Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: BrCCCc1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 19.7 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (550 mg, 3 mmol) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (42 mg, 0.15 mmol) in 50% aqueous sodium hydroxide (3 mL) followed by 1-bromo-3-phenylpropane (670 mg, 3.3 mmol). The reaction was heated to 60° C. (oil bath temperature) for 6 h. The reaction was cooled and diluted with water (30 mL) and extracted with chloroform (3×10 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to a dark red oil (690 mg). The oil was subjected to column chromatography (silica gel, eluent: 50% dichloromethane in hexane followed by 100% dichloromethane) to give a dark yellow oil (154 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[CH:15][NH2:16]
Reactant: CN
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(C=CN)cc(OC)c1OC
Yield: 95 %

Procedure:
3,4,5-Trimethoxybenzaldehyde (7.81-40.0 mmol) and a 40% aqueous solution of methylamine (20 mL) were stirred at room temperature for 2.5 h. The mixture was extracted with ether (4×75 mL), the ether layers were combined, and the solution washed with saturated aqueous sodium chloride (75 mL), dried (MgSO4), and concentrated under reduced pressure to give a colorless oil (7.94 g, 95%): IR (neat) 2940, 2840, 1646, 1576, 1500, 1453, 1407, 1369, 1323, 1230, 1115, 1013 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.18 (d, 1H, J=1.3 Hz), 6.95 (s, 2H), 3.89 (s, 6H), 3.87 (s, 3H), 3.50 (d, 3H, J=1.3 Hz); CIMS m/z (relative intensity) 210 (MH+, 100). Anal. Calcd for C11H15NO3: C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=3)[C@H:9]2[C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][CH2:69][C:70]([NH:72][C@@H:73]([C:81]([OH:83])=[O:82])[CH2:74][CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)=[O:71].[BH4-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:27])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=3)[C@H:9]2[C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH:68][CH2:69][C:70]([NH:72][C@@H:73]([C:81]([OH:83])=[O:82])[CH2:74][CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)=[O:71])=[O:35])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCCc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Temperature: 30 °C
Reaction time: 22 h
Yield: 32.5 %

Procedure:
To a solution of [4-((2R,3R)-1-(4-fluorophenyl)-4-oxo-3-{[2-oxo-2-(4-pentylphenyl)ethyl]thio}azetidin-2-yl)phenoxy]acetic acid (0.020 g, 0.037 mmol) and NMM (0.012 ml, 0.109 mmol) in DMF (2 ml) at 30° C. was added TBTU (0.019 g, 0.059 mmol). After 15 min glycyl-3-cyclohexyl-D-alanine (0.009 g, 0.039 mmol) was added and the mixture was stirred at 30° C. for 22 h. The reaction was quenched by the addition of water (1 ml) before the mixture was diluted with MeOH (2 ml). To this solution was added NaBH4 (0.020 g, 0.529 mmol) and the mixture was stirred for 10 min. This reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.009 g, 32% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])[O:6][CH:7]=1.[N:21]1([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:25]=[CH:24][N:23]=[N:22]1.[I-].[K+].C[O-].[Na+]>CO>[F:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)=[CH:31][CH:32]=2)[N:4]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(CCCCn3ccnn3)cc2)co1

Procedure:
0.305 g (1.00 mmol) 4-Chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole, 0.217 g 1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of a 30% sodium methylate solution were added to 50.0 ml methanol and heated to reflux for 10 h. After removal of solvent, partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed 3× with 15 ml 1 N NaOH, twice with 15 ml water and dried over sodium sulphate. The solution was evaporated to dryness and the residue purified by reversed phase HPLC (C4-column, eluent: methanol/water 8:2+0.2% acetic acid). After evaporation and drying of the product containing fractions, the residue was treated with diethyl ether and dried in vacuo at 40° C. 80 mg (16%) 1-[4-(4-{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36].C(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:35][NH:36][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.56 mmol) and hydrazine monohydrate (3 mL) in methanol (20 mL) was stirred at 30° C. for 4 hr. The mixture was concentrated to give crude product, which was purified by prep-HPLC to give the title compound (34 mg, yield 14%) as a white solid of formic acid salt. LC-MS (ESI) m/z: 431 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.66 (s, 6H), 4.20-4.21 (d, J=4.8 Hz, 2H), 4.39-4.42 (d, J=8.8 Hz, 1H), 4.82-4.84 (d, J=8.8 Hz, 1H), 7.15-7.20 (m, 4H), 7.25-7.27 (d, 2H), 7.35-7.42 (m, 5H), 7.46 (s, 1H), 7.58-7.62 (t, J=8.0 Hz, 1H), 9.74 (br s, 1H), 12.18 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>C(OCC)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: CN(C)CCCN
Solvent: CCOCC
Product: CN(C)CCCNC(=O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 35.9 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 46 μL (0.36 mmol) of 3-dimethylaminopropylamine. After trituration in diethyl ether, 37 mg (36%) of N-(3-dimethylamino-propyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Oc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(O)cc3C[C@@H]21
Yield: 18 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=334 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:17])=O)=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]#[N:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12

Procedure:
A solution of 7-chloro-3-(aminocarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (590 mg, 2.03 mmol) (compound of Example 14) in phosphorous oxychloride (2.56 mL) was refluxed for 70 minutes. The excess phosphorous oxychloride was distilled off at atmospheric pressure and 106° C. To the remaining dark brown residue was added water (40 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator to give the title compound as a brown/gold solid (≈216 mg, 39% yield, m.p. 370° C. dec.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][CH2:18]Cl)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C[N:21](C)[CH:22]=[O:23]>>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:17][CH2:18][NH:21][C:22]2=[O:23])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCl)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (59 mg, 60% dispersion in oil, 1.5 mmol) was added to a solution of 1-t-butoxycarbonyl-4-(2-chloroethylamino)piperidine (305 mg, 0.98 mmol) in dimethylformamide (5 mL), and the reaction stirred at room temperature overnight. The reaction was quenched with water, filtered and purified by reverse phase HPLC(C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid, gradient elution), to give the title compound (30 mg). 1H NMR (500 MHz, CDCl3) □ 4.22 (br s, 3H), 3.88 (tt, J=4, 12 Hz, 1H), 3.52 (m, 2H), 3.46 (m, 2H), 2.79 (br t, 11 Hz, 2H), 1.72 (d, J=12 Hz, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C(N)(=N)[C:2]1C=C[N:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH2:18])=[NH:17]>>[NH2:5][C:4]1[CH:3]=[CH:2][N:18]=[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[N:17]=1
Reactant: N=C(N)c1ccncc1
Reactant: N=C(N)c1ccccn1
Product: Nc1ccnc(-c2ccccn2)n1

Procedure:
Following the procedure described in Example A-1 but using in place of isonicotinamidine a molar equivalent quantity in the appropriate pyridine carboxamidine, i.e., Q--C(=NH)NH2, the 4-amino-2-Q-pyrimidines of Examples A-10 through A-13 are obtained:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH:40]C(OC(CC)(C)C)=O)[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]>>[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added under ice-cooling to 7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added either and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an 1N aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. Excess methylene chloride in the aqueous layer was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate powder. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.128 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[O:4][CH2:3]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[O:4][CH2:3]1
Reactant: CC1(C)COC(CO)OC1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2OCC(C)(C)CO2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The (5,5-dimethyl-1,3-dioxan-2-yl)methanol (2 g, 13.7 mmol) obtained in the step (1b) was mixed with sodium hydride in oil (822 mg, 20.6 mmol as the content was regarded as 60%) and dimethylsulfoxide (20 ml). The mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (2.16 g, 13.7 mmol) was added and stirred at 50° C. overnight, and further allowed to stand still for one day at room temperature. After dimethylsulfoxide was distilled off, methanol and NH silica gel were added to the residue and then methanol was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9) to obtain the title compound (3.1 g, yield: 84.6%) as a light yellow oil.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][CH:4]([C:8]([O:10]C)=[O:9])[CH2:5][CH2:6]2.[CH3:12][CH:13]([OH:24])[CH2:14][O:15][CH:16]([CH2:18][O:19][CH:20]([CH2:22][OH:23])[CH3:21])[CH3:17]>CCCCCCC>[O:1]1[CH:7]2[CH:2]1[CH2:3][CH:4]([C:8]([OH:10])=[O:9])[CH2:5][CH2:6]2.[CH3:12][CH:13]([OH:24])[CH2:14][O:15][CH:16]([CH2:18][O:19][CH:20]([CH2:22][OH:23])[CH3:21])[CH3:17]
Reactant: COC(=O)C1CCC2OC2C1
Agent: CC(O)COC(C)COC(C)CO
Solvent: CCCCCCC
Product: O=C(O)C1CCC2OC2C1
Temperature: 107.5 °C
Reaction time: 6.75 h

Procedure:
Methyl 3,4-epoxycyclohexanecarboxylate (50 g), and tripropylene glycol (33.8 g) in 60 milliliters (“mL”) of heptane were heated in a flask equipped with a 120-mL insulated Vigreaux column, Dean-Stark trap, drying tube and magnetic stirrer. The Dean-Stark trap was pre-filled with heptane. After refluxing the heptane for 60 minutes to azeotropically remove any water moisture, 0.0340 g of anhydrous sodium acetate (406 ppm by weight based on undiluted starting materials) was added as a transesterification catalyst. Methanol/heptane azeotrope was collected in the Dean-Stark trap and heating was continued for 405 minutes. The reaction temperature gradually increased from 102 to 113° C. during the course of the reaction, and the lower (methanol-rich) layer had a volume of 20.2 mL. Heating was continued and a nitrogen sparge was used to help remove any remaining heptane solvent by distillation. The product was allowed to cool to room temperature. The product consisted of 86 wt % of the mono and diepoxide adducts of tripropylene glycol, 0.8 wt % residual monoepoxide, and 14 wt % higher oligomers by uncorrected size-exclusion chromatography using THF solvent and a refractive index detector. Purity by gas chromatography was 88%. The viscosity of the product was 380 centipoise (cP) and the epoxy equivalent weight (titration) was 245 (theoretical 230). The product resin was formulated into a photo-crosslinkable material without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1.Cl>C(Cl)Cl>[CH3:13][C:7]1([CH3:14])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][C@H:49]3[CH2:53][CH2:52][O:51][CH2:50]3)=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8]1
Reactant: O[C@@H]1CCOC1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O[C@H]3CCOC3)ccc2C1

Procedure:
7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.95 g, 4.99 mmol) was dissolved in 30 ml DCM and triphenylphosphine (1.96 g, 7.49 mmol) and diisopropyl azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(−)-3-hydroxytetrahydrofuran (0.600 ml, 7.49 mmol) was added. The mixture was stirred over night. 0.5M HCl (aq.) was added and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30% EtOAc in Hex.) provided (S)-3,3-dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-dihydronaphthalen-1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl.O>ClCCl.C(Cl)(Cl)Cl>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
4-Hydroxybenzaldehyde (500 mg, 4.09 mmol) and diisopropylethylamine (2.85 mL, 16.4 mmol) were dissolved in dichloromethane (10 mL). To this, chloromethyl methyl ether (614 μL, 8.09 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 8 hours. Then, water was added to the reaction mixture, and extraction with chloroform was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 4-methoxymethoxybenzaldehyde (658 mg, yield: 97%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:13][C:14]([OH:16])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: O=C(O)COc1cccc2cccnc12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of quinolin-8-ol (500 mg, 3.45 mmol) in MeCN (5 mL) was added ethyl bromoacetate (687 mg, 4.14 mmol) and K2CO3 (952 mg, 6.90 mmol). The mixture was stirred at 80° C. for 4 hours until TLC analysis showed completion of the reaction. The mixture was filtered and the filtrate concentrated. NaOH (276 mg, 6.90 mmol) and water:EtOH (1:1, 10 mL) was then added to the residue and the resulting mixture stirred at 50° C. for 4 hours. After cooling, the mixture was acidified by addition of 1M HCl to pH 3 and then extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to yield the crude target product which was used directly for the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSc2ccc(C(=O)NC3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
Trifluoroacetic acid (1.73 mL, 22.20 mmol, 15.0 eq) is added at 0° C. to a stirred solution of 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 1.48 mmol, 1.0 eq) in dichloromethane (20 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid piperidin-4-ylamide as a light brown solid (244 mg, 51% yield).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:17][CH:16]([OH:18])[CH2:15][CH:14]2[CH2:13][O:12][N:11]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH:7]=[CH:8][CH:9]=1.[CH3:30]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:17][CH:16]([O:18][CH3:30])[CH2:15][CH:14]2[CH2:13][O:12][N:11]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(CN2OCC3CC(O)CC32c2cccc(Br)c2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2OCC3CC(OC)CC32c2cccc(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.9 %

Procedure:
Sodium hydride (0.076 g, 1.89 mmol) is added to a 0° C. solution of racemic (3aRS,5RS,6aSR)-6a-(3-bromophenyl)-1-(2,4-dimethoxybenzyl)hexahydro-1H-cyclopenta[c]isoxazol-5-ol (0.684 g, 1.57 mmol) in DMF (7 mL). The reaction is warmed to room temperature for 10 minutes and then cooled to 0° C. Methyl iodide (0.246 g, 1.73 mmol) is added and the reaction is stirred at room temperature for 6 hours. Additional sodium hydride (0.032 g, 0.790 mmol) and methyl iodide (0.112 g, 0.790 mmol) is added and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The resulting residue is purified by silica gel chromatography with 10% ethyl acetate in CH2Cl2 to give the title compound (0.443 g, 63%). ES/MS m/e (79Br/81Br) 448, 450 (M+1).