Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccco2)cc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccco2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-nitrophenyl)furan (0.378 g, 2 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951) in ethanol (20 mL) was heated to 70° C. and added stannous chloride dihydrate (2.26 g, 10 mmol) and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), the whole was extracted with ethyl acetate (30 mL×2). The organic layer was dried over Na2SO4, filtered through celite and concentrated to give the crude subtitle compound (0.35 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrophenylamine (0.560 g, 3.00 mmol) and benzoyl chloride (0.422 g, 3.00 mmol) in toluene (15 mL) was heated under reflux for 1.5 h, and cooled to room temperature. A solid crystallized from the reaction mixture upon cooling, and was isolated by vacuum filtration and dried to provide the title compound as a gray solid (0.276 g, 32%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.CC1C=CC(S(NN)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>COCCOC.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:39][CH:40]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C

Procedure:
A mixture of compound 60a (60.0 mg, 0.112 mmol), 4-methylbenzenesulfonohydrazide (104 mg, 0.558 mmol) and sodium acetate (46.2 mg, 0.558 mmol) in 3.3 mL of 10:1 DME/water was refluxed for 4 h. After cooling to rt, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-3:2 EtOAc/DCM) to afford compound 60b as a colorless oil. 1H-NMR (CDCl3; 400 MHz) δ 8.05 (d, J=8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 3.96-4.03 (m, 4H), 3.89-3.96 (m, 4H), 3.15-3.30 (m, 4H), 2.83 (t, J=6.3 Hz, 2H), 2.69 (t, J=6.3 Hz, 2H), 1.82-1.91 (m, 2H), 1.73-1.82 (m, 2H), 1.61 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H37N5O3, 540.3 (M+H). found 540.5.
Reaction SMILES: C([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18]C)=[O:16])=O.[BH4-].[K+]>CO.O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[C:15](=[O:16])[O:17][CH2:18][CH:3]1[CH2:12][CH2:11]2
Reactant: CCOC(=O)N1c2ccc(OC)cc2CCC1C=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCC1COC(=O)N21
Reaction time: 1 h

Procedure:
To a solution of 10.9 g (41.4 mmol) of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate in 100 ml of methanol, cooled to 0° C., are added portionwise 2.2 g (41.4 mmol) of potassium borohydride. The medium is stirred for 1 h and then hydrolyzed, diluted with water and extracted with diethyl ether. The organic phase is then washed with water and dried over sodium sulphate, and the solvent is evaporated off under reduced pressure. The oil obtained is redissolved in 90 ml of toluene, the solution is heated to reflux in order to remove traces of water, and a catalytic amount of 10% sodium methoxide in methanol is then added at 90° C. The mixture is again heated to reflux in order to remove the ethanol formed, followed by evaporation of the solvent. The residue is taken up in ethyl acetate and washed with water, then the organic phase is dried over sodium sulphate and concentrated under reduced pressure. After chromatography on a column of silica with a 4/1 mixture of heptane and ethyl acetate, 5.0 g of product are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:24]1[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[C:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[N:21]=2)[CH:26]=[N:25]1
Reactant: CN(C)CCO
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2CCN(C)C)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 2-dimethylamino-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Rh]>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:7]1
Reactant: O=C(O)CCCCCc1ccc(O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: O=C(O)CCCCC[C@H]1CC[C@@H](O)CC1

Procedure:
6-(4-Hydroxyphenyl)hexanoic acid (2 g) is subjected to catalytic reduction in the presence of 5% rhodium-carbon (500 mg) in ethanol (100 ml) at an initial hydrogen pressure of 10.1 kg/cm2. The catalyst is filtered off and the filtrate is concentrated under reduced pressure and subjected to silica gel column chromatography. Elution is carried out with 4% ethanol-chloroform to give three fractions. The first fraction is recrystallized from ether-ligroin to give 392 mg of cis-6-(4-hydroxycyclohexyl)hexanoic acid, m.p. 83°-85° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C1C=CN=CC=1>[CH2:1]([N:5]([C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)CC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 106.5 %

Procedure:
A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10% palladium on carbon (2.5 g) as catalyst. The reaction mixture was filtered through celite pad and the filtrate was concentrated down to give a white solid (11.46 g, 100%). This material was taken onto next step immediately. To a stirred mixture, under N2 atmosphere, of the aniline (11.46 g, 49 mmol), butryaldehyde (4.43 mL, 49 mmol) in tetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.62 g, 68.6 mmol), and glacial acetic acid (2.82 mL, 49 mmol). The reaction was stirred for two hours. The reaction was quenched with 1 N NaOH (50 mL), diluted with water, extracted with ether 3 times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give an oil (5.80g, 41%). This material was immediately taken onto next step. A solution of the N-butyl aniline (5.80 g, 19.9 mmol) in a 1:1 mixture of perchloric acid and hydrochloric acid (100 mL) was stirred at room temperature for three days. The reaction mixture was poured onto ice and made basic with concentracted ammonium hydroxide, extracted with ether four times, dried over sodium sulfate and concentrated to give a yellow oil. The yellowish oil was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 1-[4-(butylamino)phenyl]-4-piperidinone as an oil (3.84 g, 82%). To a stirred mixture of 1-[4-(butylamino)phenyl]-4-piperidinone (2.46 g, 10 mmol), triethylamine (1.81 mL, 13 mmol), and 4-(dimethylamino)pyridine (DMAP) (catalytic amount) was added ethyl 3-chloro-3-oxopropionate (2.18 g, 13 mmol) dropwise. The reaction was stirred for 18 hours. The reaction mixture was filtered, concentrated in vacuo, taken up in methylene chloride, and washed with saturated sodium bicarbonate two times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give a yellow oil (3.84 g, 68%); MS (ES) m/z: 361.3(MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.Cl[Si](C)(C)C.CN([CH:25]=[O:26])C>>[CH3:5][C:4]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[CH2:10][C:12]([O:26][CH3:25])=[O:13]
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Cl
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Yield: 62 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(furan-2-yl)methanone (0.440 g, 1.886 mmol), methyl levunilate (0.26 mL, 1.886 mmol), chlorotrimethylsilane (0.964 mL, 7.54 mmol) in DMF (3.7 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-50%) in heptane furnished 0.385 g (62%) of the title compound as a yellow solid.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=O)[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:11][CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:25]=[C:16]1[C:17]2[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 83.1 %

Procedure:
Methyl α-methylthio-α-(p-phthalimidophenyl)propionate (355 mg), 600 mg of zinc powder and 32 mg of anhydrous copper sulfate were heated under reflux for 5 hours in 3 ml of acetic acid. Methylene chloride (30 ml) was added, and the insoluble matter was separated by filtration and washed with 20 ml of methylene chloride. The filtrate and the washing were combined, washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride as an eluent to afford 245 mg of methyl α-[p-(1-oxo-2-isoindolinyl)phenyl]propionate as colorless crystals in a yield of 83%.
Reaction SMILES: [CH2:1](OC(=O)COC1C2C(=CC=CC=2)C(=O)N1CC1C=CC=CC=1)C.[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][C:36]([CH3:1])=[CH:37][CH:38]=2)[CH:33]1[O:42][CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:45])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Reactant: O=C(COC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccccn1
Product: Cc1ccc2c(c1)C(OCC(=O)Nc1ccccn1)N(Cc1ccccc1)C2=O

Procedure:
Compound 61 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 21 to compound 23 and illustrated in Scheme 2. NMR (300 MHz, CDCl3): δ 8.8(br s, 1H), 8.45(m, 1H), 8.1(m, 1H), 7.75(m, 2H), 7.4-7.2(m, 7H), 7.05(m, 1H), 5.9(s, 1H), 5.0(d, J=15 Hz, 1H), 4.4(d, J=15 Hz, 1H), 3.65(d, J=19 Hz, 1H), 3.5(d, J=19 Hz, 1H), 2.4(s, 3H). MS: m/z (MNa+) 410.
Reaction SMILES: [OH:1][C:2]([P:8]([OH:10])[OH:9])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][CH2:13][CH2:14]O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CCOCC>[OH:1][C:2]([PH:8](=[O:10])[O:9][CH2:14][CH2:13][O:12][CH3:11])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)(O)P(O)O
Reactant: COCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(C)(O)[PH](=O)OCCOC
Reaction time: 3 h

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid prepared as described in Example 8 (0,166 g. 0,001M), 2-methoxyethanol (0.076 g. 0,001M) and dimethylaminopyridine (0.01 g.) are stirred in THF (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0,001M) is added portionwise and the mixture is stirred for 3 hours. Ether (10 ml.) is added and the dicyclohexylurea is filtered off. The filtrate is evaporated and the residue is dissolved in chloroform and washed with water. Evaporation of the chloroform gives an oil which is purified on silica using ethyl acetate as eluant. There is obtained 2-methoxyethyl (1-hydroxy- 1, 4-dimethylbutyl)phosphinate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[C:7]([CH3:13])[CH:6]=1)[CH:2]=[CH2:3].[N:14]1([CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:18]=[CH:17][N:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:20][CH2:19][N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)=[C:7]([CH3:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: C=CCOc1ccc(CS)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CSCCn2ccnn2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
To a mixture of 1.98 g (10.2 mmol) (4-allyloxy-2-methyl-phenyl)-methanethiol and 2.72 g (10.2 mmol) toluene-4-sulfonic acid 2-[1,2,3]triazol-1-yl-ethyl ester in 25 ml N,N-dimethylformamide was added under argon at −50° C. 515 mg (20.4 mmol) sodium hydride. The mixture was allowed to warm up to room temperature and was stirred under argon for 12 hours. 80% of the DMF was stilled off in vacuo, ethyl acetate and water given to the mixture. The aqueous phase was reextracted with ethyl acetate and the combined organic extracts dried and evaporated to yield 2.8 g of 1-[2-(4-allyloxy-2-methyl-benzylsulfanyl)ethyl]-1H-[1,2,3]triazole as brown oil. The raw material (73% purity) was used without further purification.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])(C)C.[C:16]([NH:23][C@@H:24](C(O)=O)[C:25]([CH3:28])(C)C)(OC(C)(C)C)=O.[CH2:32]([N:34]1[CH:38]=[C:37]([C:39]2[N:44]=[C:43]3[C:45](C(O)=O)=[CH:46][N:47](COCC[Si](C)(C)C)[C:42]3=[N:41][CH:40]=2)[CH:36]=[N:35]1)[CH3:33]>>[CH:10]1([C@@H:9]([NH:8][C:6]([C:45]2[C:43]3[C:42](=[N:41][CH:40]=[C:39]([C:37]4[CH:36]=[N:35][N:34]([CH2:32][CH3:33])[CH:38]=4)[N:44]=3)[NH:47][CH:46]=2)=[O:7])[C:13](=[O:15])[N:23]2[CH2:16][CH2:28][CH2:25][CH2:24]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCCC4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting Boc-D-cyclopropyl glycine for Boc-D-tert-leucine and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2, 3-1)]pyrazine-7-carboxylic acid. MS: (M+H)+=408; mp=210.0-212.0.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CS(C)=O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
1-Benzyl-5-methylisatin was suspended in DMSO (100 mL) and cooled to 0° C. Hydrazine hydrate (5 mL) was added dropwise over 5 min. After addition, the resulting clear red solution was heated at 120° C. for 2 h then 140° C. for 5 h. After cooling to rt, it was poured into a 1 L Erlenmeyer flask, rinsed with H2O (50 mL) and ice was added until a total volume about 300 mL. 2 M HCl (50 mL) was added and the mixture was extracted with EtOAc (200 mL×2, then 100 mL), and the organic layer was dried (Na2SO4). Removal of solvents followed by drying under high vacuum for 2 days gave the title compound as a dark red solid (12.53 g, quantitative yield over 2 steps, contained some DMSO residue). 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 7.09 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 3.60 (s, 2H), 2.31 (s, 3H); MS ESI 238.0 [M+H]+, calcd for [C16H15NO+H]+ 238.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([NH2:15])=[O:14]>C1COCC1>[N+:19]([C:18]1[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][C:17]=1[O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)([O-:21])=[O:20]
Reactant: OC1CCOC1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc([N+](=O)[O-])c(OC2CCOC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of 3-hydroxytetrahydrofuran (2.57 ml, 1.2 eq, 23.0 mmol) in THF (50 ml) was added sodium hydride as a 60% dispersion in oil (0.84 g, 1.1 eq, 20.91 mmol) this mixture was then stirred at 0° C. for 30 minutes. The preceding mixture was added dropwise to a solution of 3-fluoro-4-nitrobenzamide (3.5 g, 1.0 eq, 19.01 mmol) in THF (30 ml) and stirred at room temperature for 3.5 hours. The reaction was quenched with water and extracted with DCM (3×50 ml), the organics were combined, dried over sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a yellow solid (4.77 g, 18.9 mmol, 96% corrected). LCMS: [M+H]+=253, Rt=1.41 min, 100% purity
Reaction SMILES: [NH2:1][C:2](=[N:26][OH:27])[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1.[CH3:28][C:29](C)([O-])C.[K+].C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[Cl:18][C:13]1[CH:12]=[C:11]([C@@H:10]2[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:5][C@H:4]2[CH2:3][C:2]2[N:1]=[C:28]([CH3:29])[O:27][N:26]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=NO)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)no1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-[2-amino-2-(hydroxyimino)ethyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (388 mg, 0.93 mmol) in toluene (4 mL) were added potassium tert-butoxide (208 mg, 1.86 mmol) and ethyl acetate (1 mL, 0.93 mmol). The reaction mixture was stirred at 100° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (183.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (300 mg, 1.0 mmol), toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (386 mg, 1.06 mmol) and Cs2CO3 (423 mg, 1.3 mmol) were combined in anhydrous DMF (7 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) to provide the ethyl ether compound as a colorless oil (177 mg, 28%).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[O:17][CH3:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl.O>[C:1]([CH:5]1[CH2:20][CH2:19][CH:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[O:17][CH3:18])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(Nc2ccc(C(C)(C)C)cc2)ccnc1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(NC2CCC(C(C)(C)C)CC2)ccnc1C

Procedure:
1 g of 4-(4-tert-butylanilino)-3-methoxy-2-methylpyridine in 20 ml of methanol, 3.7 ml of 2N HCl and 1.3 ml of water are hydrogenated at room temperature and normal pressure until absorption of hydrogen has ended using 1 g of rhodium on alumina (5% strength). After filtering and concentrating 1 g of syrup remains=100% isomer mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[Br:19]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2].CO>[Br:19][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of methyl 3-nitrobenzoate (122 g, 674 mmol), silver sulphate (100 g, 320.7 mmol) and concentrated sulfuric acid (750 mL) was stirred mechanically and heated at 90° C. To this mixture was added bromine (37 mL), dropwise, over 2 h. The reaction was stirred another hour, cooled and filtered. The filtrate was mixed with 2 L water and 1 Kg crushed ice. The solid was filtered and dried to afford a mixture of the desired methyl ester and free acid hydrolysis product. The mixture was taken up into methanol (1 L), treated with 10 drops concentrated sulfuric acid and refluxed for 12 h. The reaction mixture was allowed to cool and the crystals that were deposited were collected and dried in a desiccator to afford 126 g (72% yield) of methyl 3-bromo-5-nitrobenzoate (EX-119A): 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 3.94 (s, 3H).