Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[CH2:11])[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].[OH-].[Li+].S([O-])(O)(=O)=O.[K+]>O1CCCC1.O>[CH3:1][S:2]([CH2:5][C:6](=[CH2:11])[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: C=C(CS(C)(=O)=O)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of methyl 2-(methylsulfonylmethyl)acrylate (970 mg, 5.44 mmol) in 15 mL of tetrahydrofuran was treated with a solution of lithium hydroxide (270 mg, 6.4 mmol) in 7 mL of water. The solution was stirred at room temperature for 5 m and then acidified to pH=1 with 1 N aqueous potassium hydrogen sulfate and the solution extracted three times with ethyl acetate. The combined ethyl acetate solution was dried over anhydrous. magnesium sulfate, filtered, and concentrated to give 793 mg, 89% of 2-(methylsulfonylmethyl)acrylic acid, mp 147-149° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Oc1ccccc1
Yield: 67.4 %

Procedure:
Using the general method of Example 47, phenyl chloroformate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of phenyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a solid. Analysis: Calculated for C24H28N6O2: % C, 66.65; % H, 6.53; % N, 19.43; Found: % C, 66.49; % H, 6.59; % N, 19.32.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].BrC1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].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.CO>[CH2:24]([C:5]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]2[CH:3]=[CH:2][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: Brc1ccccc1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a stirred mixture of 9,9-dioctyl 2,7-fluorenediboronate (27.42 g, 51.2 mmol), 2,7-dibromo-9,9-dioctylfluorene (27.43 g, 50 mmol) in toluene (450 mL) under nitrogen are added sequentially the phase transfer catalyst, Aliquat® 336 (1.4 g, 3.4 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.032 mmol), and 2M aqueous sodium carbonate (80 mL, 160 mmol). The mixture is stirred and heated under gentle reflux for 20 hours when a viscous reaction mixture is observed. One gram of bromobenzene is added and stirring and heating continued for 5 hours. The reaction mixture is cooled to about 50° C., added slowly to a vigorously stirred mixture of 3.5 L of methanol and 200 mL of 1N aqueous HCl. The polymer fibers are collected by filtration, washed successively with methanol (1 L), deionized water (500 mL), and methanol (1 L), and dried in a vacuum oven at 60° C. for 16 hours. The polymer weighed 39 g (100% yield). The inherent viscosity of the polymer is found to be 1.65 dL/g (THF, 25° C., 0.5 g/dL). The polymer is purified further by passing a toluene solution of the polymer through a column of silica gel and re-precipitation from 4 L of methanol. The purified polymer weighs 37 g (95% yield).
Reaction SMILES: [C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([NH:15]S(C(C)(C)C)=O)[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(NS(C(C)(C)C)=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl.[NH4+].[OH-]>O1CCOCC1.O>[NH2:15][C:10]([C:22]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([C:8]1[NH:7][C:6]2[CH:49]=[CH:50][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)[C:11]([F:14])([F:13])[F:12]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 36-D) (0.37 g, 0.504 mmol) in dioxane (5.04 mL) was added HCl (4.0M in dioxane) (2.52 mL, 10.08 mmol) and this was stirred at room temperature. After 15 minutes this was cooled in an ice bath, neutralized with 30% aq. NH4OH (2.52 mL), diluted with water, extracted twice with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 500.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.C([O-])(=O)C.[K+]>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>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Reactant: c1ccc2scnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 170 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (300 mg, 0.98 mmol) in 1,3-benzothiazole (266 mg, 1.97 mmol) was added Pd(PPh3)4 (57 mg, 0.05 mmol,) and potassium acetate (193 mg, 1.97 mmol) under an atmosphere of nitrogen. The resulting solution was stirred for 2 h at 170° C. and then quenched by the addition of NH4Cl solution (150 mL), extracted with dichloromethane (3×20 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-5% ethyl acetate in petroleum ether to afford methyl 2-(1,3-benzothiazol-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (80 mg, 20%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:19][N:18]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCSc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2nnc(SCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Yield: 98.1 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.42 g of ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl]thio]butyrate, 0.59 g of oily ethyl 4-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]butyrate was obtained in a manner similar to Example 1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)NCC=Cc1ccc2oc(=O)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Product: NCC=Cc1ccc2oc(=O)[nH]c2c1

Procedure:
A solution of 5-(3-(t-butoxycarbonylamino)-1-propenyl)-2-benzoxazolone in trifluoroacetic acid is stirred at ambient temperature for 30 min, then evaporated to dryness to yield 5-(3-amino-1-propenyl)-2-benzoxazolone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1.BrCC1C=CC=C(F)C=1>>[F:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([F:20])[CH:16]=1)[CH2:12][O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2cc(F)cc(F)c2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromomethyl-3,5-difluoro-benzene according to the procedure from Example 199A substituting 1-bromomethyl-3,5-difluoro-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [Na].[H-].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1>CN(C=O)C.O.C(OCC)(=O)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:34])=[C:23]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:16][CH:15]=1)#[N:14]
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Agent: [H-]
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium, hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and benzoic acid 5-bromomethyl-2-fluoro-phenyl ester (CAB02146, 1.55 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.32) to give a white solid. Yield: 1.16 g (56%). 1H-NMR (400 MHz, CDCl3) δ=4.91 (s, 2H), 6.67 (d, J=9.0 Hz, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 7.18 (dd, J=9.4, 8.6 Hz, 1H), 7.24 (dd, J=7.0, 2.3 Hz, 1H), 7.49-7.56 (m, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H). LRMS (FAB+): 414.2 (100, [M+H]+).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1)=[O:2].N([O-])=O.[Na+]>O>[C:3]1([S:1]([OH:11])(=[O:10])=[O:2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccccc1
Temperature: 60 °C

Procedure:
1.384 g of sulfanilic acid were mixed with 50 ml of deionized water in a beaker and heated to 60° C. 5 g of SP-3 particles were added to the mixture. 2.76 g of a 20% solution of sodium nitrite in water were added slowly, and the mixture was left to react for 90 minutes. The reaction mixture was filtered and the particles were reslurried and washed with a 1% NaOH solution in water. The particles were refiltered and washed with deionized water, and subsequently washed with ethanol and tetrahydrofuran. The particles were soxhlet extracted in ethanol overnight. The starting sulfur content of the particles was 0.39 wt %. After the surface modification the sulfur content was 1.39 wt % indicating the attachment of benzenesulfonic groups.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[C:25]([NH:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccccc1

Procedure:
1.3 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1 was dissolved in 80 ml of dimethylformamide. To this solution was added 1.2 g of triethylamine, then under an ice-cooled condition, 0.8 g of benzoyl chloride was added dropwise thereto. The reaction mixture was stirred under an ice-cooled condition for 3 hours, then the reaction mixture was concentrated under a reduced pressure, to the residue thus obtained was added water, the crystals formed were collected by filtration. Recrystallized from ethanol-water to obtain 0.5 g of 2-benzamido-3-(oxindol-3-yl)propionic acid in the form of light brown powdery substance. Melting point: 140°-142° C. (decomp.) [α]D20 -66° (C=0.1, methanol)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:12].CC#N.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:19].C([O-])(O)=O.[Na+]>CO>[OH:12][N:3]1[C:2](=[O:19])[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccc(=O)n(O)c1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL round bottom flask containing 2-chloro-5-(methoxycarbonyl)pyridine 1-oxide (2.45 g, 13.06 mmol) was added MeCN (10 mL). The resulting mixture was stirred at 23° C. for 5 min. At this time, trifluoroacetic anhydride (20 mL) was added and the reaction was stirred 1 h. Solid NaHCO3 (25 g) was added to the flask followed by MeOH (100 mL). The solid was filtered away and the filtrate was concentrated and subjected to silica gel chromatography (80 g ISCO column, 0-5% MeOH in CHCl3) to give methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a yellow solid.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH:33]=O>CS(C)=O.O1CCCC1>[Cl:2][CH:3]=[CH:33][C:32]1[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=CCl)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 11.94 g of (chloromethyl)-triphenylphosphonium chloride in 85 ml of absolute dimethylsulfoxide and 170 ml of absolute tetrahydrofuran were added dropwise at 0° C., while stirring in an atmosphere of dry nitrogen, 21.5 ml of n-butyllithium solution. After stirring for 30 minutes a solution of 5.48 g of 3,4,5-trimethoxybenzaldehyde in 20 ml of absolute tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature. After about 4 hours the reaction mixture was worked up in the manner described in Example 5e. Column chromatography of the raw product with petroleum ether/ether (2:1) yielded 4.64 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]1)=[CH:15][C:14]3=[O:26].[O:28]1CCCC1>O>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][C:14](=[O:26])[C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH2:12][C@@H:7]2[O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:27])[CH3:1])[CH2:17]1
Reactant: CC(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Solvent: O
Product: CC(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 3 parts of 3β-{(1,1-dimethylethyl)dimethylsilyl] oxy}-17β-[(4-methylpentyl)oxy]androst-5-en-7-one, 45 parts of tetrahydrofuran, 15 parts of acid, and 10 parts of water is heated at approximately 60° for 48 hours, whereupon 300 parts of water is added and the resultant mixture is extracted with 1,1'-oxybisethane. The extract is washed with aqueous 5% potassium bicarbonate, dried over magnesium sulfate, and strippd of solvent by vacuum distillation. The residue is chromatographed on silica gel, using mixtures of benzene and ethyl actate (initially comprising 10% ethyl acetate and progressively increasing the proportions thereof to 25%) as developing solvent. Eluates are selected via thin layer chromatography which, upon evaporation of solvent and recrystallization of the residues from a mixture of 1,1'-oxybisethane and hexane, afford 3β-hydroxy-17β-[(4-methylpentyl)oxy]androst-5en-7-one melting at approximately 133.5°-134.5°. The product has the formula ##STR8##
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(OC([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=O)(C)(C)C.[CH2:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[CH3:35].CCN(C(C)C)C(C)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>ClCCl.CN(C=O)C>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:27][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH2:16][CH2:15][NH:14][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:26]=1)[C:21]([N:36]([CH2:34][CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])=[O:23]
Reactant: CCNc1ccccc1F
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.080 ml) and DMF (0.001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.050 g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 2 h then a solution of N-ethyl-2-fluoroaniline (0.029 g) DMAP (0.001 g) and DIPEA (0.070 ml) were added. The reaction mixture was stirred at room temperature for 16 h and then triflouroacetic acid (1 ml) was added. The solvent was removed in vacuo, the residue was subjected to preparative hplc and the required fraction dried by repetitive addition of acetonitrile and concentration under reduced pressure to give the title compound (0.020 g) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH3:15][NH:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1.O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:16]([CH2:17][CH3:18])[CH3:15])=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: CCNC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(Cl)nc1N(C)CC
Temperature: 90 °C
Yield: 44.6 %

Procedure:
A mixture of 8.2 g (35.0 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethylester, 3.7 ml (43.8 mmol) N-methylethylamine and 8.9 ml (52.5 mmol) DIPEA in NMP (25 ml) was heated in the MW to 90° C. for 1 h. Then the solution was diluted with water, a 1M aq. NaOH sol. and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 4.0 g (15.6 mmol, 44%) 6-chloro-2-(ethyl(methyl)amino)-4-methyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11](=[O:38])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22](=[O:24])[N:21](CC4C=CC(OC)=CC=4OC)[S:20]3(=[O:37])=[O:36])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11](=[O:38])[C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:23][C:22](=[O:24])[NH:21][S:20]3(=[O:36])=[O:37])=[CH:16][CH:17]=2)=[CH:39][CH:40]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccc(S(C)(=O)=O)cc4)cc3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(COC(=O)c2ccc(CN3CC(=O)NS3(=O)=O)cc2)cc1

Procedure:
90 mg (150 μmol) of the title D compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 4-methanesulfonyl-benzyl ester are stirred in 4 mL of 1:1—TFA:CH2Cl2 for 50 min. The solvent is removed and the residue triturated with 4 mL of 1:1—MeCN:H2O. This mixture is filtered through a 0.2μ disk and the solvent is removed. The resulting material is purified by LC/MS and afforded 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-methanesulfonyl-benzyl ester: 1H-NMR (DMSO-d6) δ 3.22 (3H, s), 3.71 (2H, s), 4.27 (2H, s), 5.48 (2H, s), 7.54 (2H, d, J=8.1), 7.74 (2H, d, J=8.1), 7.96 (2H, d, J=8.5), 8.01 (2H, J=8.5); [M−1]−=437.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7](CC2C=CC=CC=2)[CH2:6][C@@H:5]([CH2:15][N:16]([CH3:18])[CH3:17])[O:4][CH2:3]1>CCO.[Pd]>[CH3:1][C@@H:2]1[NH:7][CH2:6][C@@H:5]([CH2:15][N:16]([CH3:17])[CH3:18])[O:4][CH2:3]1
Reactant: C[C@H]1CO[C@H](CN(C)C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CO[C@H](CN(C)C)CN1
Temperature: 130 °C

Procedure:
{[(5S,2R)-5-methyl-4-benzylmorpholin-2-yl]methyl}dimethylamine (1 equivalent), was dissolved in EtOH and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered over a pad of Celite, and then evaporated. The desired amine was obtained in quantitative yield as a pale yellow oil. GC/MS: 128 (10%, M+−2×CH3), 58 (100%, NHCH2CHO), Rt=8.16 minutes.