Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:8](=[O:9])[CH:7]=[CH:6][C:5]2=[O:14].[Br:15]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:15][C:6]1[C:5]([C:4]2[C:10]([C:8](=[O:9])[CH:7]=1)=[CH:11][C:12]([CH3:13])=[C:2]([CH3:1])[CH:3]=2)=[O:14]
Reactant: BrBr
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Reaction time: 2 h

Procedure:
A solution of 6,7-dimethyl naphtho-1,4-quinone (20.0 g.; 0.107 mole) in glacial acetic acid (250 ml) was stirred during the dropwise addition of bromine (5.6 ml; 17.2 g; 0.107 mole) in acetic acid (10 ml.) at 15° C. and allowed to stir at this temperature for a further 2 hours. Anhydrous sodium acetate (20 g) was added and the mixture stirred at 100° C. for 11/2 hours after an initial half hour period at room temperature; cooled, poured into water (2.5 l) and the yellow bromo product filtered off. It had m.p. (ethanol, chloroform) 156°-159° C. (Found; C, 53.47; H, 3.39; Br, 30.23; C12H9BrO2 requires; C, 54.36; H, 3.42; Br, 30.14%):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:30](OC)([O:33]C)[O:31]C>C(OCC)C>[CH:14]1([CH2:13][C:4]2[C:5]3[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=3[CH:12]=[C:2]([B:30]([OH:33])[OH:31])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)COc2c(CC3CCCCC3)cc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)COc2c(CC3CCCCC3)cc(B(O)O)cc21

Procedure:
Following General Procedure A and using 5-bromo-7-cyclohexylmethyl-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 46, 0.58 g, 1.79 mmol),15 mL of anhydrous diethyl ether, 1.7M solution of t-butyllithium in n-pentane (2.21 mL, 3.77 mmol) and trimethyl borate (0.42 mL, 3.77 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(/C=C/C(=O)O)cn2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propenoate (887 mg), 1 N aqueous sodium hydroxide solution (4 ml), ethanol (8 ml), and tetrahydrofuran (8 ml) was stirred at 40° C. for 3 hours. After the reaction mixture was acidified with 1 N hydrochloric acid, the obtained crystals were collected by filtration, and (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoic acid (672 mg, yield: 81%) was obtained. This was recrystallized from ethanol. Melting point: 186–187° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:24])([F:25])[F:26])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCc3c2c2cccc(OC(F)(F)F)c2[nH]c3=O)c1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c1C
Reaction time: 0.5 h
Yield: 162.4 %

Procedure:
1-(2,3-Dimethylphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydro-pyrrolo[3,2-c]quinoline(4.4 g, 11.8 mmol) was dissolved in phosphoryl chloride(10 ml). The reaction mixture was refluxed for 2 hours. After removing the excess phosphoryl chloride by simple distillation, the residue was poured into iced water, neutralized with aqueous solution of sodium hydroxide(1N), and stirred for 30 minutes. The resultant was extracted with dichloromethane(20 ml) for 3 times, and the organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 4.0 g of desired compound as solid in 87% of yield.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15]C(=O)C)=[N:12][CH:11]=2)=[N:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:15][C:13]1[S:14][C:10]([S:9][CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=2)=[CH:11][N:12]=1
Reactant: CCc1cnc(CSc2cnc(NC(C)=O)s2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cnc(CSc2cnc(N)s2)o1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (1.3 g, 4.6 mmol) in 1 N hydrochloric acid (15 mL) was stirred at 80-90° C. for 3 h. It was cooled to rt and the pH of the solution was adjusted to 7 with sodium carbonate. The product was extracted with methylene chloride (3×10 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was triturated with ethyl ether and the precipitated solid was collected to afford 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (610 mg, 55%) as a solid, mp 119-120° C. 1H NMR (CDCl3) δ6.93 (s, 1 H), 6.61 (s, 1 H), 5.41 (s, 2 H), 3.82 (s, 3 H), 2.62 (q, J=7.6 Hz, 2 H), 1.18 (t, J=7.6 Hz, 3 H); MS m/e 242 (M+H)+ ;
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:37][CH2:38][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 41.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-1-piperidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=[N:24]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:23]([C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:14])[NH2:24]
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.00 g), 1H-1,2,3-benzotriazol-1-ol (0.48 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.68 g) at room temperature. The mixture was stirred at 50° C. for 30 min, and hydrazine monohydrate (0.74 g) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.88 g, yield 84%) as colorless crystals. melting point 273-274° C. (decomposition).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])=[CH:12][CH:11]=2)[CH2:5][N:4]1[CH2:28][CH3:29])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[S:39])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])=[CH:12][CH:11]=2)[CH2:5][N:4]1[CH2:28][CH3:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=S)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Yield: 139.6 %

Procedure:
To a solution of N-(1,2-diethyl-4-pyrazolidinyl)-4-geranyloxybenzamide (1.50 g) in toluene (50 ml) was added Lawesson's reagent (0.76 g). After the reaction solution was refluxed with heating for 30 minutes, ethyl acetate was added thereto. Then, the reaction solution was washed with aqueous sodium bicarbonate solution and then with brine. Its organic layer was concentrated under a vacuum and thus obtained residue was pulled by silica gel column chromatography (chloroform:methanol=30:1), thereby yielding 1.09 g (70%) of the aimed compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
The crude 4-(4-Chloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.10 g, 10.0 mmol) was dissolved in methylene chloride (1 mL) and treated with 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated to yield 1.00 g (48%) of the title compound. 1H-NMR (CDCl3) δ: 1.90 (2H, m), 2.23 (1H, brs), 2.83 (2H, m), 3.02 (2H, m), 3.54 (4H, m), 6.58 (2H, d, j=9.3 Hz), 7.13 (2H, d, j=9.3 Hz). ESI-MS m/z: 211 (M+1), FAS method rt: 1.04 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11](=[O:13])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 1.1 g of aniline and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue recrystallized from methanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 173°-174°; it is identical with that obtained according to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[NH2:18].CCCCC.[OH2:24]>[OH-].[Na+].CCO>[NH2:18][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:7][C:4]=1[C:5]([NH2:6])=[O:24]
Reactant: O
Reactant: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCC
Product: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C(N)=O)c1

Procedure:
A mixture containing 1.02 g of 3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 25 ml of H2O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55°-65° C. under N2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl3. The CHCl3 extract is washed with 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to afford 0.74 g. This solid is stirred with pentane and filtered to afford 0.6 g, mp 135°-145° C., of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=O)[O:21]C3C(F)=C(F)C(F)=C(F)C=3F)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:43][C:44]1[CH:45]=[C:46]2[C:67](=[CH:68][CH:69]=1)[CH2:66][C@:48]1([C:56]3[C:51](=[N:52][CH:53]=[CH:54][CH:55]=3)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:49]1=[O:65])[CH2:47]2.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=[O:21])[O:43][C:44]3[CH:45]=[C:46]4[C:67](=[CH:68][CH:69]=3)[CH2:66][C@:48]3([C:56]5[C:51](=[N:52][CH:53]=[CH:54][CH:55]=5)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:62])([CH3:63])[CH3:64])[C:49]3=[O:65])[CH2:47]4)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)C(=O)C12CCCC2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(O)cc3C2)c2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2
Temperature: 150 °C

Procedure:
A mixture of tert-butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-9-[2-oxo-2-(pentafluorophenoxy)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate from Step A (119 mg, 0.197 mmol), (2R)-5-hydroxy-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (77 mg, 0.201 mmol, described in Intermediate 35), and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) in DMF (0.5 mL) was heated at 150° C. in a microwave reactor for 30 min. The reaction mixture was cooled and partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to provide the title compound. MS: m/z=803.7 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:11][CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(=CC)C.C1C[O:30]CC1.[O-]Cl=O.[Na+]>C(O)(C)(C)C.O>[Si:1]([O:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:11][C:12]([OH:30])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC=O)c1ccc(F)c(Cl)c1
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)c1ccc(F)c(Cl)c1
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of 314 (302 mg, 0.913 mmol) in tert-BuOH (20 mL) and H2O (5 mL) was added 2M solution of 2-methyl-2-butene in THF (4.56 mL, 9.13 mmol) then NaH2PO4 (1.204 g, 10.0 mmol). The reaction was stirred 5 min, then NaClO2 (495 mg, 5.48 mmol) was added and the reaction stirred at RT overnight. The reaction was partitioned between EtOAc (50 mL) and 0.5M HCl (30 mL), phases separated and the aqueous phase extracted with EtOAc (50 mL). The combined organic extracts were washed with satd. aq. NaCl (50 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 270 mg (85%) of 4-(tert-butyldimethylsilyloxy)-3-(3-chloro-4-fluorophenyl)butanoic acid (316) as a gray crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J=2.3, 7.1 Hz, 1H), 7.08 (m, 2H), 3.74 (m, 1H), 3.61 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 0.86 (s, 9H), −0.03 (d, J=1.6 Hz, 6H); MS LRMS (APCI neg) m/e=345.1 (M−H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]1([S:7]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccccc1)c1ccccc1
Yield: 80.9 %

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 25 ml flask equipped with a magnetic stirring bar and a calcium chloride drying tube. The flask is charged with benzenesulfonyl chloride (11.60 g, 65.7 mmol), phenol (5.60 g, 59.6 mmol), and 4-dimethylaminopyridine (0.36 g, 2.98 mmol), and anhydrous pyridine (20 ml). The reaction mixture is stirred and heated at reflux, and the progress of the reaction is monitored by high performance liquid chromatography. At the conclusion of the reaction, the mixture is cooled and quenched with water (25 ml), extracted with ether (50 ml), and washed successively with 50 ml portions of water, 5% sodium hydroxide (2×), water, and brine. The organic phase is then dried over magnesium sulphate, filtered, and concentrated to yield 13.1 g (94%) of the crude product as a yellow oil. This product is further purified by distillation on a Kugelrohr apparatus under vacuum to give 11.3 g (81%) of the product as a colorless oil. The oxidative stability of the product is determined by pressure differential scanning calorimetry (PDSC). The results are reported below in Table 1.
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=2)[C:6]1=[O:16])(C)(C)C.O.[NH2:18]N>CC(O)=O.O>[CH3:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:16])[NH:18][N:5]=[CH:13]2
Reactant: NN
Reactant: Cc1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)[nH]ncc2c1
Temperature: 80 °C

Procedure:
To a solution of 2-tert-butyl-3-hydroxy-5-methylisoindolin-1-one (10.54 g, 48.1 mmol) in AcOH (250 ml) charged to a 500 mL round bottom and stirred at 80° C., hydrazine hydrate (3.51 ml, 72.1 mmol) was added. The reaction mixture was stirred at 80° C. for 90 min. The reaction mixture was then cooled and diluted with water and extracted with 4 L DCM. The organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum to give 6-methylphthalazin-1(2H)-one. MS (M+H)+ 161.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH:16]([O-])([O-])OC.S(=O)(=O)(O)O>CO>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8])([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Yield: 82.2 %

Procedure:
To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added conc. sulfuric acid (20 ml) dropwise with stirring. The reaction mixture was heated under reflux for 18 hours and concentrated to dryness. After addition of water (30 ml) to the residue, the mixture was stirred at 3-10° C. for one hour. The precipitated crystals were recrystallized from ethyl acetate-hexane to give pale yellow prisms (185 g, 82%), m.p. 166-168° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]=1>CO>[CH3:15][O:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1
Reactant: COCC1=NCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COCC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (8.11 g, 38.3 mmol) was added to a stirred, ice-cooled solution of the product from (b) above (6.1 g, 34.8 mmol) in methanol (80 ml), then the resulting mixture stirred for 18 hours at room temperature before being quenched with water. The bulk of the solvent was removed under reduced pressure, then the residue basified with 1M aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to furnish the required product (6.19 g) as an orange oil, Rf 0.25 (SS 3), m/e 178 (M+H)+, which was used without further purification in the next step.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)#[N:11]>ClCCl>[Br:5][CH2:6][C:7]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)=[O:8]
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.68 g aluminium chloride (35.15 mmol) are dissolved in 45 ml dichloromethane and treated dropwise with 3.38 g (16.74 mmol) bromoacetyl bromide at 0° C. After 30 min 3 g (16.74 mmol) 4-cyanobiphenyl, dissolved in 15 ml dichloromethane, are added dropwise. The reaction mixture is stirred overnight at ambient temperature, added to ice-water and extracted 2 times with dichloromethane. The organic phase is washed with water and brine, dried and evaporated. The residue is triturated with petrol ether, filtered and dried. Yield: 4.24 g (83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(Br)cc(I)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(Br)cc(C#C[Si](C)(C)C)c1=O
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (8.0 g, 25.48 mmol), ethynyltrimethylsilane (2.7 g, 27.52 mmol), CuI (485 mg, 2.55 mmol), Pd(PPh3)2Cl2 (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol) in dry THF (100 mL) was heated to 60° C. under an atmosphere of nitrogen for 2 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=5:1) to give the title compound (6 g, 82%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=2.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 3.54 (s, 3H), 0.25 (s, 9H). LCMS (M+H)+=285.