Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C[O-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].CS(C)=O>C(OCC)(=O)C>[CH2:16]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture was prepared containing the following ingredients: 33 g. of L-ascorbic acid, 10.2 g. of sodium methylate, 34.5 g. of n-butyl iodide and 250 ml. of DMSO. The reaction mixture was stirred at ambient temperature and the progress of the reaction monitored by thin layer chromatography. After 24 hours, the reaction mixture was added to 500 ml. of ethyl acetate. 3-O-n-Butyl-L-ascorbic acid formed in the above reaction precipitated and was separated by filtration. Further precipitation was caused by adding 300 ml. of toluene to the filtrate. These crystals were also collected and the combined crystals dissolved in 500 ml. of methanol. (weight=about 20 g.) 45 g. of silica gel was added to this solution. The solution was evaporated to dryness in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[CH2:13][CH2:14][C:15](=[O:16])[C:7]1=[C:6]2[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:26](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]3[CH2:13][CH2:14][C:15](=[O:16])[C:7]3=[C:6]2[C:17]2[CH:18]=[CH:19][C:20]([C:21]#[CH:26])=[CH:23][CH:24]=2)=[CH:11][CH:12]=1
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(C=O)cc4)c2c1)C(=O)CC3
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2c3c(cc4ccc(N(C)C)cc24)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A flame-dried 25 mL two-necked round-bottomed flask equipped with a nitrogen inlet, a septum and a stir bar was charged with compound 19 (0.031 g, 0.094 mmol) and methanol (7 mL). To this solution was added potassium carbonate (0.064 g, 0.48 mmol) followed by the Bestmann-Ohira reagent (0.054 g, 0.28 mmol) in methanol (5 mL). The reaction was stirred at rt overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 2:8). The solution was diluted with ether (10 mL) and then transferred to a separatory funnel containing sat'd aq NaHCO3 solution (15 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 2:8, to provide 0.018 g of the title compound as an orange solid in a 59% yield.
Reaction SMILES: C(S([N:6]1C[CH2:10][CH:9]([C:12]2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)[CH2:8][CH2:7]1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.CC(C)CCN.[BH3-]C#N.[Na+]>>[CH3:10][CH:9]([CH3:12])[CH2:8][CH2:7][NH:6][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CC(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CCNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 38.3 mg of the title compound (37%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]12([NH:18][S:19]([C:22]3[CH:33]=[C:26]4[C:27](OC(=O)[NH:31][C:25]4=[CH:24][CH:23]=3)=[O:28])(=[O:21])=[O:20])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:27](=[O:28])[C:26]2[C:25](=[CH:24][CH:23]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][C:8]34[CH2:17][CH:12]5[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]5)[CH2:9]3)[CH2:15]4)[CH:33]=2)[NH2:31])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC34CC5CC(CC(C5)C3)C4)cc2c(=O)o1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2cc(S(=O)(=O)NC34CC5CC(CC(C5)C3)C4)ccc2N)CC1
Temperature: 25 °C

Procedure:
2.7 g of 1-methylpiperazine are added slowly to a suspension of 10.2 g of 5-[N-(1-adamantyl)-sulfamoyl]-isatoic anhydride in 250 ml of absolute toluene, at 100° with stirring. After the addition is ended, the mixture is stirred for a further 1 hour at 100° and is allowed to cool to room temperature, the precipitate is separated off by decanting and the crude product thus obtained is recrystallised from ethanol. 5-[N-(1-Adamantyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 214°-215° is obtained. (Melting point of the hydrochloride: 298°-300°).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[N:8]1)=[O:4].[C:39]([OH:42])(=[S:41])[CH3:40].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:39]([S:41][CH:12]([C:11]1[N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:8]=[N:9][CH:10]=1)[C:13]1[CH2:14][N:15]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:42])[CH3:40]
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1nncc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of (E)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (13.22 g) in toluene (200 ml) were added thioacetic acid (3.7 ml) and N,N-dimethylformamide dineopentyl acetal (14.5 ml) with stirring at room temperature, and the resulting mixture was stirred at the same temperature for 2 hours. After addition of aqueous sodium chloride solution, products were extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using a mixed solvent of ethyl acetate and hexane (2:1) as the eluent to afford 5-((acetylsulfanyl){1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (8.17 mg, yield: 55%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[CH3:10][I:11]>O1CCCC1>[I-:11].[CH3:1][O:2][CH2:3][CH2:4][N+:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH3:10]
Reactant: CI
Reactant: CCN(CC)CCOC
Solvent: C1CCOC1
Product: CC[N+](C)(CC)CCOC
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Next, 8.2 g of the 2-methoxyethyldiethylamine was dissolved in 10 ml of tetrahydrofuran (Wako Pure Chemical Industries), then 4.0 ml of methyl iodide (Wako Pure Chemical Industries) was added under ice cooling. After 30 minutes, the mixture was removed from the ice bath and stirred overnight at room temperature. The solvent in this reaction solution was subsequently driven off by vacuum distillation, and the resulting solids were recrystallized from an ethanol (Wako Pure Chemical Industries)—tetrahydrofuran system, yielding 16 g of 2-methoxyethyldiethylmethylammonium iodide.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH:18]([OH:47])[CH:19]([O:21][C:22](=[O:46])[CH2:23][CH2:24][CH:25]([NH:38]C(OC(C)(C)C)=O)[C:26](=[O:37])[NH:27][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH3:29])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([NH2:48])=[N:11][C:10](=[O:49])[C:9]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:58]>>[ClH:58].[ClH:58].[NH2:48][C:12]1[NH:11][C:10](=[O:49])[C:9]2[NH:8][CH:17]([CH:18]([OH:47])[CH:19]([O:21][C:22](=[O:46])[CH2:23][CH2:24][CH:25]([NH2:38])[C:26](=[O:37])[NH:27][CH:28]([C:30]([OH:32])=[O:31])[CH3:29])[CH3:20])[CH2:16][NH:15][C:14]=2[N:13]=1
Reactant: CC(NC(=O)C(CCC(=O)OC(C)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)C(N)CCC(=O)OC(C)C(O)C1CNc2nc(N)[nH]c(=O)c2N1)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The product of step b) (0.048 g, 0.07 mmol) was treated with trifluoroacetic acid (1 ml, 27 mmol) in 1 ml of DCM. The mixture was stirred at room temperature under an atmosphere of nitrogen for 2 h. The product was precipitated by the addition of 20 ml of diethyl ether. The product was filtered and dried in a nitrogen purged vacuum oven to give the title compound as a white solid (0.051 g, 98%). 1H NMR (CD3OD) δ 4.45-4.39 (m, 2H), 4.23-4.20 (m, 2H), 3.94 (t, J=6.3 Hz, 1H), 2.60-2.55 (m, 2H), 2.49-2.24 (m, 2H), 2.17-2.12 (m, 3H), 1.45 (dd, J=7.4 Hz, J=9.7 Hz, 6H). MS: ESI (positive): 442 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.O>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: C=CC(=O)OC
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
5-Hydrox-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (550 mg, 1.3 mmol), 550 mg (4 mmol) of K2CO3 and 0.2 mL of methyl acrylate in 40 mL of acetone was heated to maintain reflux for 100 hours (additional methyl acrylate was added at various times). After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2SO4). After concentrating, the residue was chromatographed on silica (eluted with CH2Cl2→1% MeOH/CH2Cl2) and crystallized from CH2Cl2/ether to give 375 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]-propanic acid methyl ester, mp, 113-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2.O.O.[Sn](Cl)Cl>C(O)C>[ClH:1].[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])=[CH:4]2
Reactant: CNC(N)=NC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2[nH]1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CNC(N)=NC(=O)c1cc2c(Cl)ccc(Oc3cccc(N)c3)c2[nH]1
Product: Cl
Yield: 130.4 %

Procedure:
The reaction was carried out in a manner similar to Example 186 c) except for using 0.055 g (0.14 mmol) of 4-chloro-1-methyl-7-(3-nitrophenoxy)-2-indoloylguanidine, 0.16 g (0.71 mmol) of tin (II) chloride dihydrate and 5 ml of ethanol. Thus, 0.036 g (59.0%) of 7-(3-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li][CH3:17]>C(OCC)C.O>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:17])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1sc(C(=O)O)cc1-c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cc(-c2ccccc2)c(C)s1
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-4-phenyl-thiophene-2-carboxylic acid (1.50 g, 6.87 mmol) in diethyl ether (100 mL) MeLi (7 mL, 1.5 M in diethyl ether) is added at 5° C. The mixture is stirred at it for 90 min before another portion of MeLi (1 mL) is added. Stirring is continued for 1 h. The mixture is diluted with water and extracted with EA. The organic extracts are evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(5-methyl-4-phenyl-thiophen-2-yl)-ethanone (490 mg) as a colourless oil, LC-MS: tR=1.00 min, [M+1]+=217.10; 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.48-7.33 (m, 5H), 2.54 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.28 (s, 1H), 7.78-6.70 (m, 13H), 5.08-4.98 (m, 1H), 3.64-3.46 (m, br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, br, 4H), 2.56-2.34 (m, br, 2H), 2.05-1.75 (m, br, 6H), 1.64-1.48 (m, br, 1H), 1.48-1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 533.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[O:24][CH:27]=[N:26][N:25]=4)[C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Product: Clc1cccc(Nc2nc3c(-c4nnco4)cccc3c3cnccc23)c1

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbohydrazide (24 mg) was stirred in triethylorthoformate (1 ml) at 120° C. for 4 hours. The solid was filtered and triturated in CH2Cl2/MeOH. Impurities (mainly starting material) were removed by filtration and the filtrate containing the expecting compound was concentrated. The material was purified by preparative TLC on silica gel (5% methanol in CH2Cl2) to afford N-(3-chlorophenyl)-7-(1,3,4-oxadiazol-2-yl)benzo[c][2,6]naphthyridin-5-amine as a solid (8 mg). LCMS (ES): >95% pure, m/z 374 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (126 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare a solution. Potassium carbonate (156 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 3-(6-methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (48 mg, yield 33%).
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].CO[CH:21](OC)[N:22](C)C>CN(C)C=O.C(OCC)(=O)C>[C:9]1([SH:6]2(=[O:7])[CH:5]=[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=3)[N:22]=[CH:21][NH:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N=S(=O)(C=Cc1ccccc1N)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=CN1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of 2 g (7.75 mmole) of S-(2-aminostyryl)-S-phenyl sulfoximine in 20 ml of dimethylformamide was added 1 g (8.5 mmole) of dimethylformamide dimethyl acetal and the mixture was heated at 80° C. for 15 minutes. The mixture was then cooled and diluted with 100 ml of ethyl acetate. The organic phase was washed 3 times with 75 ml of water, dried over magnesium sulfate and evaporated to an oil which was crystallized from ether/petrol to obtain 1.67 g (80%) of 1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 110°-111° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].P(Cl)(Cl)(Cl)=O>CN(C)C=O.O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 2.1 g.) was dissolved in a solution of N,N-dimethylformamide (0.8 ml.) and tetrahydrofuran (7.6 ml). To the solution was added a solution of N,N-dimethylformamide (0.78 ml) and phosphorus oxychloride (0.9 ml) in tetrahydrofuran (0.7 ml) all at once at -5° C., and stirred at the same temperature for 30 minutes and at 22° C. for 30 minutes. The resultant solution was poured into ice water. The precipitates were washed with water (50 ml) and diisopropyl ether (25 ml) and dried over phosphorus pentoxide to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1.37 g.). The mother liquid was extracted with ethyl acetate (100 ml.). The extract was washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo and the precipitates were pulverized with diisopropyl ether to give the same objective compound (syn isomer, 0.2 g.). Similar result was obtained by using SOCl2 in stead of POCl3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].[CH:30](=O)[CH2:31][CH2:32][CH3:33]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:30][CH2:31][CH2:32][CH3:33])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Yield: 83 %

Procedure:
Following general procedure Q and using 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.2 g, 0.64 mmol), sodiumcyanoborohydride (0.121 g, 1.92 mmol) and butyraldehyde (1 mL, 11.09 mmol) in 5 mL of acetic acid and 5 mL of tetrahydrofuran, the title compound (0.21 g, 88%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.1 Hz), 7.11 (d, 1H, J=8.7 Hz), 7.07 (d, 1H, J=8.1 Hz), 6.90 (s, 1H), 6.68 (d, 2H, J=8.9 Hz), 4.32 (q, 2H, J=7.1 Hz), 3.70 (t, 2H, J=7.8 Hz), 1.74-1.62 (m, 2H) 1.55 (s, 6H), 1.51 (s, 6H), 1.45-1.33 (m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.95 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][O:20][CH2:21][CH2:22][OH:23]>C1COCC1>[Si:5]([O:23][CH2:22][CH2:21][O:20][CH2:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: OCCOCc1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1nccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 544.8 %

Procedure:
TBDMS-Cl (2.4 g, 15.7 mmol) and imidazole (1.10 g, 16.9 mmol) were added to a sol. of 2-(thiazol-2-ylmethoxy)ethanol (2.45 g, 15.39 mmol) in THF (80 mL). The reaction mixture was stirred at rt over 15 h, partitioned between aq. sat. NH4Cl and Et2O. The phases were separated and the aq. layer was extracted with Et2O (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil (22.93 g, 87%) that was not further purified. LC-MS: tR=1.06 min, ES+: 274.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C[NH:10][CH2:11][CH2:12][NH:13][CH3:14].N1C=CC=C[CH:16]=1>>[CH3:16][N:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CNCCNC
Reactant: c1ccncc1
Product: CN(C)CCNc1cccc(Cl)n1
Yield: 70 %

Procedure:
A solution of 2,6-dichloropyridine (29.6 g., 0.20 mole) and unsymmetrical dimethylethylenediamine (52.9 g., 0.60 mole) in 100 ml of pyridine is stirred at reflux for 48 hours. The pyridine is removed under reduced pressure and the residual mixture is poured into water and made basic with excess sodium hydroxide. The product is extracted into ethyl acetate which is then concentrated and the residual oil is distilled. 2-(2-Dimethylaminoethylamino)-6-chloropyridine boiling at 104°-105° at 0.2 mm is collected in 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cccc(C#CCCO[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cccc(CCCCO)c1
Yield: 64.3 %

Procedure:
A solution of {3-[4-(t-butyidimethylsilyloxy)but-1-ynyl]phenyl}acetic acid methyl ester (700 mg, 2.1 mmol) in MeOH (15 ml) was treated with 5% Pd/C (100 mg) and hydrogen gas (1 atm) for 1 hr. The catalyst was filtered, and the solvent evaporated. The residue was dissolved in THF (1 ml), and treated with tetrabutyl ammonium fluoride (2 ml of a 1N solution in THF) for 2 hr. The reaction was diluted with water and extracted with diethyl ether. The organic extracts were washed with water, dried, evaporated, and the volatile organics removed by vacuum to give the title compound as an oil (300 mg, 64%). MS (ESI) 223.2 (M+H)+.