Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:27][C:26]2=[O:39]>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[O:29][C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][C:26]3=[O:39])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 6-hydroxyflavone in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H26O6[M+H]+:483.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[NH2:6].C[S-].[Na+]>CN1CCCC1=O>[NH2:6][C:5]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(N)cc(OC)c1
Agent: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(N)cc(O)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-dimethoxyaniline (2.53 g, 16.5 mmol) in N-methylpyrrolidinone (10 ml) was added sodium thiomethoxide (2.32 g, 33.1 mmol). The reaction mixture was heated to 140° C. for 2.5 hours and then stirred at ambient temperature for a further 18 hours. The mixture was poured into a saturated solution of NaH2PO4 (50 ml) and then extracted with ethyl acetate. The combined organic layers were filtered through a hydrophobic frit and the solvent was removed under reduced pressure to give a dark red oil. The crude residue was purified by normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give 3-amino-5-methoxyphenol, as a pale yellow solid (1.53 g).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])=[N+]=[N-].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]=[C:24]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[NH:23][C:24]1[O:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:1]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=O
Reactant: [N-]=[N+]=NCC(=O)c1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2cccnc2)o1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 3-azidoacetylpyridine (800 mg, 4.94 mmol) in dioxane 10 mL was added 2-methyl-5-nitrophenyl isocyanate (880 mg, 4.94 mmol) (commercially available), and triphenylphosphine (1.29 g, 4.94 mmol). The reaction mixture was placed in an oil bath preheated to 100° C. and stirred for 30 min. After evaporation of the solvent under reduced pressure the residue was partitioned between 4N HCl (20 mL) and dichloromethane (20 mL). The aqueous layer was neutralized with 15% NaOH and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, concentrated. The residue was silica gel column chromatographed (dichloromethane/ethanol:97/3) to give the title compound as yellow micro crystals (1.14 g, 78%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[O:10][C:11]=1[CH3:12].CO.Cl>O.C1COCC1>[C:19]([C:17]1[CH:18]=[C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH2:6][C:5]([OH:28])=[O:4])[N:8]=2)[CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CC(=O)O
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Sodium hydroxide (2N, 5.0 mL, 10.0 mmol) was added to a solution of [2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazol-4-yl]-acetic acid methyl ester (1.5 g, 4.18 mmol), MeOH (15 mL), and THF (15 mL). After stirring for 1 hour, the mixture was poured into water, acidified with HCl(2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ethyl ether/hexane gave a white solid (1.25 g, 87% yield), m.p. 205°-206° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:30]([C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:5][N:6]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 130 °C
Yield: 52.7 %

Procedure:
To a solution of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (100 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (85 mg) and tripotassium phosphate (145 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.5 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (31.5 mg). The reaction vessel was sealed and heated under microwave at 130° C. for 8 min. After cooling the reaction, water was added to quench the reaction. After filtered through the celite, the filtrate was partitioned between the organic and aqueous layers. The aqueous layer was extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated, and purified by column chromatography to afford 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzaldehyde (D6) (60.4 mg). MS (ES): C21H19F3N2O2S requires 420. found 421.1 (M+H+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:34]=C[C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=CC(CN)=[N:44]C=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@@H:20]([CH:30]([CH3:31])[CH3:32])[C:17]3=[N:18][CH:19]=2)=[O:13])=[N:44][CH:34]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reactant: CCS(=O)(=O)c1ccc(CN)nc1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)nc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using (5-(ethylsulfonyl)pyridin-2-yl)methanamine as a starting material. LC-MS tR=0.86 min in 1 min chromatography, MS (ESI) m/z 489.4 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of rotamers): δ 9.06 (s, 1H), 8.96 (s, 1H), 8.20 (dd, J=2.0 Hz, 8.4 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 4.99 (m, 2H), 4.90 (m, 2H), 4.80 (d, J=15.2 Hz, 1H), 4.51 (m, 1H), 3.17 (q, J=7.6 Hz, 2H), 2.63-2.54 (m, 0.5H), 2.48-2.39 (m, 0.5H), 1.52 (s, 9H), 1.33 (t, J=7.6 Hz, 3H), 1.10 (d, J=7.2 Hz, 1.5H), 1.01 (d, J=6.8 Hz, 1.5H), 0.78 (d, J=6.8 Hz, 1.5H), 0.73 (d, J=7.2 Hz, 1.5H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]2.COCC(O)C>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]5)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: CN1C(=O)Cc2cc(N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CC(=O)N5C)nn23)cn1
Yield: 8.3 %

Procedure:
2-Methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004335 mol), N,N-Diisopropylethylamine (0.249 mL, 0.00143 mol) and 5-Amino-1-methyl-1,3-dihydro-indol-2-one (0.141 g, 0.000867 mol) were dissolved in 1-Methoxy-2-propanol (0.498 mL, 0.00510 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 13.85 mg of 5-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1-methyl-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=387.1. 1H NMR (400 MHz, DMSO, d6) δ 9.40 (s, 1H), 8.96 (s, 2H), 8.47 (d, 1H, J=8.73 Hz), 7.82 (s, 1H), 7.51 (d, 1H, J=8.40 Hz), 7.16 (d, 1H, J=4.37 Hz), 7.04 (d, 1H, J=8.65 Hz), 6.91 (m, 2H), 3.95 (s, 3H), 3.59 (s, 2H), 3.12 (s, 3H).
Reaction SMILES: [N+](C1C(N2CCC(NC(=O)OC(C)(C)C)CC2)=NC=CC=1)([O-])=O.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.Br[C:39]1[S:40][C:41]([C:44]([NH2:46])=[O:45])=[CH:42][N:43]=1>>[NH2:46][C:44]([C:41]1[S:40][C:39]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]2)=[N:43][CH:42]=1)=[O:45]
Reactant: NC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(C)(C)OC(=O)NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(N)=O)s2)CC1

Procedure:
Title compound was synthesized by an analogous method to Intermediate 38 by coupling tert-butyl piperidin-4-ylcarbamate (commercially available) with 2-bromo-1,3-thiazole-5-carboxamide (J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: [S:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]=[C:9]([NH:11][C:12]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[O:13])[S:10][C:6]=2[CH:5]=1)C#N.SCC(C(CS)O)O>P([O-])(O)(O)=O.[K+]>[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][NH:14][C:12]([NH:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([SH:1])[CH:25]=[CH:24][C:7]=3[N:8]=2)=[O:13])[CH2:22][CH2:21]1
Reactant: CN1CCN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)CC1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: CN1CCN(CCNC(=O)Nc2nc3ccc(S)cc3s2)CC1
Yield: 40.7 %

Procedure:
The 1-[2-(4-methylpiperazin-1-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1b, but using 1 g of 1-(6-thiocyanato-1,3-benzothiazol-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea, 14 mg of potassium dihydrogen phosphate and 1.16 g of DL-dithiothreitol. 380 mg of 1-[2-(4-methylpiperazin-1-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH2:15][CH:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[CH3:23][C:21]1[CH:22]=[C:17]([CH:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[CH2:15][CH2:14][C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)[CH:18]=[C:19]([CH3:24])[CH:20]=1
Reactant: Cc1cc(C)cc(C(CCc2cncn2Cc2ccccc2)c2cc(C)cc(C)c2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)cc(C(CCc2c[nH]cn2)c2cc(C)cc(C)c2)c1

Procedure:
2,0 g of 1-benzyl-5-[3,3-bis(3,5-dimethylphenyl)propyl]-1H-imidazole hydrochloride is hydrogenated in the mixture of 30 ml of 2N hydrochloric acid and 10 ml ethanol at 80° C. Pd/C (10%) as catalyst. When the uptake of hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to ethylacetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The residue is the product as base and it is made to its hydrochloride salt in ethyl acetate using dry hydrochloric acid. Yield 0,6 g. M.p. of the product is 101°-105° C.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13])=[N-:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>C1(C)C(C)=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][C:4](=[O:13])[N:1]3[N:2]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:16]=[C:3]3[C:11]=2[CH:10]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(Cl)cc21
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
Seven and one-half g (0.039 mole) of 3-diazo-5-chloro-oxindole and 8.4 g (0.086 mole) of ethyl propiolate are dissolved in 400 ml of xylene and heated to reflux (under nitrogen) for 1.5 hours, during which time a copious amount of solid forms. The reaction mixture is cooled to room temperature, filtered, washed with ether and dried to give 10 g (88% yield) of TLC pure material. This is crystallized from chloroform/methanol (4:1) and then from methanol to give 8.1 g of analytically pure compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>>[NH2:14][C:15]1[CH:16]=[CH:17][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[CH2:12][C:13]([OH:18])=[O:19]
Reactant: [OH-]
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: [Na+]
Product: Nc1ccc(C(=O)c2ccccc2)cc1CC(=O)O

Procedure:
A mixture of 1.0 g. (0.004 mole) of 5-benzoylindolin-2-one and 30 ml. of 3 N sodium hydroxide was refluxed for 0.5 hour. The reaction mixture was cooled, acidified to pH 6 with 3 N hydrochloric acid and slightly acidic solution was extracted with chloroform. The chloroform extracts were dried (magnesium sulfate) and concentrated to a solid. Recrystallization from ethanol-water gave 0.9 g. (84.5%) of pure product which melted at 143°-145° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15]1)[CH2:8]2.B(Br)(Br)Br.Cl>ClCCl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:15]1)[CH2:8]2
Reactant: COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)nn1CC1CCc2c(O)cccc2C1
Reaction time: 2.5 h
Yield: 75.8 %

Procedure:
To a solution of 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.60 g) in dry dichloromethane (5 ml) was added dropwise 1N boron tribromide in dichloromethane (1.5 ml) under ice bath cooling. The mixture was stirred at the same temperature for 2.5 hours. The mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1) to give 2-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.44 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][O:23][C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>C(O)C>[CH2:25]([N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(c1ccccc1)CO2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1c1ccccc1
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (336 mg, 1.01 mmol) in ethanol (3 mL) was added acetaldehyde (62 μL, 1.11 mmol) then sodium cyanoborohydride (89 mg, 1.42 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, partitioned between DCM (50 mL) and 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was further extracted with DCM (2×25 mL). The combined organics were dried with MgSO4 and concentrated in vacuo to give tert-butyl 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (298 mg, 82%). ESI-MS m/z calc. 360.5. Found 361.7 (M+1)+; Retention time: 1.30 minutes (3 min run).
Reaction SMILES: [N+](C1C(N[C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=C(C=CC=1)C(O)=O)([O-])=O.[BH4-].[Na+].[CH3:26][C:27]([OH:29])=[O:28]>[OH-].[Na+].O>[N:15]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[C:19]2[N:22]=[CH:23][CH:14]=1)[N:15]=[C:14]1[C:23]([C:26]([C:27]([OH:29])=[O:28])=[CH:17][CH:16]=[CH:21]1)=[N:22]3
Reactant: CC(=O)O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cnc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2nc3ccc4nccnc4c3nc12
Yield: 73 %

Procedure:
A solution of 3-nitro-(quinoxalinylamino)benzoic acid (0.8 g, 2.58 mmol) in 5M NaOH (40 mL) was treated with NaBH4 (0.9 g, 12.9 mmol), and the mixture was heated under reflux for 2 h. The cooled mixture was diluted with water (40 mL), then neutralized with glacial AcOH to give pyrazino[2,3-α]phenazine-11-carboxylic acid (0.52 g, 73%): mp (MeOH/Et3N/AcOH)>350° C. 1H NMR [CF3CO2D] δ 8.62 (dd, J=8.8, 7.3 Hz, 1 H, H-9), 8.91 (d, J=9.8 Hz, 1 H, H-5 or H-6), 8.97 (d, J=9.8 Hz, H-5 or H-6), 9.18 (dd, J=8.8, 1.0 Hz, 1 H, H-8), 9.47 (dd, J=7.3, 1.0 Hz, 1 H, H-10), 9.57 (d, J=2.2 Hz, 1 H, H-2 or H-3), 9.65 (d, J=2.2 Hz, 1 H, H-2 or H-3),
Reaction SMILES: [CH2:1]([CH:5]1[CH2:8][CH:7]([C:9]([OH:11])=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:9]([CH:7]1[CH2:8][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6]1)=[O:11]
Reactant: CNOC
Reactant: CC(C)CC1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(CC(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
3-Isobutylcyclobutanecarboxylic acid (62.7 g) and DMF (500 mL) were mixed. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (46.9 g), triethylamine (83.9 mL), HOBt.H2O (73.8 g) and WSC.HCl (92.3 g). The resulting mixture was stirred at RT overnight. To the reaction mixture was added water (500 mL). The mixture was extracted with ethyl acetate/hexane=1/1 (250 mL×2). The combined organic layer was washed with water (250 mL), aqueous 10 w/v % sodium carbonate (250 mL), water (250 mL), 1 N hydrochloric acid (500 mL), water, saturated aqueous sodium bicarbonate (250 mL) and then brine (250 mL). The organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (87.5 g) as a crude product.
Reaction SMILES: [Mg].[CH3:2][CH2:3][CH2:4]Br.[OH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Cl-].[NH4+]>O1CCCC1>[OH:16][C:9]([C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=1[OH:6])([CH2:2][CH2:3][CH3:4])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCCBr
Reactant: O=C(Cn1ccnc1)c1ccccc1O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)(Cn1ccnc1)c1ccccc1O
Yield: 28.4 %

Procedure:
To a tetrahydrofuran solution of Grignard reagent prepared from 73 mg of magnesium and 369 mg of n-propyl bromide, 202 mg of 1-(2-hydroxyphenacyl) imidazole (II) was added dropwise under ice-cooled conditions while stirring, and the mixture was refluxed for 2 hours. After ice-cooling, an aqueous solution of ammonium chloride was added to the mixture to decompose the surplus amount of the Grignard reagent and addition salts produced in the reaction. Extraction with chloroform was performed on this mixture and the chloroform layer was washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: chloroform) to produce 70 mg of the title compound at a yield of 29%.
Reaction SMILES: C[O:2][C:3]([C:5]([C@@H:7]([OH:14])[C@H:8](O)[C@@H:9]([OH:12])[CH2:10][OH:11])=[O:6])=[O:4].C(=O)([O-])[O-].[Na+:19].[Na+]>CO>[O:4]=[C:3]1[O:2][C@H:8]([C@H:9]([CH2:10][OH:11])[OH:12])[C:7]([O-:14])=[C:5]1[OH:6].[Na+:19]
Reactant: COC(=O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 40 °C
Yield: 203.8 %

Procedure:
208.4 g of methyl 2-keto-L-gulonate are dissolved in 500 g of methanol and the solution is heated to boiling while stirring. 52 g of sodium carbonate are added in the course of 2 hours. The pH value is then 8. The mixture is stirred for 30 minutes, cooled to 40° C. and the precipitated sodium ascorbate is filtered off and washed with 100 g of methanol. The moist sodium ascorbate is dried in a drying oven at 40° C. under reduced pressure. There are obtained about 198.1 g of crude sodium ascorbate with a content of pure sodium ascorbate of about 94%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:16][C:17]1[S:18][C:19]([S:22][CH2:23][C:24]2[CH2:31][S:30][CH:29]3[N:26]([C:27](=[O:33])[CH:28]3[NH2:32])[C:25]=2[C:34]([OH:36])=[O:35])=[N:20][N:21]=1>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:10]([OH:12])=[O:11])[C:13]([NH:32][CH:28]2[C:27](=[O:33])[N:26]3[CH:29]2[S:30][CH2:31][C:24]([CH2:23][S:22][C:19]2[S:18][C:17]([CH3:16])=[N:21][N:20]=2)=[C:25]3[C:34]([OH:36])=[O:35])=[O:15])=[CH:7][CH:8]=1
Reactant: O=C(O)C(C(=O)O)c1ccc(CCl)cc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(C(=O)O)c4ccc(CCl)cc4)C3SC2)s1

Procedure:
When in the above procedure appropriate amounts of an acid derivative and acephalosporin derivative listed in the following Table X are substituted respectively for p-chloromethylphenylmalonic acid and 3-[(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the above procedure, the respective products listed in the following Table X are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH2:23][C:24]([OH:26])=[O:25].S(=O)(=O)(O)O.[CH3:32]O>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH2:23][C:24]([O:26][CH3:32])=[O:25]
Reactant: CO
Reactant: COc1nc2sc3c(c2c(-c2ccc(C)cc2)c1CC(=O)O)CCCC3
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(OC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3

Procedure:
The compound is prepared from the [2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid following standard esterification procedures known to the skilled in the art. As an example, the transformation is achieved using a catalytic amount of sulphuric acid in methanol.