Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a solution of 100 g (763 mmol) of 4-hydroxy-L-proline in 750 ml of water was added 169.9 g (1602 mmol) of sodium carbonate at 0° C. along with 174.5 g (916 mmol) of 4-toluenesulfonyl chloride (added in 3 portions over a period of 1 hour). The slurry was then warmed to room temperature and allowed to stir for 48 hours. The reaction was acidified with concentrated hydrogen chloride solution to pH 2 and the product was isolated via filtration. The filter cake was washed with pH 2 buffer and dried in a vacuum oven at 60° C. for 16 hours to obtain 215.3 g of the product as a white crystalline solid in 99% yield. M.P.=149°-151° C.
Reaction SMILES: ClC(OCC)=O.C1C=CC=CC=1.C1(C[N:17]2[CH2:35][CH2:34][C@H:20]3[N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C@@H:19]3[CH2:18]2)CC1.[OH-].[K+]>C(O)CCC>[C:28]1([N:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C@@H:19]3[CH2:18][NH:17][CH2:35][CH2:34][C@@H:20]23)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CN(CC4CC4)CC[C@H]32)cc1
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: c1ccccc1
Product: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Reaction time: 1 h

Procedure:
A solution of ethyl chloroformate (22 g., 0.2 mole) in 100 ml. dry benzene was added to a solution of (±)-trans-2-cyclopropylmethyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-1H-pyrido[4,3-b]indole (16 g. crude material, prepared as described above, 0.047 moles in theory) in 400 ml. anhydrous benzene with stirring. The resulting mixture was refluxed for three hours. As the mixture was refluxing, a whitish solid precipitated. After refluxing, the mixture was cooled and filtered to remove the precipitate, then the filtrate was evaporated to dryness under vacuum, yielding a yellow oil. This oil was dissolved in 400 ml. n-butanol, 40 g. of KOH pellets were added, and the resulting mixture was refluxed with stirring for one hour. After refluxing, the mixture was cooled, and concentrated under vacuum. Water and toluene were added and the mixture was placed in a separatory funnel. The toluene layer was removed and washed with water until the waste water was neutral to litmus. The toluene layer was then extracted four times with 125 ml. of 1 molar tartaric acid. The combined extracts were then washed once with ether, made basic by addition of 50% aqueous NaOH, cooled, and extracted two times with 75 ml. CHCl3. The CHCl3 extract was washed with water until the wash water was neutral to litmus, dried with K2CO3, filtered, and evaporated to dryness under vacuum, yielding 9.7 g. of an oil. This was left in a refrigerator overnight, then was triturated with hexane, yielding a solid. Recrystallization from hexane yielded 4.9 g. of the title compound, m.p. 94°-94.7° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:34][C:25]1[C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][CH2:7]4)=[CH:12][CH:13]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=[C:27]([C:30]([F:32])([F:31])[F:33])[N:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1Nc1ccc(-c2ccc(C3CCC(CC(=O)O)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (332 g, 0.69 mmol) was dissolved in THF/MeOH (3:1, 4 mL) and to it was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the organic solvent was removed via rotary evaporation. The remaining crude was diluted with water and the pH was adjusted to 2 with 1 M HCl. The resulting precipitate was collected by filtration and dried under vacuum to obtain the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.04 (m, 2H) 1.44 (dd, J=12.51, 2.91 Hz, 2H) 1.67 (br. s., 1H) 1.74-1.87 (m, 6H) 2.47 (m, 1H) 2.60 (s, 3H) 7.25 (d, J=8.59 Hz, 1H) 7.30 (d, J=8.34 Hz, 2H) 7.56 (d, J=8.34 Hz, 2H) 7.66 (d, J=8.34 Hz, 1H) 7.97 (dd, J=8.72, 2.65 Hz, 1H) 8.48 (d, J=2.27 Hz, 1H) 8.67 (d, J=8.34 Hz, 1H) 8.80 (s, 1H); MS (M+H)+470.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37])C>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:34][C:32]3[CH:31]=[CH:30][C:29]([O:36][CH3:37])=[C:28]([CH:33]=3)[C:27]([OH:38])=[O:26])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(CCC4COCCO4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.06 g (0.19 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 0.071 g (0.26 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.019 g (65% of yield) were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][C:8]1[N:9]=[C:10]([C:19](OC)=[O:20])[S:11][C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>O>[CH3:7][C:8]1[N:9]=[C:10]([C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:20])[S:11][C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: CN(C)CCN
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Solvent: O
Product: Cc1nc(C(=O)NCCN(C)C)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Dimethylethylenediamine (1.4 ml) was added to a suspension of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) in water (2.8 ml) at room temperature, and the mixture was stirred at room temperature for overnight. The mixture was evaporated to dryness and the residue was chromatographed on an activated alumina column and eluted with chloroform to give 4-methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][C:22]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:35][CH3:36])(=[O:34])[C:27]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)CC>[C:26]([C:27](=[CH:28][C:22]1[CH:21]=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[CH2:16][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][C:30]([O:32][CH3:33])=[O:31])([O:35][CH3:36])=[O:34]
Reactant: COc1ccc(Br)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COC(=O)CC(=Cc1ccc(OC)cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A 500 mL flask was charged with 3-bis(tert-butoxycarbonyl)aminomethyl-4-bromoanisole(15 g, 36 mmol), dimethyl itaconate (7.5 g, 47 mmol), tri-o-tolylphosphine (1 g, 3 mol), palladium acetate (0.4 g, 2 mmol), diisopropylethylamine (12.8 mL, 72 mmol), and propionitrile (150 mL). The mixture was purged with argon (several evacuation/argon flush cycles), then was heated to reflux under argon for 1 hr. The reaction was allowed to cool to RT, then was poured into ice-cold ethyl ether (500 mL). The resulting precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on silica gel (10%-20% ethyl acetate in hexane) to give the title compound (11.8 g, 66%) as a pale yellow oil: 1H NMR (CDCl3) δ 7.94 (s, 1 H, 7.15 (d, J=8.1 Hz, 1 H), 6.77 (d, J=8.1 Hz, 1 H, 6.76 (s, 1 H, 4.73 (s, 2 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.38 (s, 2 H), 1.45 (s, 18 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1N=C=O.[NH2:9][C@H:10]([C:12]([NH:14][CH:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([CH3:32])[C:16]1=[O:33])=[O:13])[CH3:11]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:16][CH2:15][NH:14][C:12]([NH:9][C@H:10]([C:12]([NH:14][CH:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([CH3:32])[C:16]1=[O:33])=[O:13])[CH3:11])=[O:13]
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C=Nc1cccs1
Product: C[C@H](NC(=O)NCCc1cccs1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2-thiophene-yl isocyanate and 3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: (M+H).
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+].[Na+].[OH-:17].[Na+]>>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH-:17].[Na+:14]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Electrodialysis was carried out similarly to Example 2, using 1000 parts of a one-molar aqueous trisodium citrate solution in compartment (9) and 1000 parts of 0.1 molar sodium hydroxide solution in compartment (8). 940 parts of an aqeuous solution of citric acid (1.0 mole/kg, corresponding to a material yield of 94% and a current efficiency of 92%) were obtained in compartment (9), and 1264 parts of sodium hydroxide solution (1.72 moles of NaOH per kg, corresponding to a material yield of 69%) were obtained in compartment (8).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH2:21][O:22][CH2:23][C:24]#[CH:25])[CH2:19][OH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:27][CH3:28])[C:15]([NH:17][C:18]([CH3:26])([CH2:21][O:22][CH2:23][C:24]#[CH:25])[CH:19]=[O:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#CCOCC(C)(CO)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C#CCOCC(C)(C=O)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Temperature: 25 °C
Yield: 110.6 %

Procedure:
2-(3-Ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (1.0 g) from Stage 3 above in dichloromethane (40 ml) was treated with Dess-Martin periodinane (1.277 g). The reaction mixture was stirred at room temperature for 2.5 and then treated with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The organic layer was washed with sat. aqueous NaHCO3. After separation, the organic phase was dried over sodium sulphate, filtered and evaporated to yield 1.10 g of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methyl-2-oxo-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl acetamide as a crude product which was used in the next step (Stage 5, described below) without any further purification. 1H NMR (CDCl3) δ ppm: [{9.51 (s), 9.49 (s) 1H}, isomer A and isomer B]; 8.86 (1H, d); 8.22 (1H, d); 8.07 (1H, d); 7.53-7.50 (1H, m); [{7.58 (s br), 7.48 (s br) 1H}, isomer A and isomer B]; 7.26 (1H, m); 5.72 (1H, s); 4.16-3.87 (4H, m); 3.28 (1H, s); 2.48 (1H, m); [{2.22 (s), 2.20 (s) 3H}, isomer A and isomer B]; 1.52 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].C[O-:39].[Na+]>CO>[CH2:1]([C:5]1([OH:39])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:31])(=[O:32])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCC1(O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 28.8 %

Procedure:
A mixture of Example 1G (0.3 g, 0.55 mmol) in 30% weight sodium methoxide in methanol (3 mL) was stirred at 25° C. for 24 h. The solution was quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (4% methanol/ethyl acetate) afforded the title compound as a white solid (0.095 g, 28.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.72 (m, 3H), 0.95-1.29 (m, 5H), 1.63 (m, 2H), 2.99 (s, 3H), 4.95 (s, 1H), 7.17-7.59 (m, 8H), 7.93 (d, J=7.35 Hz, 1H), 9.89 (s, 1H); MS(ESI) m/z 504.1 (M+H)+.
Reaction SMILES: NCC[NH:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.C(#N)C=C.[C:19]([O:23][C:24](=[O:42])[N:25]([CH2:39][CH2:40][NH2:41])[CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1.ClC(O[C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=1)=O>C(Cl)Cl.O>[C:19]([O:23][C:24](=[O:42])[N:25]([CH2:39][CH2:40][NH2:41])[CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])([CH3:20])([CH3:22])[CH3:21].[C:5](=[O:6])([O:14][C:56]1[CH:55]=[CH:54][CH:59]=[CH:58][C:57]=1[N+:60]([O-:62])=[O:61])[NH2:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N(CCN)CCNC(=O)OCc1ccccc1
Solvent: C=CC#N
Solvent: O
Solvent: ClCCl
Product: NC(=O)Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
(2-Amino-ethyl)-(2-benzyloxycarbonylamino-ethyl)-carbamic acid tert-butyl ester was prepared from benzyl 2-aminoethylcarbamate using the same reaction sequence outlined by Andruszkiewicz et al in Synthetic Communications 2008, 38, p. 905-913 (reaction with acrylonitrile, followed by protection of the secondary amine with the BOC group, and conversion of the nitrile group to an amino group with one less methylene unit using the Hoffmann rearrangement). (2-Amino-ethyl)-(2-benzyloxycarbonylamino-ethyl)-carbamic acid tert-butyl ester (500 mg, 1.48 mmol) was taken up in 15 mL of CH2Cl2 along with 4-methylmorpholine (449 mg, 4.44 mmol) and cooled to 0° C. 4-Nitrophenyl chloroformate (328 mg, 1.63 mmol) was then added at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 16 h. It was then diluted with water. The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded the intermediate nitrophenyl carbamate (480 mg; 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: BrCC1CC1
Product: Cc1cc(Cl)ncc1OCC1CC1
Yield: 86 %

Procedure:
The title compound is prepared in 86% yield (3.57 g, colorless oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and (bromomethyl)cyclopropane (3.39 g, 25.1 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: [C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.BrC1C=CC(C(O)=[O:24])=CC=1.C=CC1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>[C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:24])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C=Cc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: C=Cc1ccccc1
Product: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Yield: 55 %

Procedure:
Stilbene-4-carboxylic acid chloride can be prepared as follows: 25.15 g (125 mmols) of 4-bromobenzoic acid, 16.25 g (156.25 mmols) of styrene, 26.55 g (262.5 mmols) of triethylamine, 0.28 g (1.25 mmols) of palladium acetate and 1.52 g (5 mmols) of tri-o-tolylphosphine are stirred at 100° C. for 3.5 hours. The reaction mixture is poured into 100 ml of 2N HCl and the crude product is filtered off and recrystallised from tetrahydrofuran/toluene. 15.3 g (55% of theory) of stilbene-4-carboxylic acid are obtained in the form of white crystals; melting point 252.4° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>C1COCC1>[C:19]([C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][CH2:2][C:3]([CH3:10])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:20]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCNC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 3-hydroxy-2,2-dimethyl-N-propylpropanamide (1.59 g, 10.0 mmol) (Example 215d) in dry THF (30 mL) was carefully added NaH (60% in mineral oil, 400 mg, 10.0 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (1.93, 10.0 mmol), and the reaction solution was stirred at 0° C.—RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 60% EtOAc in hexanes to give the title compound as a pale yellow solid (2.21 g, 72%). MS 306 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1(N=C=N)CCCCC1>C1COCC1>[O:28]=[C:23]1[CH2:24][CH2:25][C:26](=[O:27])[N:22]1[O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:9]=[C:10]([OH:11])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(C(=O)c2cc(O)c(O)c(C(=O)O)c2)cc1
Agent: N=C=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cc(O)c(O)c(C(=O)ON3C(=O)CCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2,3-dihydroxy-5-(4-methyl-benzoyl)-benzoic acid (214 mg, 0.79 mmol) in 10 mL dry THF cooled to 0° C., N-hydroxysuccinimide (136 mg, 1.18 mmol, 1.5 eq.) and N-cyclohexylcarbodiimide, N′-methyl polystyrene HL (Novabiochem) (1.9 eq./g, 832 mg, 2 eq.) were added and the solution was stirred 14 h while the cooling bath slowly warmed up to r.t. The solution was filtered and the filtrate was evaporated under reduced pressure. The crude product was recrystallised from H2O to yield the desired product as a brownish solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH2:13](Cl)Cl.C[N+](C)=C.[I-].[Cl-].[NH4+]>C(N(CC)CC)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:13])[CH:11]=[O:12])=[CH:8][CH:9]=1)[CH3:1]
Reactant: ClCCl
Reactant: CC(C)c1ccc(CC=O)cc1
Agent: C=[N+](C)C
Agent: [Cl-]
Agent: [I-]
Solvent: CCN(CC)CC
Product: C=C(C=O)c1ccc(C(C)C)cc1
Reaction time: 2.5 h

Procedure:
4.65 g of aldehyde 43 is introduced into 300 ml of methylene chloride under nitrogen, and 7.9 ml of triethylamine and 6.9 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.84 g of title compound 44 accumulates as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1CO
Reaction time: 8 h
Yield: 106.9 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol) in THF (150 mL) was added BH3-THF (1 M, 231 mL) at room temperature, and the reaction mixture was stirred overnight. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. The reaction was quenched with water (150 mL) and extracted with EtOAc (3×500 mL). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (10 g, crude), which was directly used in the next step without further purification. MS (ES+) C7H8BrNO requires: 201. found: 202, 204 [M+H]+.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=O)=[CH:8][CH:7]=1.[N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+:17]=[N-:18]>C(O)C>[N:16](/[C:19](=[CH:14]\[CH:13]=[CH:12]\[C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][CH:10]=1)/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+:17]=[N-:18]
Reactant: Cc1ccc(/C=C/C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=C/C=C/c1ccc(C)cc1)N=[N+]=[N-]

Procedure:
Following General Procedure I, a 1.38 M solution of NaOEt in ethanol (30 ml), (E)-3-(4-methylphenyl)acrylaldehyde (Compound 43, 1.1 g, 7.5 mmol) and ethyl azidoacetate (12 ml, 37.5 mmol) in EtOH (20 ml) were reacted to produce the title compound as a solid.