous, cooled to 0° C., and charged with a solution of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinamine (4.37 g, 18.6 mmol) in concentrated sulfuric acid (55 mL) at 0° C. The reaction was allowed to warm to 25° C., stirred for 15 min, then at 45° C. for 1 h. The reaction was poured onto ice and the pH was adjusted to ˜4 with 10N NaOH. The resulting tan precipitate was filtered, washed with water, and air-dried to afford a tan solid. The solid was refluxed in EtOH (300 mL), hot-filtered, and the filtrate concentrated to afford 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (3.16 g, 72% yield, purity=87%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ8.14 (d, 1H, J=1.2 Hz), 7.72-7.86 (m, 2H), 7.24-7.15 (m, 2H), 2.52 (s LRMS (ESI), m/z 237 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=1)=[S:21])[NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=3)=[S:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
From 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (42.8 mg, 0.17 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (61.1 mg, yield 68%)
Reaction SMILES: [C:1]([O:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([O:14][C:15]2[CH:16]=[C:17]([C:37](=[O:40])[CH2:38][Br:39])[CH:18]=[C:19]([O:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+].Cl>O1CCOCC1.O>[C:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][C:19]2[CH:18]=[C:17]([CH:37]([OH:40])[CH2:38][Br:39])[CH:16]=[C:15]([O:14][C:12](=[O:13])[C:11]3[CH:41]=[CH:42][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:9][CH:10]=3)[CH:20]=2)=[O:36])=[CH:28][CH:27]=1)(=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(=O)CBr)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(O)CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.8 g (0.012 moles) of 3',5'-bis-(4-pivaloyloxybenzoyloxy)-2-bromoacetophenone in 200 ml of dioxane and 40 ml of water was added portionally 0.45 g (0.012 moles) of NaBH4 dissolved in 30 ml of water. After each addition pH was adjusted with 1 N HCl so that the pH of the reacting mixture never exceeded pH 7. The mixture was stirred at ambient temperature for 1 h, whereafter the solution was evaporated to dryness and the residue taken up in diethyl ether. The ether phase was washed with water, dried over MgSO4 and then evaporated to dryness to yield a crystalline residue. The identity of the product was confirmed with NMR.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.[BH4-].[Na+]>CCO>[CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) was added EtOH (1.1 M) and CeCl3-7H2O (1.3 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.3 equiv.) was added in portions. Stirred for 2 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, dried with brine, then Na2SO4, and concentrated to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (91%). LC/MS=235.2 (M+H), LC=2.62 min.