Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:21][C:22]([Cl:26])([Cl:25])CO>>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH2:7][C:22]([Cl:26])([Cl:25])[Cl:21])=[O:5]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)OCC(Cl)(Cl)Cl

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate and 2,2,2-trichloroethyl alcohol were reacted according to a similar manner to that of Preparation 1 to give (S)-(2,2,2-trichloroethyl) 3-hydroxyhexadecanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=2)[N:8]=1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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>O1CCCC1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][O:18][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(CO)ccc2n1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2cc(COc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(2-Methoxy-benzylamino)-quinolin-6-yl]-methanol (200 mg, 0.680 mmol) was dissolved in 13 mL tetrahydrofurane. Phenol (70 mg, 0.745 mmol) and triphenylphosphine (200 mg, 0.763 mmol) were added at room temperature. Diisopropyl azodicarboxylate (159 mg, 0.787 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL 2N sodium carbonate. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as an off-white solid (105 mg, 41%), MS: m/e=371.4 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH:21]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2CCCCC2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis(diphenylphosphino)propane] nickel (II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. The mixture was stirred at room temperature in nitrogen atmosphere for 1 hour, followed by heating under reflux for 72 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 5 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[NH2:17]N>CO.[Ni]>[NH2:17][C:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: NN
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1ccc(N)c2c1oc1ccccc12
Reaction time: 2 h

Procedure:
Intermediate 38 (550 mg, 2.26 mmol) was taken in methanol (10 ml) and raney nickel catalyst (100 mg, 18% w/w) was added. The reaction mixture was refluxed and to this was added hydrazine hydrate (99%) solution (2 ml) slowly over a period of 10 min. The refluxing continued for 2 h. The catalyst was filtered and the filterate was concentrated and diluted with water (100 ml) and further extracted with ethyl acetate (3×25 ml). The organic layer was washed with water and concentrated to give the product as brown solid (500 mg);mp: 167-169° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH2:25])[N:21]=4)[CH:18]=3)[N:13]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O1[CH2:43][CH2:42][O:41][CH2:40]C1>>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH:25][CH2:19][C:11]5[CH:12]=[CH:43][C:42]([O:41][CH3:40])=[CH:8][CH:9]=5)[N:21]=4)[CH:18]=3)[N:13]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nc(N)ns4)ccc32)cc1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cncc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a solution of 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-3-amine (0.5 g, 0.99 mmol) in 1,4-dioxane (5 mL) was added 10% aq NaOH (2.5 mL) and the reaction was heated at 100° C. for 2 hr. The mixture was cooled to RT and was treated with ice cold water to give off white precipitate. The precipitate was filtered and washed with ice cold water and further purified by preparative HPLC (eluent: 10-70% MeCN:MeOH (1:1) in water with 0.01% TFA) to give 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (70 mg, 20%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.27 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.20 (m, 1H), 4.61 (m, 1H), 1.32 (d, J=6.4 Hz, 6H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[O:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:5]([C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:9]2[S:8][CH:7]=1)[C:32]1[O:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccco3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and 0.027 g of furane are simultaneously dissolved in 2 ml of trifluoroacetic acid; the solution is left to stand for 15 minutes at room temperature and is then diluted with an equal volume of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-Furfuryl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained, showing the following Rf values in a thin layer chromatogram (silica gel): 0.75 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([CH2:11][N:12]3[C:17]4=[N:18][C:19]([C:23]5[CH:28]=[CH:27][N:26]=[CH:25][N:24]=5)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][C:14]([CH3:30])([CH3:29])[CH2:13]3)[CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:29][C:14]1([CH3:30])[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)[N:18]=[C:17]2[N:12]([CH2:11][CH:6]2[CH2:5][C:4]3[N:3]=[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:13]1
Reactant: CC1(C)CN(CC2Cc3ccc(Cl)nc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC1(C)CN(CC2Cc3ccc(-c4ccccc4)nc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 140 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
A solution of 0.22 g (0.52 mmol) of (+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous toluene and 0.5 ml of ethanol was treated with 0.625 ml (2M solution in water) of sodium carbonate, 36 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.095 g (0.780 mmol) of phenyl-boronic acid. After being stirred for 24 h at 140° C., water was added, the mixture was extracted with dichlomethane. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to give 0.133 g of pure product obtained in the form of free base. Mp: 209–211° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1COCC1.[Br:18]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(B(O)O)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
An oven-dried, two liter, three-necked, round-bottomed flask was charged with 4-acetyl-phenylboronic acid (20 grams, 0.152 mole). While stirring, 175 ml of THF were added to the reaction mixture, followed by 700 ml of chloroform. To the resulting solution was added 5 ml of glacial acetic acid. A chloroform solution of bromine (prepared by dissolving 7 ml of bromine in 30 ml of chloroform) was added slowly to the reaction mixture at about 5° C. After the completion of the addition of bromine, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation and the residue was dissolved in 1 liter of ethyl acetate. The resulting solution was extracted with deionized water (3×200 ml) and brine (2×100 ml). The organic layer was dried over anhydrous sodium sulfate for 1 hour. The solution was then filtered and concentrated to about ⅓ of its volume. The resulting solution was kept in a freezer to crystallize the product. The solid was filtered to give an off white solid. Yield=16 grams.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10])[CH3:19]
Reactant: CCOC(=O)CC#N
Reactant: COc1cccc(C(C)=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-methoxyacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36][CH3:37])=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[CH:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH:3]1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A mixture of methyl(1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65 L of absolute ethanol and 0.65 L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165°-168° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:19][NH2:20])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:16](=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:20][N:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=NN)c2ccc(F)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 120 °C

Procedure:
A mixture of 12.1 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine hydrazone, 11.8 g of potassium carbonate and 120 ml of dimethylformamide was stirred and heated at 120° C. for 16 hrs. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give a solid. Recrystallization of the solid from ethyl acetate (twice) yielded 4.1 g (42% with concentration of mother liquor) of product, mp 162°-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:8].[N:9]([O-])=O.[Na+]>O>[Br-:8].[C:2]1([N+:1]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1
Product: [Br-]

Procedure:
Into a 4-liter three-neck flask, provided with a thermometer, a mechanical agitator, and a dropping funnel, one introduces 93 g of aniline (i.e. 1 mole), 500 ml of water and 425 g of 48% hydrobromic acid (i.e. 2.5 moles). To this mixture, maintained between 0°C and 4°C, one adds a solution of 70 g of sodium nitrite in 100 ml of water.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCCCCC.CCO>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[C@H:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OCC2C1
Solvent: CCCCCC
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OC[C@@H]2C1

Procedure:
A solution of 50 mg/mL of a mixture of diastereomers 1, 2, 4a, 5-Tetrahydro-8-[5-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-pyrazino[2, 1-c][1, 4]benzoxazine-3(4 H)-carboxylic acid phenylmethyl ester (EXAMPLE 1, Step 8) is made in the mobile phase that consisted of 35% EtOH in hexane (V/V). The solution (200 mg) is injected into a 5.1×50 cm Chiralcel OD column at 30° C. The column is eluted at 45 ml/min and monitored at 305 nm. The two diastereomers are collected using a peak recognition program and fractions are pooled appropriately. Each diastereomer is obtained at >98% diastereomer excess. Diastereomeric excess is determined on a 0.46×25 cm Chiralcel OD-H column at ambient column temperature, using the mobile phase consisted of 0.1% TEA in EtOH and the monitor set at 218 nm detection. The retention times are 58.9 and 65.6 minutes. (α=1.14; 0.2 mL/min).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH2:34][CH2:35][CH3:36])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH2:34][CH2:35][CH3:36])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(Br)CCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C(=O)OCC
Yield: 74.1 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.95 g, 3.09 mmol), butyl 3-bromo-2-oxohexanoate obtained in Example (116a) (5.1 g, 19.2 mmol), sodium bicarbonate (0.64 g, 7.6 mmol) and THF (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 1/1, 3/2, 2/1) to obtain 1.02 g of the title compound as a light yellow solid (70%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[F:10][C:11]1[CH:16]=[CH:15][C:14]([Zn+])=[CH:13][CH:12]=1.C(OCC)(=O)C.O>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=[N:4][CH:5]=1
Reactant: Fc1ccc([Zn+])cc1
Reactant: Clc1cnnc(Cl)c1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2cc(Cl)cnn2)cc1
Temperature: -65 °C
Yield: 58 %

Procedure:
To a mixture of S-chloropyridazin-3(2H)-one (7.33 g, 56 mmol) was suspended in phosphorous oxychloride (55 ml, 594 mmol) and the mixture was heated at 80° C. for 3 hours. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (50 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash column (10% ethyl acetate-iso-hexane) to yield 3,5-dichloropyridazine (5.6 g, 67%) as a pale yellow solid. A sample of 3,5-dichloropyridazine (0.43 g, 2.9 mmol) was dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to −65° C. 1,2-(Bis(diphenylphosphino)ethane)-dichloronickel(II) (0.08 g, 0.15 mmol) was added followed by 4-fluorophenylzinc bromide (11.6 ml of a 0.5 M solution in tetrahydrofuran). The mixture was warmed to −10° C. over 4 hours and poured onto a mixture of ethyl acetate/water (30 ml/10 ml). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flask column chromatography (10% ethyl acetate-iso-hexane) gave the title compound (0.35 g, 58%) as a red solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10](OC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O-:23].[Na+].N#N.[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][OH:49])=[CH:42][CH:41]=2)([CH3:39])[CH3:38])=[CH:33][CH:32]=1>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:49][CH2:48][CH2:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([C:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][O:27][C:10](=[O:11])[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:22]([OH:23])=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)=[CH:36][CH:35]=2)([CH3:39])[CH3:38])=[CH:45][CH:44]=1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[O-]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Agent: N#N
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(CCC(=O)OCCOc2ccc(C(C)(C)c3ccc(OCCOC(=O)CCc4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc2)cc(C(C)(C)C)c1O
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 896.3 %

Procedure:
Methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate (6.42 g) was added to a flask equipped with a reflux condenser heated to 65° C. with hot water. The material was heated to 140° C. under N2 with magnetic stirring. Sodium methoxide (0.054 g) was added and a vacuum (10 mm) was applied. After 15 min., the vacuum was broken with N2 and 2,2-bis[4-(2-hydroxy)ethoxyphenyl]propane (3.16 g) was added. Vacuum was reapplied and temperature was slowly increaded to 160° C. After 4 hrs., the reaction was quenched with acetic acid and crystallized from isopropanol to give 7.5 g (89%) of the desired product, mp 104°-106° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][O:8][CH3:9])=[CH:5][CH:6]=1.C([Li])CCC.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:8][CH2:7][C:4]1[S:3][C:2]([CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: COCc1ccc(Br)s1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
To a solution of 2-bromo-5-(methoxymethyl)thiophene (439 mg, 2.12 mmol) in 6 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.93 mL, 2.5 M in hexanes) dropwise. After stirring for 2 minutes at −78° C., dimethylformamide (0.82 mL, 10.6 mmol) was added in a single portion and the reaction mixture was allowed to warm to room temperature before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (3×30 mL), washed with water (2×30 mL, brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-20% ethyl acetate in hexanes) to give 5-(methoxymethyl)thiophene-2-carbaldehyde (103 mg, 31%) as an oil. Used without further characterization.