Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(F)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (102 mg), p-fluorophenol (129 mg) and triphenylphosphine (132 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (81 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:10) and then with recrystallization from dlisopropylether to obtain the entitled compound (99 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](O)[CH2:8][CH3:9].[N:11](C([C@H]1CCCO1)CC)=[N+:12]=[N-:13]>>[N:11]([CH:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[CH2:8][CH3:9])=[N+:12]=[N-:13]
Reactant: CCC(N=[N+]=[N-])[C@H]1CCCO1
Reactant: CCC(O)c1cnccn1
Product: CCC(N=[N+]=[N-])c1cnccn1

Procedure:
The title compound is prepared from 1-(pyrazin-2-yl)propan-1-ol (prepared according to the procedure of ‘Some reactions of mono substituted pyrazine monoxides’ Journal of Heterocyclic Chemistry (1982), 19(5), 1061-7, Compound 18) analogously to (2R)-2-(1-azidopropyl)tetrahydrofuran (Intermediate DA, step 4).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][Si:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C:18]2[CH:19]=[CH:20][N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:23])([CH3:22])[CH3:10])[N:17]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 405.9 mg of 2,4-dichloro-6-methylpyrimidine, 585.5 mg of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (WO2006/046734, page 132, Reference 2), 231.9 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 208.6 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 751.2 mg of potassium phosphate and 20 ml of 1,4-dioxane was stirred at 80° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with ethyl acetate. An insoluble matter was filtered off using Celite, and washed with ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1−2/3) to give the title compound.
Reaction SMILES: Br[C:2]1[N:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:8])=[O:5].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCOCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:20])[N:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:27]=[CH:28][CH:29]=[N:30][C:2]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH3:8])=[CH:18]2
Reactant: C1COCCN1
Reactant: C[C@H](NC(=O)c1cccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cccnc1N1CCOCC1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
To a mixture of (S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (52) (150 mg, 0.31 mmol) in anhydrous 1,4-dioxane (3 mL) in a sealed tube, morpholine (1 mL, excess amount) was added and the resulting mixture was stirred at 140° C. for 6 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) followed by prep-TLC plate purification (10% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-morpholinonicotinamide (compound 53). ESI-MS m/z: 489.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:29]=[CH:28][C:22]3[N:23]([CH3:27])[C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)=[O:18])=[C:12]([Cl:31])[CH:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:29]=[CH:28][C:22]3[N:23]([CH3:27])[C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)([OH:18])[C:2]([F:4])([F:3])[F:1])=[C:12]([Cl:31])[CH:11]=1
Reactant: CC(C(=O)c1ccc2c(c1)oc(=O)n2C)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 1.48 mL) was added at 0° C. to a solution of 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (531 mg) in THF (15 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (424 mg). Stirring was continued for 48 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3) to give the title compound as a orange amorphous foam (440 mg, 70%). MS (neg. ion, m/e)=464.0 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([N+:24]([O-])=O)[CH:3]=1.Cl.O>C(O)C.B#[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:19])[F:20])=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([NH2:24])[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: B#[Ni]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
The freshly prepared nickel boride (1.06 g) was added to a solution of ethyl 4-(4-chloro-2-nitrobenzoyl)-3- trifluoromethyl-1H-pyrazole-5-carboxylate (437.0 mg, 1.116 mmol) in ethanol (20 mL) followed by addition of 1.0N aqueous hydrochloric acid (5.0 mL). This mixture was stirred at 60° C. for 30 minutes and then at room temperature overnight (17 hours). The reaction mixture was poured into water (250 mL) and extracted with diethyl ether (2×250 mL). The organic extract was filtered to remove residual black solids, washed successively with water (250 mL) and saturated aqueous sodium chloride (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to afford 0.42 g of greenish-yellow solid. This material was dissolved in ethyl acetate (50 mL) and preabsorbed onto 4.1 g of silica gel, which was then applied to the top of a 40 g (2.84×14.2 cm) silica gel flash chromatography column. The column was eluted with hexane-ethyl acetate (90:10 then 80:20) to give 235.6 mg (58.41%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccc(-c3cccnc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3cccnc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 65 was synthesized using 9-pyridin-3-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.: 240-242° C.; 400 MHz 1H NMR (DMSO-d6) δ 9.04 (d, J=2.0 Hz, 1H), 8.69 (dd, J=1.6, 4.8 Hz, 1H), 8.24 (dt, J=1.6, 8.8 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.93 (dd, J=1.6, 8.4 Hz, 1H), 7.59 (dd, J=4.8, 8.0 Hz, 1H), 7.55-7.47 (m, 3H), 7.41 (d, J=7.6 Hz, 1H), 4.32 (br, 1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.03 (m, 1H), 1.90 (m, 2H); LC MS: 519 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Pt]=O>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2=CCCN(C)C
Agent: O=[Pt]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: Cc1cccc2c1CCc1ccccc1C2CCCN(C)C

Procedure:
39.5 g. of 1-methyl-10,11-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene are dissolved in 400 ml. of glacial acetic and hydrogenated at room temperature and under normal pressure in the presence of 3 g. of platinum oxide. When the uptake of hydrogen ceases, the catalyst is removed by filtration. The filtrate is evaporated, and the residue distilled whereby 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene goes over at 140° C. under 0.01 mmHg. The corresponding hydrochloride salt has a melting point of 181°-183° C. after recrystallization from ethanol-ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1)[C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[OH:51]/[N:52]=[C:53](/[C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)\[NH2:54]>O1CCOCC1.CN(C=O)C.CC(=O)OCC>[C:20]([O:19][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]3[O:51][N:52]=[C:53]([C:55]4[CH:56]=[CH:57][C:58]([C:61]5[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=5)=[CH:59][CH:60]=4)[N:54]=3)=[CH:33][CH:34]=2)=[O:24])=[CH:11][CH:12]=1)=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-c2ccc(/C(N)=N/O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C(=O)O)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(NC(=O)OC(C)(C)C)cc5)cc4)n3)cc2)cc1
Temperature: 110 °C
Yield: 30 %

Procedure:
Prepared from INT-62 and INT-40. To a stirred solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-((tert-butoxycarbonyl)amino)benzamido)methyl)benzoic acid INT-62 (1.57 g, 3.24 mmol) in dioxane (40 mL) and 4-methylmorpholine (0.712 mL, 6.48 mmol) was added isobutyl carbonochloridate (0.420 mL, 3.24 mmol) dropwise. After 30 min the reaction mixture was added to a solution of (Z)—N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 (0.733 g, 3.24 mmol) in DMF (4 mL). After 30 mins the reaction was heated at 110° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with EA (150 mL) and washed with brine (200 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (MeCN/DCM) to afford 659 mg (30%) of tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-63 as a viscous oil. LCMS-ESI (m/z) calculated for C40H42N4O6: 674; no m/z observed, tR=3.29 min (Method 10).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[CH3:11][CH2:12][OH:13].CC(O)=O.O>[Pd]>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:13])[CH3:11]
Reactant: OCCCc1ccncc1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCC1CCNCC1
Reaction time: 24 h

Procedure:
Commercially available 4-pyridinepropanol (6-10) (38 g, 277 mmol) was dissolved in 100 ml EtOH/HOAc/H2O (4:1:1) and treated with 2.0 g 10% Pd/C. This mixture was hydrogenated on a Parr reactor for 24 h at 55 psi. The catalyst was removed by filtration and the filtrate evaporated to give 3-(4-piperidinyl)propyl acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:45]([N:41]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:24]2[O:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([NH:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:18]3[C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:37][CH:36]=1)([CH3:47])[CH3:46]
Reactant: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1)C(C)C
Temperature: 0 °C

Procedure:
A solution of 4-(2-{2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10a (0.075 g, 0.117 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. Trifluoroacetic acid (1.0 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. and was allowed to warm to room temperature over 2 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford {2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-yl}-(2-piperazin-1-yl-ethyl)-amine 10b as an off-white solid. MS (MH+) 542.3; Calculated 541 for C33H43N5O2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12](=[O:13])[O:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCC2)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Aminoindan (212 mg, 1.59 mmol) was dissolved in CH2Cl2 (10 mL), p-nitrophenyl chloroformate (417 mg, 2.07 mmol) was added, and the reaction mixture was stirred at rt overnight. The solid was removed by filtration (discarded), and the filtrate was concentrated under reduced pressure. This gave the title compound as a grey solid which was about 50% pure and was used without further purification. LC-MS: RT=9.98 min, [M+H]+=299.1.
Reaction SMILES: S=[C:2]([CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)[C:3](=[O:5])[OH:4].BrC(O)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOCCOC>[OH:5][C:3]([CH2:2][CH2:6][CH2:7][CH2:8][C@H:9]1[C@@H:17]2[C@@H:12]([NH:13][C:14]([NH:16]2)=[O:15])[CH2:11][S:10]1)=[O:4]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCC(=S)C(=O)O)N1
Agent: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 0.1 %

Procedure:
A diglyme solution (3 ml) containing dl-thioxobiotin (255 mg, 0.981 mol) and bromoethanol (140 μl, 1.98 mmol) was allowed to reflux (150°) for 2.5 hours. The solution was cooled, dilute sodium carbonate (50 ml) was added, and the solution was extracted with hexane (50 ml). The pH of the aqueous phase was adjusted to 1.5 with 6N HCL and extracted with ethyl acetate (4×100 ml). The ethyl acetate extract was dried over magnesium sulfate, filtered and concentrated in vacuo to give 148 mg (62%) of crude biotin, mp 220°-223° C. which was recrystallized from water IR (KBr) 3279, 2899, 1724; NMR (d, DMSO) 0.76-1.95 (6H, m, C--CH2), 2.00-2.40 (2H, t, CH2 --CO), 2.70-2.98 (1H, m, CH2S) 3.00-3.54 (2H, m, CH2S, CHS) 4.00-4.44 (2H, m, CHN), 6.44 (1H, bs, NH), 6.55 (1H, bs, NH), 11.8-12.4 (1H, bs, OH). Analysis calculated for C10H16O3N2S: C, 49.18; H, 6.56; N, 11.48; Found: C, 49.30; H, 6.23; N, 11.37. Mass spectrum: calculated: 244.0880, found: 244.0925.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:33]([N:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])[N:36]=[N:35]2)[C@@H:32]([O:46]C(=O)C)[C@@H:31]([CH2:50][O:51]C(=O)C)[O:30][C@H:6]1[S:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:16]=[N:15]2)[C@H:9]1[O:26]C(=O)C)(=O)C>C[O-].[Na+]>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]1[N:36]=[N:35][N:34]([C@H:33]2[C@@H:32]([OH:46])[C@@H:31]([CH2:50][OH:51])[O:30][C@@H:6]([S:7][C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]4[CH:18]=[C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[F:25])[N:16]=[N:15]4)[C@H:9]3[OH:26])[C@@H:5]2[OH:4])[CH:38]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](S[C@@H]2CCC[C@H](n3cc(-c4ccccc4F)nn3)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](n2cc(-c3ccccc3F)nn2)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: OC[C@H]1O[C@@H](S[C@@H]2CCC[C@H](n3cc(-c4ccccc4F)nn3)[C@H]2O)[C@H](O)[C@@H](n2cc(-c3ccccc3F)nn2)[C@H]1O
Reaction time: 21 h
Yield: 55 %

Procedure:
Compound 10 (12.0 mg, 15.6 μmol) was dissolved in NaOMe (0.05 M, 1 mL). After 21 h the mixture was neutralized (Duolite C436) and concentrated. Purification was made by reverse-phase HPLC using a linear gradient of H2O:MECN (100%->0% H2O). The reaction yielded 55% of 15. 1H-NMR (MeOD) 8.38 (d, J=3.53 Hz, 1 H), 8.35 (d, J=3.55 Hz, 1 H), 8.08-8.18 (m, 2 H), 7.33-7.43 (m, 2 H), 7.18-7.33 (m, 4 H), 4.92 (dd, 1 H), 4.76 (d, 9.48 Hz, 1 H), 4.47-4.57 (m, 1 H), 4.28 (dd, J=9.51, 10.55 Hz, 1 H), 4.15 (d, J=2.98 Hz, 1 H), 3.83-3.93 (m, 2 H), 3.76 (dd, J=6.87, 11.35 Hz, 1 H), 3.68 (dd, J=5.19, 11.37 Hz, 1 H), 3.07-3.17 (m, 1 H), 2.28-2.38 (m, 1 H), 2.08-2.25 (m, 2 H), 1.90-2.00 (m, 1 H), 1.60-1.77 (m, 2 H).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>CC#N.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.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(CCSC)OC(C)=O
Reactant: CSCC=COC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: CC#N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 120 °C
Yield: 10 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z:E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of CH3CN as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 500 psi (at room temperature) was charged to the bomb, and the bomb was heated to 120° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 3 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 10 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([OH:20])=[C:14]([Br:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[C:14]([Br:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(Br)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: N#CC(=Cc1cc(O)c(O)c(Br)c1)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
Demethylation was effected in the same manner as in Example 2 with N-(3-chlorophenyl)-2-cyano-3-(3-bromo-4-hydroxy-5-methoxyphenyl) propenamide (1.38 g, 3.39 mmol) and 1M solution of boron tribromide in methylene chloride (8.5 ml, 8.5 mmol). The resultant solid was mixed with ethanol, refluxed for 10 minutes, allowed to cool to room temperature and filtered to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-bromo-4, 5-dihydroxyphenyl) propenamide (360 mg, 27% in yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:25]#[N:26].[Br:27][C:28]1[C:33]([OH:34])=[C:32]2[O:35][CH2:36][O:37][C:31]2=[CH:30][CH:29]=1>>[Br:27][C:28]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:25]#[N:26])=[C:32]2[O:35][CH2:36][O:37][C:31]2=[CH:30][CH:29]=1
Reactant: Oc1c(Br)ccc2c1OCO2
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Product: COc1cc2c(Oc3c(Br)ccc4c3OCO4)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 14, 4chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline was reacted with 6-bromo-2,3-methylenedioxyphenol to give the title compound as a solid in 52% yield; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.25-2.4 (m, 2H), 2.95 (s, 3H), 3.24-4.0 (m, 8H), 3.48 (m, 2H), 3.98 (s, 3H), 4.35 (m, 2H) 6.02 (s, 1H), 6.08 (s, 1H), 6.92 (d, 1H), 7.25 (d, 1H), 7.6 (d, 2H), 8.9 (s, 1H); Mass Spectrum: M+H+ 555 and 557.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1>>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)c1

Procedure:
3-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=349.