Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22].[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28].C(N(CC)CC)C.C(O)C>O1CCCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22])=[O:28]
Reactant: O=C=NCCCl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCCl)c2Cl
Temperature: 25 °C

Procedure:
5 g (0.016 M) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 85 ml of absolute tetrahydrofuran are treated with 11.1 ml of chloroethylisocyanate and 1 ml of triethylamine. The mixture is stirred at room temperature for 1 week and heated at reflux for 5 hours. The mixture is treated with 50 ml of ethanol and concentrated. The residue is treated with methylene chloride/water and extracted several times with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column using methylene chloride/ethyl acetate (3:1) as the eluting agent, there being obtained 1-(2-chloroethyl)-3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which is further processed directly.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)#[N:12]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCSCc1ccsn1
Product: CNC(NCCSCc1ccsn1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 3-[(2-aminoethyl)-thiomethyl]isothiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Compound A (4.5 g) was dissolved in pyridine (80 mL). Hydroxylamine hydrochloride (1.8 g, 26.4 mmol) was added, followed by sufficient water to dissolve the solids. The mixture was stirred at room temperature overnight. The solids were filtered, washed with water, and dried under vacuum to yield compound B (4.0 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)CC(c2ccncc2[N+](=O)[O-])=CC1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1C(C)CC(c2ccncc2N)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a degassed solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl acetate (1.0 equiv.) in MeOH and EtOAc (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under a hydrogen balloon for 3 days. Upon completion, the solution was filtered through a pad of Celite, the pad was washed with ethyl acetate and the filtrate was concentrated. The crude material contained about 10% of the undesired isomer. The crude was dissolved in ethyl acetate (˜20%) and hexanes and heated until all dissolved. The solution was allowed to sit at room temperature for 2 days. The precipitate was then collected to give (+/−)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate as the pure product in 59% yield. LC/MS=364.3 (M+H), Rt=0.63 min. The racemic material was resolved using an AD-H chiral column (20% i-PrOH/80% n-heptanes, 20 mL/min flow rate) to (1S,2S,4S,6R)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl acetate (peak#1, Rt=3.76 min on AD-H chiral analytical column, 20% i-PrOH/80% n-heptanes, 1 mL/min) and (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl acetate (peak#2, Rt=6.79 min on AD-H chiral analytical column, 20% i-PrOH/80% n-heptanes, 1 mL/min)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH:13]([CH3:15])[CH3:12])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CC(C)=O
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1ccc2nc(Cl)sc2c1
Reaction time: 2 h

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol acetone (14.5 followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclopentanone (100.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IIc-a (141.43 g, 83.9%) as a pale-yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 107.6 %

Procedure:
The title compound (148 mg) was prepared according to Example 189 using 206 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 219 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3O, 285.18; found, m/z 286.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.28 (m, 2H), 7.13-7.11 (m, 2H), 4.68 (m, 1H), 4.47 (m, 1H), 3.87 (s, 3H), 3.47-3.44 (m, 1H), 3.25-3.23 (m, 1H), 2.89-2.81 (m, 2H), 1.43 (d, J=6.6 Hz, 6H).
Reaction SMILES: C(N)CN.C(C1OC=NC=1CCl)C1C=CC=CC=1.[CH2:19]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH2:31][NH:32][CH2:33][CH2:34][NH2:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37]=[C:38]=[S:39]>>[CH3:36][NH:37][C:38]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:39]
Reactant: NCCNCc1ncoc1Cc1ccccc1
Reactant: CN=C=S
Agent: ClCc1ncoc1Cc1ccccc1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>O>[C:15]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (˜1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. The desired cyclohexene derivative was obtained as a beige solid (451.0 g, 100% yield).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]=[CH:9][CH2:10][CH:11]([CH2:15][C:16]([CH3:33])=[CH:17][CH2:18][C:19]1[C:20]([OH:32])=[C:21]2[C:25](=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29])[CH2:24][O:23][C:22]2=[O:31])[C:12]([OH:14])=[O:13])([O:5][CH3:6])=[O:4].[CH3:34][Si:35]([CH:38](O)[CH3:39])([CH3:37])[CH3:36].C1(P([C:54]2[CH:59]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:34][Si:35]([CH3:37])([CH3:36])[CH2:38][CH2:39][O:13][C:12](=[O:14])[CH:11]([CH2:10][CH:9]=[CH:8][CH2:7][P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[CH2:15][C:16]([CH3:33])=[CH:17][CH2:18][C:19]1[C:20]([O:32][CH2:54][CH2:59][Si:35]([CH3:37])([CH3:36])[CH3:34])=[C:21]2[C:25](=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29])[CH2:24][O:23][C:22]2=[O:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)O)C(=O)OC2
Reactant: CC(O)[Si](C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
A solution of 2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol) in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33 mmol). To this solution was added diethyl azodicarboxylate (230 μL, 1.33 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692 mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethyl azodicarboxylate (115 μL, 0.665 mmol) were added and the reaction mixture was stirred for another 1 day at room temperature. The reaction was worked up by removing the solvents in vacuo and purifying the residue by silica gel chromatography to provide 192 mg (85%) of the product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 0.05 (s, 9H), 0.93-0.96 (m, 2H), 1.20-1.29 (m, 2H), 1.78 (s, 3H), 2.01-2.32 (m, 4H), 2.17 (s, 3H), 2.51 (d, 1H, J=22 Hz), 2.58 (d, 1H, J=22 Hz), 2.50-2.60 (m, 1H), 3.37 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=8 Hz), 4.30 (appt t, 2H, J=8 Hz), 5.12 (s, 2H), 5.15-5.25 (m, 1H), 5.36-5.63 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 29.3 ppm; MS (m/z) 705.3 [M+Na]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]([CH3:13])[N:6]=1)[NH2:4].[CH3:14]OC(OC)OC.FC(F)(F)C(O)=O>CO>[CH3:13][N:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:5]([C:3]2[N:4]=[CH:14][O:1][N:2]=2)=[N:6]1
Reactant: Cn1nc(C(N)=NO)cc1[N+](=O)[O-]
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1nc(-c2ncon2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of N′-hydroxy-1-methyl-5-nitro-1H-pyrazole-3-carboximidamide (1.66 g, 8.97 mmol) and trimethoxymethane (17.6 mL, 161 mmol) in MeOH (2.8 mL) was added 2,2,2-trifluoroacetic acid (0.35 mL, 4.48 mmol) and the mixture was refluxed for about 1 h. The reaction was cooled to ambient temperature and continued to stir for about 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (25 mL) and saturated NaHCO3 (10 mL). The aqueous layer was back extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 3-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,2,4-oxadiazole (1.75 g, 8.97 mmol, 100%, which was used without further purification). LC-MS (Table 1, Method g) Rt=1.56 min, m/z 196 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) 9.79 (s, 1H), 7.72 (s, 1H), 4.27 (s, 3H).
Reaction SMILES: [C:1](O)(=O)C(O)=O.C(N1CN(C(C)(C)C)CN(C(C)(C)C)C1)(C)(C)C.[CH3:25][C:26]1[C:31]2[O:32][C@:33]3([CH3:73])[O:36][CH:37]=[CH:38][C@H:39]([O:71][CH3:72])[C@@H:40]([CH3:70])[C@@H:41]([O:66][C:67]([CH3:69])=[O:68])[C@H:42]([CH3:65])[C@H:43]([OH:64])[C@H:44]([CH3:63])[C@@H:45]([OH:62])[C@@H:46]([CH3:61])[CH:47]=[CH:48][CH:49]=[C:50]([CH3:60])[C:51]([NH:53][C:54]4[C:58](=[O:59])[C:28](=[C:29]([C:56](=[O:57])[CH:55]=4)[C:30]=2[C:34]3=[O:35])[C:27]=1[OH:74])=[O:52].[NH2:75][N:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH3:25][C:26]1[C:31]2[O:32][C@:33]3([CH3:73])[O:36][CH:37]=[CH:38][C@H:39]([O:71][CH3:72])[C@@H:40]([CH3:70])[C@@H:41]([O:66][C:67]([CH3:69])=[O:68])[C@H:42]([CH3:65])[C@H:43]([OH:64])[C@H:44]([CH3:63])[C@@H:45]([OH:62])[C@@H:46]([CH3:61])[CH:47]=[CH:48][CH:49]=[C:50]([CH3:60])[C:51]([NH:53][C:54]4[C:55](/[CH:1]=[N:75]/[N:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[C:56]([OH:57])[C:29]([C:30]=2[C:34]3=[O:35])=[C:28]([C:58]=4[OH:59])[C:27]=1[OH:74])=[O:52]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: O=C(O)C(=O)O
Reactant: CN1CCN(N)CC1
Agent: CC(C)(C)N1CN(C(C)(C)C)CN(C(C)(C)C)C1
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Solvent: CN(C)C=O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Reaction time: 1 h

Procedure:
0.36 g. Oxalic acid and 1.0 g. 1,3,5-tri-(tert.-butyl)-hexahydro-1,3,5-triazine are added to a solution of 2.8 g. rifamycin S in 10 ml. dimethylformamide. The mixture is kept at 75° C. for about 1 hour, then 1.7 g. of acidified 1-amino-4-methylpiperazine are added directly, according to the process described in Example 7. The chloroform extract finally obtained is concentrated to a small volume and diluted with an appropriate mixture of ethyl acetate-acetone to give a high yield of pure rifampicin.
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH2:21][OH:22])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:21][O:22][C:3]1([CH3:5])[CH3:4])=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
120 ml of isopropenyl methyl ether are added to a solution of 159.5 g of methyl 4(S)-tert-butoxycarbonylamino-5-hydroxyvalerate and 3 g of p-toluenesulfonic acid hydrate in 500 ml of methylene chloride at 0° C. The reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction solution is washed with 100 ml of saturated sodium bicarbonate solution and evaporated. The title compound is obtained by FC (800 g of silica gel, mobile phase E): [α]D =+20.5 (c=0.8 in CHCl3); Rf (D)=0.24; MS: (M)+ =287.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30]C1C=CC=CC=1>C(O)C.[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 98.8 %

Procedure:
A solution of nonaethylene glycol benzyl methyl ether (10 g, 19.3 mmol) in ethanol (200 mL) was shaken with 10% palladium on activated charcal (Aldrich, 1.0 g) under hydrogen (50 psi) on a Parr apparatus for 3 h. The catalyst was filtered off (Celite), and the filtrate was concentrated in vacuo and dried by evaporation of toluene to provide nonaethylene glycol monomethyl ether as an oil (8.17 g, 99%), 1H-NMR (DMSO-d6) δ: 4.56 (t, 1 OH), 3.60–3.35 (m, 36, 18 OCH2), 3.22 (s, 3, CH3).
Reaction SMILES: C(O)C.[Cl-].[NH4+].O1CCCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][N:18]([C:25](=[O:41])[C@@H:26]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-])=O)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:17][CH2:16]2>[Fe].O>[NH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C@@H:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:19]1)=[O:41]
Reactant: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1[N+](=O)[O-])C(C)(C)C)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1N)C(C)(C)C)CC2
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Ethanol (5 ml) and a saturated aqueous ammonium chloride solution (5 ml) were added to a tetrahydrofuran (5 ml) solution of (2S)-1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-3,3-dimethyl-2-((2-nitrophenyl)amino)butan-1-one (395 mg, 0.92 mmol) obtained in Example 24, and the mixture was stirred at room temperature. Water was added to the reaction solution until the insoluble matter was dissolved, powdery iron (6 g) was added, and the mixture was refluxed with heating for 2 hours. The reaction solution was cooled to room temperature, and the excessive iron and tinorganic salt were filtered off using Celite. The filtrate was diluted with ethyl acetate (150 ml), washed with a 1 N aqueous sodium hydroxide solution (50 ml×2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:1) and then chloroform and methanol (20:1) as eluents to obtain the captioned compound (321 mg, 87%) as a colorless foamy substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:29][OH:30].Cl>O.C1COCC1.CCO>[OH:30][NH:29][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N=C(NO)c1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 107 %

Procedure:
A mixture of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid (2.70 g, 9.60 mmol), EtOH (10 ml), THF (15 ml), K2CO3 (3.35 g, 24.2 mmol), and hydroxylamine hydrochloride (1.50 g, 21.6 mmol) was stirred at room temperature for 3.5 d, and then at 80° C. for 24 h. Water (100 ml) and 1N HCl (50 ml) were added, and the product was isolated by filtration and washed with water. The solid was suspended in MeCN (70 ml), heated to reflux, kept at room temp overnight, filtrated off, and dried under reduced pressure to yield 3.23 g (100%) of 4-(4′-(N-hydroxycarbamimidoyl)biphenyl-4-yloxy)butyric acid.
Reaction SMILES: C(C(C(OC(C(OC(=C(F)F)F)(F)F)(C(F)(F)F)F)(F)F)(F)F)(F)(F)F.[C:27]([C:31]([C:34]([O:37][C:38]([C:44]([O:47][C:48]([C:51]([O:53]C)=[O:52])([F:50])[F:49])([F:46])[F:45])([C:40]([F:43])([F:42])[F:41])[F:39])([F:36])[F:35])([F:33])[F:32])([F:30])([F:29])[F:28].[NH3:55].C(OC=C)=C>CO>[C:34]([O:37][C:38]([C:44]([O:47][C:48]([C:51]([O-:53])=[O:52])([F:49])[F:50])([F:46])[F:45])([C:40]([F:41])([F:42])[F:43])[F:39])([C:31]([C:27]([F:30])([F:29])[F:28])([F:33])[F:32])([F:36])[F:35].[NH4+:55]
Reactant: COC(=O)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N
Agent: C=COC=C
Agent: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: O=C([O-])C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Product: [NH4+]

Procedure:
Conversion of CF3CF2CF2OCF(CF3)CF2OCF═CF2 to CF3CF2CF2OCF(CF3)CF2OCF2COOCH3 (bp 91-92° C. at 133 mbar) was carried out as described in U.S. Pat. No. 4,987,254. The ester was reacted with aqueous ammonia and methanol was removed by distillation resulting in CF3CF2CF2OCF(CF3)CF2OCF2COONH4. All structures were confirmed by F-NMR spectra. Due to an isomer content in the vinyl ether, an isomer with the structure CF3CF2CF2OCF2CF(CF3)OCF2COOX(X═CH3, NH4) was found.