Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([OH:27])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(C)C=O.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([Cl:36])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 10 g of product from Example 67, 0.0965 g of dimethylformamide and 150 ml of methylene chloride is added dropwise 3.46 ml of oxalyl chloride. The reaction is stirred at room temperature for 20 hours and the solvent concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as colorless needles.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:46](Cl)Cl>COCOC>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:46])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: ClCCl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: COCOC
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione in 35 ml of anhydrous methylene chloride and 22.5 ml of methylal is combined in incremental portions at room temperature with a mixture of 1.0 g of phosphorus pentoxide and 7.5 g of silica gel. The mixture is agitated for 3 days at room temperature and then another 11 ml of methylal, 500 mg of phosphorus pentoxide, and 3.75 g of silica gel are added. After another 2 days, the reaction mixture is vacuum-filtered, the residue is washed thoroughly with methylene chloride, and evaporated to dryness under vacuum. The crude product is purified on 350 g of silica gel with a hexane/ethyl acetate gradient (0-50% ethyl acetate), thus obtaining 3.6 g of 17α,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C. [α]D25 =+165° (chloroform).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1)=[O:2].[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[OH:2][CH2:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1
Reactant: O=CCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
the aldehyde (19) (0.303 gm., 1 mmol) was dissolved in absolute ethanol (5 mL) and sodium borohydride (0.05 gm., 1 mmol) was added at room temperature. After stirring for 30 min. the mixture was poured into 10 mL brine and extracted with CH2Cl2 (3×10 mL). The extracts were dried over MgSO4 and evaporated to dryness to yield the desired alcohol (20) (0.264 gm., 0.86 mmol, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([O:12][C@@H:46]1[CH:47]2[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]2)[CH2:45]1)=[O:11]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccc(F)cc1F)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1F)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
2-(2,4-Difluorophenyl)-2-(piperidin-1-yl)acetic acid (304 mg, 1.19 mmol), DCC (491 mg, 2.38 mmol), and HOBT (365 mg, 2.38 mmol) were dissolved in dry THF (12 ml). (R)-quinuclidin-3-ol (454 mg, 3.57 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1+0.1% NH4OH) to obtain the title product as colorless oil (280 mg, 64.5% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:20]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:5]=[N:6][CH:7]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Oc2cncc(Br)c2)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(Oc2cncc(C#N)c2)cc(C)n1
Temperature: 140 °C
Yield: 81 %

Procedure:
Methyl 4-(5-bromopyridin-3-yloxy)-6-methylpicolinate (313 mg, 0.969 mmol, 1.00 eq), Tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.0969 mmol, 0.1 eq), Zn(CN)2 (125 mg, 1.06 mmol, 1.1 eq), and DMF (5 mL) were added to a microwave vial and heated at 140° C. for 10 minutes. The reaction was filtered and concentrated on silica gel (2 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 210 mg (81%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J=1.5 Hz, 1H), 8.84 (d, J=2.7 Hz, 1H), 8.35-8.34 (m, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H); [M+1]+: 270.1.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(CC)C(C)C)(C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (3.2 g, 6.08 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (1.11 mL, 6.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (1.18 g, 6.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (2.23 g, 63%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[CH2:29][CH:28]=[CH2:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Sodium hydride (47 mg of 60% oil dispersion, 1.2 mmol) was added to a solution of 4-(benzyloxycarbonylamino)-1-(t-butoxycarbonyl)piperidine (200 mg, 0.598 mmol) from Procedure 4, Step C and allyl bromide (0.251 mL, 351 mg, 2.9 mmol) in 2.0 mL of DMF, and the reaction was stirred overnight at rt. The reaction mixture was poured into 20 mL of water and extracted with 3×20 mL of ethyl ether. The combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 246 mg of the title compound as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH3:26].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:25][CH3:26])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of compound 35 (4 mmol, 948 mg) in 5 mL DMF, potassium carbonate (K2CO3, 8 mmol, 1.1 g) and bromoethane (4.8 mmol, 523 mg) were added. The reaction was stirred overnight at 60° C. Water (2 mL) was added to dissolve the unreacted potassium carbonate, and the reaction mixture was then extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried over Na2SO4. After removal of the solvent, the crude product was purified by using flash chromatography (0-30% ethyl acetate/hexane) to give the title product 36 (90% yield).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Boc-Asp(OBn)-OH 2.4 g (1 equiv, 7.45 mmol) was dissolved in 17 mL of dry DMF in a 100 mL round-bottom flask. Finely ground K2CO3 (1.5 g, 11 mmol) was added to the solution to form a suspension. The mixture was cooled to 0° C. in an ice-bath over five minutes. MeI (1 mL, 15 mmol) was then added to the mixture over 20 seconds under a positive flow of nitrogen. A yellow color developed within 30 min. The resulting mixture was stirred for 3 hours. The ice-bath was removed and 25 mL of water were added and the mixture left standing at room temperature 2 hours. The mixture was then treated with 30 mL of water and extracted with 3×25 mL AcOEt. The organics were washed with saturated NaHCO3 1×, brine 3×, dried over Na2SO4 filtered and concentrated to yield a yellow oil. This material was passed through a short silica column (eluting w/ AcOEt), after concentration of the pure fractions 2.42 g of Boc-Asp(OBn)-OMe as a yellow oil was obtained (98% yield). 1H NMR (DMSO d6, 500 mHz): δ 7.36 (m, 5H), 5.10 (s, 2H), 4.40 (q, 1H), 3.6 (s, 3H), 2.80 (dd, 1H), 2.72 (dd, 1H), 1.38 (s, 9H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C17H23NO6 (M+H)+ 338.23. found by LC-MS 338.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14]([O:23]C(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>CCCCCC.O1CCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][B:14]([OH:23])[OH:19])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of 4-bromotoluene (743 mmol) and 500 ml of tetrahydrofuran (THF) was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-methylphenyl boric acid (545 mmol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C1(CNCC2CCCCC2)CCCCC1.[C:27]([NH:35][C:36]1[CH:48]=[C:47]([CH:49]=[CH2:50])[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C(=O)C>[C:27]([NH:35][C:36]1[CH:48]=[C:47](/[CH:49]=[CH:50]/[C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)NC(=O)C3)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 35 %

Procedure:
0.20 g of 6-bromo-2-oxoindoline, 0.40 mL of N,N-dicyclohexylmethylamine and 18 mg of trans-di(μ-acetato)bis-o-(di-o-tolylphosphino)benzyl dipalladium(II) were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.46 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 7 hours. After the reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoate as green solid.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[C:8]([Si:12]([CH3:33])([CH3:32])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17]/[CH:18]=[C:19]1\[C:20](=[O:29])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CO>[C:8]([Si:12]([CH3:32])([CH3:33])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17][CH:18]([CH:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:29])[CH2:4][N+:1]([O-:3])=[O:2])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CCO[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of nitromethane (Aldrich) (0.21 g, 3.5 mmol) in methanol (20 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (0.74 g, 3.5 mmol). After the mixture was stirred at room temperature for 10 min, a solution of E/Z-3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentylidene]-6-chloro-1,3-dihydro-indol-2-one (0.68 g, 1.7 mmol) in methanol (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then acetic acid (0.6 g, 10 mmol) was added. The mixture was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give the racemic 3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dim ethyl-1-nitromethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one as a white foam (0.5 g, 64%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22])[CH3:5].C1(=O)[NH:28][C:27](=O)C2=CC=CC=C12.[K].CNN>CN(C)C=O.CCOC(C)=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:28][CH3:27])[S:7]1(=[O:22])=[O:23]
Reactant: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CNN
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNCCC(C)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 36.6 %

Procedure:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.25 mmol) was dissolved in dimethylformamide (2 mL) in a microwave cuvette and potassium phthalimide (0.06 g, 0.3 mmol) was added. The mixture was irradiated at 100° C. for 3 minutes. Upon cooling the mixture was diluted with EtOAc and washed with water and brine then dried with Na2SO4. Upon concentration, the residue was dissolved in MeOH (5 mL), methyl hydrazine (0.06 g, 1.25 mmol) was added and the mixture heated to reflux for 5 hours. Upon cooling the reaction was concentrated and water (10 ml) added followed by acetic acid (to pH 4). After 1 hour the mixture was filtered and basified to pH 14 with NaOH then extracted with dichloromethane. The organic extracts were washed with water, dried with Na2SO4 and purified via Isco chromatography (Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 32 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][CH2:27][CH3:28])[CH:20]=1.C(OCC)(=O)C>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]=1[CH2:26][CH2:27][CH3:28]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCCc1cc(I)ccc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 4-iodo-2-propylphenol under the conditions described in Example 1. The product was isolated by chromatography over the 40 fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. It was crystallized from ether/hexane to give off-white crystals with m.p. 154°-156°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:22]([OH:24])C>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH:22]=[O:24]
Reactant: CCO
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
4-Phenoxyphenol (20.0 g, 107 mmol) and sodium hydroxide (3.8 g, 845 mmol) are dissolved in a water/ethanol (130 mL/26 mL) mixture and heated at 70° C. To this reaction mixture is added chloroform (24.6 g, 215 mmol) dropwise over 45 minutes, and heating is continued for 3 hours. The mixture is cooled to room temperature, and then evaporated. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1-3, and extracted with ether. The organic phase is dried over magnesium sulfate and evaporated. Purification of the residue by silica-gel flash chromatography gives 2-hydroxy-5-phenoxybenzaldehyde as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (2.8 g), piperidine (3.4 g), and water (13 ml) was stirred at 95°C for 2 hours. Then the reaction mixture was adjusted to a pH of 2.5 by the addition of 4N hydrochloric acid, and the precipitated 3-nitro-4-piperidino-5-sulphamyl-benzoic acid was collected and recrystallized from aqueous methanol. The melting point was 237°-238°C (decomp.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:21][CH:22]=[CH2:23])[C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.O=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31][CH2:30]1>ClC(Cl)C>[CH3:20][O:19][C:17]([CH:16]([NH:15][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:31][CH2:30]1)[CH2:21][CH:22]=[CH2:23])=[O:18]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CCC(N)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C=CCC(NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Sodium triacetoxyborohydride (11.2 g, 52.6 mmol) was added to a solution of methyl 2-aminopent-4-enoate (3.4 g, 26.3 mmol), acetic acid (2.37 g, 39.5 mmol) and benzyl 4-oxopiperidine-1-carboxylate (9.21 g, 39.5 mmol) in dichloroethane (60 mL) at room temperature. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 0 to 8% methanol in methylene chloride gradient elution), which gave the title compound (9.42 g). MS 347.2 (M+1).