Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:29])[CH:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)O)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]4[CH:20]([C:22]5[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=5)[C:19](=[O:29])[NH:18][C:15]=4[CH:16]=3)[NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(NC(=O)C(O)c2ccc(Br)cc2)cc1)C(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=C1Nc2cc3c(cc2C1c1ccc(Br)cc1)NC(=O)C3c1ccc(Br)cc1
Reaction time: 18 h
Yield: 83 %

Procedure:
2-(4-Bromo-phenyl)-N-{4-[2-(4-bromo-phenyl)-2-hydroxy-acetylamino]-phenyl}-2-hydroxy-acetamide (18.00 g, 33.70 mmol) (1.1) is added to concentrated sulfuric acid (180 cm3) at 21° C. in a 500 cm3 round-bottom flask. After 18 hours stirring, the reaction mixture is poured onto ice and filtered off. The recovered precipitate is washed with water and dried for 18 hours at 80° C. in a vacuum oven. The crude product is used without further purification (13.88 g, Yield: 83%).
Reaction SMILES: [CH:1]([O:5][C:6](=[O:26])[CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:3][CH3:4])[CH3:2].[Br-:27].[Li+]>CC(C)=O>[CH:1]([O:5][C:6](=[O:26])[CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:27])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)OC(=O)CC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CCC(C)OC(=O)CC(C)CCCCCBr
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
A mixture of 337 mg of 3-methyl-8-(p-toluenesulphonyloxy)octanoic acid sec-butyl ester (prepared as described hereafter), 5 ml of acetone and 156 mg of lithium bromide was stirred at 70° C. for 1.5 hours. After evaporation under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as eluent to give 204 mg of the title compound having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:13][C:4]1[N:3]=[C:2]([NH:23][C@H:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH3:22])[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=1
Reactant: Clc1cc(-c2cnco2)cc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-c2cnco2)cc(Cl)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
630 mg of 5-(2,6-dichloropyridin-4-yl) oxazole obtained by Step 1, 408 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 182 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.9 g of cesium carbonate and 66 mg of palladium acetate were added in turn to 30 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 600 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)pyridine-2-amine as pale yellow powder. 10 ml of degassed toluene was added to the obtained powder, and 180 mg of 2-aminopyrazine, 180 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl, 254 mg of sodium t-butoxide and 98 mg of tris(dibenzylideneacetone)dipalladium were added in turn, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the objective compound as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH:7]([CH2:19][C:20]([O:22]CC)=[O:21])[C:8](=[O:18])[N:9]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(O)(=O)C.C(O[N:35]=O)CC(C)C.[OH-].[Li+]>C(Cl)(Cl)(Cl)Cl.ClCCl.O>[CH2:13]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]3[NH:1][N:35]=[CH:12][C:11]3=2)[CH2:6][CH:7]([CH2:19][C:20]([OH:22])=[O:21])[C:8]1=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)CC1Cc2ccc(N)c(C)c2N(CC(C)(C)C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CN1C(=O)C(CC(=O)O)Cc2ccc3[nH]ncc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (170 mg, 0.51 mmol) in carbon tetrachloride (4.5 mL) was added acetic acid (0.5 mL) followed by isoamylnitrite (0.04 mL) and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with dichloromethane (40 mL), washed with aqueous NaHCO3 and dried. The solvent was removed and the crude product was dissolved in THF (15 mL) followed by addition of lithium hydroxide (43 mg, 1 mmol) and water (5 mL). After stirring for 12 h, the solvent was removed, acidified with 6 M HCl and extracted with ethyl acetate to give 2-(1-neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)acetic acid. MS (ESI) 316 (M+H); Rf=1.31.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:11]O>OS(O)(=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(C)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 70° C. The solid material dissolves and stirring is continued at 70° C. for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR=0.39 min, [M+1]+=152.05. This material is dissolved in 7 N NH3 in methanol (25 mL) and the mixture is stirred in a sealed vial for 20 h at 60° C. before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. To a solution of this material in DCM (25 mL), pyridine (5.24 g, 54.0 mmol) is added. The mixture is cooled to 0° C. before trifluoroacetic anhydride (8.10 g, 38.6 mmol) is added portionwise. Stirring is continued at 0° C. for 2 h before the reaction is quenched with water. The mixture is diluted with DCM and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 4:1 to give 2-methyl-isonicotinonitrile (330 mg); LC-MS: tR=0.55 min, [M+1]+=119.13.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[O:13]=[C:14]1[N:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)[CH2:17][CH2:16][O:15]1>>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([N:18]2[CH2:17][CH2:16][O:15][C:14]2=[O:13])[CH:20]=1
Reactant: O=Cc1cccc(N2CCOC2=O)c1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(N3CCOC3=O)c2)c(=O)[nH]1
Yield: 41.2 %

Procedure:
According to the same manner as that of Example 16 except that 0.33 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 0.30 g of 3-(2-oxo-oxazolidin-3-yl)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.22 g of 4-hydroxy-3-[3-[3-(2-oxo-oxazolidin-3-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-37)] was obtained as a yellow crystal.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([CH3:20])[S:22][C:23]=4[CH:29]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: Cc1nc2ccc(C=O)cc2s1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 397.76 g/mol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: COc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.0 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[O:17])=[O:14])C.[Si]([O:25][C:26]1[CH:31]=[C:30]([O:32][Si](C(C)(C)C)(C)C)[CH:29]=[CH:28][C:27]=1[C@H:40]1[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42][CH2:41]1)(C(C)(C)C)(C)C>CN(C)C=O>[C:16]([NH:15][C:13]([O:12][CH3:10])=[O:14])([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:27]2[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=2[OH:25])[CH2:45][CH2:44]1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N,N-Diisopropylethylamine (497 μl) and ethylisocyanatoformate (177 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dimethylformamide (2 ml). After 120 hr at 50° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (10 ml) and was stirred with fluoride resin (300 mg) for 16 hr at room temperature. The suspension was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo and the residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) and then preparative HPLC to give the title compound (4 mg, 2%) as a pale yellow gum. δH (CD3OD) 1.20-1.40 (4H, m), 1.55 (3H, t), 1.80-1.90 (2H, m), 2.00-2.18 (2H, m), 2.72-2.82 (1H, m), 4.20 (2H, q), 6.20-6.25 (2H, m), 6.84 (1H, d); m/z (ES−) 322 (M−H−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:35][CH:36]=1)([O-:30])=[O:29]>N1C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:38][CH2:39][N:40]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:41][CH2:42]2)=[N:35][CH:36]=1)([O-:30])=[O:29]
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(N3CCN(c4ccc([N+](=O)[O-])cn4)CC3)c2-c2ccccc2)c1
Reaction time: 11 h

Procedure:
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with 1-(5-nitropyridin-2-yl)piperazine (0.075 g, 0.363 mmol) and stirred for 11 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to give the crude material. Purification by column chromatography (elution with 70% ethyl acetate in hexane) yielded the title compound. 1H-NMR (CDCl3) δ: 3.45-3.46 (m, 4H), 3.72 (m, 4H), 6.52-6.54 (d, 1H), 7.08-7.11 (d, 2H), 7.21-7.26 (m, 2H), 7.32-7.34 (d, 1H), 7.40-7.42 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.84-7.89 (m, 1H), 8.21-8.23 (d, 1H), 8.99 (s, 1H); MS m/z: 585.8 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8])([O-])=O.[BH4-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
3-Nitro-4-amino-benzonitrile (4.38 g) was dissolved in ethanol (600 ml) and added with stannous chloride dihydrate (34.6 g) and the whole was heated to 60° C. Sodium borohydride (366 mg) was gradually added thereto and the whole was stirred overnight at 60° C. After completion of the reaction, the resultant was filtrated through Celite and the filtrate was subjected to distillation of the solvent under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was allowed to recrystallize (hexane/ethyl acetate), thereby obtaining the subject compound (2.56 g) as a brown crystal.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[SH:27][CH2:28][CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:25][CH3:26])[N:4]=[C:3]([CH2:2][S:27][CH2:28][CH2:29][OH:30])[N:12]=[C:11]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CSCCO)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline (4.5 g), 2-mercaptoethanol (1.13 g), potassium carbonate (2.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethylthiomethyl)quinazoline (4.1 g, 82%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-155° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH3:21])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][CH3:21])[CH:14]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(Br)ccc1OC(C)=O
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Acetyl chloride (1.06 mL, 14.9 mmol) followed by triethylamine (2.08 mL, 14.9 mmol) were added to a cooled 0° C. solution of 4-Bromo-2-ethyl-phenol (2.5 g, 12.4 mmol, from Step 1) dissolved in CH2Cl2. The reaction was stirred for 2 hrs and then partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (2.44 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8](=[C:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([C:8](=[C:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)[C@H](C)[C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]([C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Yield: 76.2 %

Procedure:
285 mg of methyl 3-(tert-butoxycarbonyl)-4-hydroxy-4-[N-[(1R,2R)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-3-butenoate was dissolved in a mixture of 15 ml of tetrahydrofuran and 10 ml of water and stirred together with 4 ml of 1N aqueous sodium hydroxide at room temperature for 2.5 days. The reaction solution was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform/methanol=100/1→10/1] to give 213 mg (yield: 76%) of the title compound as a colorless foamy substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1.[SH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(O)CO.Cl>CCOC(C)=O.O.[Cu]I.CC(O)C>[O:17]=[C:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=[O:22])=[CH:9][CH:10]=2)[NH:14]1
Reactant: O=C1Cc2ccc(I)cc2N1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Solvent: CC(C)O
Product: O=C1Cc2ccc(Sc3ccccc3C(=O)O)cc2N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 19.2 %

Procedure:
CuI (40 mg, 0.05 mmol), potassium carbonate (1.66 g, 12 mmol), 6-iodooxindole (as prepared in Preparation 1; 1.0 g, 4.0 mmol) and 2-mercapto-benzoic acid (0.62 g, 4.0 mmol) were added to a dry schlenk tube. The tube was evacuated and refilled with Ar(g) (3 times). 2-Propanol (5.0 mL) and ethylene glycol (0.5 mL, 8.0 mmol) were injected into the schlenk tube. The schlenk tube was sealed with a teflon valve and was heated to 80° C. and stirred for over 24 hours. Subsequently the reaction mixture was allowed to reach room temperature then diluted with EtOAc (10 mL) and water (10 mL). The mixture was acidified of to a pH=3-4 with the addition of 1 M HCl(aq) and the organics were separated and set aside. The aqueous phase was washed with additional EtOAc (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording a yellow solid. The solid was then purified via flash silica gel chromatography (gradient eluant starting with 5% MeOH in CHCl3 increasing to 10% MeOH in CHCl3) affording the title compound as a pale yellow solid (0.228 g, 0.77 mmol, 20% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([O:20]CC)=O)[C:7]2=[O:12])#[N:2].[NH3:23]>CO>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:23])=[O:20])[C:7]2=[O:12])#[N:2]
Reactant: CCOC(=O)c1nccn1C1Cc2c(C#N)cccc2C1=O
Reactant: N
Solvent: CO
Product: N#Cc1cccc2c1CC(n1ccnc1C(N)=O)C2=O

Procedure:
1-[(4-Cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide can be obtained in the following way: a solution of 1.5 g of ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate in 130 ml of methanol is kept saturated for one hour at a temperature in the region of 20° C. with a stream of gaseous ammonia. The reaction mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50° C. 1.2 g of 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide are thus obtained, which product melts at 216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:29]2[CH:28]=[N:27][C:26]([NH:25][CH2:24][CH2:23][N:22]([CH3:33])[CH3:21])=[CH:31][CH:30]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCNc1ccc(N)cn1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCNc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cn1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (113 mg, 0.63 mmol). The title compound was obtained as a yellow solid (9.0 mg, 3% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.37 (1H, br), 8.99 (2H, m), 8.61 (1H, m), 8.20 (1H, m), 7.60 (1H, m), 6.53 (2H, m), 2.65 (2H, m), 2.50 (6H, m), 2.37 (2H, m). MS m/z: 513.17, 515.17 [M+H]+.
Reaction SMILES: C([O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2=[CH:17][S:18][CH:19]=[C:13]2[O:12]1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O>[O:15]1[CH2:16][CH:11]([CH2:10][OH:9])[O:12][C:13]2=[CH:19][S:18][CH:17]=[C:14]12
Reactant: O=C(OCC1COc2cscc2O1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCC1COc2cscc2O1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a 100 mL round bottom flask, 7.5 g (0.027 mol) (2,3-dihydrothieno[3,4-b][1,4]dioxin-3-yl)methyl benzoate was dissolved in a minimal amount of warm ethanol and dropwise added to a refluxing solution of 4.58 g (0.081 mol) potassium hydroxide in 50 mL water. After heating overnight, the reaction was cooled to room temperature and acidified to pH 7 by dropwise addition of concentrated hydrochloric acid. The reaction mixture was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 3.95 g (85% yield) of (2,3-dihydrothieno[3,4-b][1,4]dioxin-3-yl)methanol. Structure was confirmed by 1H/13C NMR and LC-MS.