Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.CO.[H][H]>[Pd].C(O)(=O)C>[OH:24][C@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 14 h
Yield: 66.5 %

Procedure:
A mixture of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (33.7 g, 84.7 mmol), methanol (60 ml), acetic acid (60 ml), and 10% palladium on carbon (6 g) was treated with hydrogen gas (40 psi) on a Parr shaker. After 14 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol/ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-3-methylxanthine (15 g).
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:35])([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])=[CH:11][CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:7]([CH3:35])(=[NH:6])=[O:8])=[CH:14][CH:13]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[S:29][CH:30]=[N:31][N:32]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3nncs3)ncnc2cc1OCc1ccc(S(C)(=N)=O)cc1
Yield: 74 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)-phenyl]sulphoximide (33 mg, 0.064 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (21 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:38])[CH2:36][CH2:35]1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Reactant: O=C(Cl)C1CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:43][CH:44]1[C:65](=[O:66])[N:46]2[C:47]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])=[C:48]([OH:51])[CH2:49][S:50][C@H:45]12>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:10]([NH:43][CH:44]2[C:65](=[O:66])[N:46]3[C:47]([C:52]([O:54][CH2:55][C:56]4[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=4)=[O:53])=[C:48]([OH:51])[CH2:49][S:50][C@H:45]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-propoxyiminoacetic acid (syn isomer, 0.515 g.), N,N-dimethylformamide (0.161 g.), phosphoryl chloride (0.337 g.) and ethyl acetate (7.9 ml.) were treated in a similar manner to that of Example 15-(1) to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.60 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.703 g.) in ethyl acetate (10 ml.), and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above at -10° C. all at once, and stirred at the same temperature for an hour. To the resultant solution were added water (20 ml.) and ethyl acetate (20 ml.). The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (8 ml.) and water (14 ml.) and dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was pulverized with diethyl ether, and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-propoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.75 g.).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1.C(Cl)[Cl:28].Cl.O1CCOCC1>>[ClH:28].[NH:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1
Reactant: ClCCl
Reactant: COC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc2nccn2c(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
In a 100 mL flask, methyl 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.477 g, 1.28 mmol) (Example 45; Step C) was dissolved in DCM (12.8 mL, 1.28 mmol). To this was added 4N HCl in dioxane (4.79 mL, 19.2 mmol). After stirring at ambient temperature for 4 hours, the reaction mixture was concentrated down to remove solvents. The resultant solid was diluted in DCM, sonicated and filtered to afford 0.363 g (100% yield) of the HCl salt as a light yellow solid. MS (apci) m/z=244.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][N:23]=[CH:22]5)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(#N)C>[C:36]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:8]([C:7]5[C:2]([F:1])=[C:3]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH:4]=[CH:5][C:6]=5[F:28])=[O:9])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc5[nH]ncc5c4)cc23)c1F
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc5c(cnn5C(C)=O)c4)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a round bottom flask, propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-0001, 0.020 g, 0.040 mmol) is combined with acetic anhydride (0.023 mL, 0.24 mmol) and 4 mL of acetonitrile. The reaction is stirred at room temperature for 3 hours, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of 20-100% ethyl acetate (with 2% acetic acid) in hexanes. Appropriate fractions are combined and concentrated under vacuum, and the resulting solid is further washed with a mixture of ethyl acetate:hexanes to provide the desired compound. MS (ESI) [M+H+]+=538.0.
Reaction SMILES: C1(=O)OC(=O)CC1.NC1C=C(O)C=CC=1.[C:16]1(=[O:29])[N:20]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[C:19](=[O:28])[CH2:18][CH2:17]1.[OH-].[Na+].Cl[CH2:33][CH2:34][CH2:35][Si:36]([O:41][CH3:42])([O:39][CH3:40])[O:37][CH3:38]>O.C1(C)C=CC=CC=1.CS(C)=O.C(O)(=O)C>[C:16]1(=[O:29])[N:20]([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[O:27][CH2:33][CH2:34][CH2:35][Si:36]([O:41][CH3:42])([O:39][CH3:40])[O:37][CH3:38])[C:19](=[O:28])[CH2:18][CH2:17]1
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: O=C1CCC(=O)N1c1cccc(O)c1
Agent: Nc1cccc(O)c1
Agent: O=C1CCC(=O)O1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CO[Si](CCCOc1cccc(N2C(=O)CCC2=O)c1)(OC)OC
Temperature: 25 °C

Procedure:
A solution containing 200 g of succinic anhydride, 218 g m-aminophenol and one liter of glacial acetic acid was heated at the boiling point for 16 hours in a reactor equipped with a mechanically driven stirrer and a water-cooled reflux condenser. The reaction mixture solidified upon cooling to ambient temperature. The solid was pulverized, washed with water to remove the acetic acid, then dried. The resultant m-succinimidophenol (105.1 g, 0.55 mole) together with 43.28 g of a 50% by weight aqueous solution of sodium hydroxide, 112 cc dimethylsulfoxide and 120 cc toluene were placed in a reactor equipped with a nitrogen inlet, water-cooled reflux condenser and Dean-Stark trap. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowed to cool to about 75° C., at which time 109 g (0.56 mole) of 3-chloropropyl trimethoxysilane was added dropwise while the reaction mixture was stirred. Following completion of the addition the reaction mixture was heated at 115° C. for about 16 hours, following which the mixture was allowed to cool and was filtered to remove any solid material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to 0.5 mm of mercury and the material boiling at 228° C. was collected. Analysis by vapor phase chromatography indicated that the purity of the product, a white solid, was greater than 98%. The infrared and nuclear magnetic resonance spectra of the product were consistent with the proposed structure.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O.C(OCC)(=O)C>[CH3:32][N:33]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)=[O:3])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCCOc1ccc2c(c1)CCC(=O)N2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, and then 1.0 ml of ethyl chloroformate is added dropwise to this solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.1 ml of N-methylaniline, followed by additional 2-hour agitation. The reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from chloroform-petroleum ether to obtain 2.2 g of 6-[3-(N-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needlelike crystals, m.p. 129.5°-131.5° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:36][CH2:35][CH:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([N:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]3=[O:1])[CH2:16][CH2:15]2)[CH:18]=1)=[O:25]
Reactant: OCC1Cc2ccccc2N1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1c2ccccc2CC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.25 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of trans [4-(2-cyano-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.68 g, 10.6 mmol) in DCM (30 mL) was treated with trifluoroacetic acid (30 mL) and the mixture was stirred at ambient temperature for 30 mins then concentrated under vacuum. The residue was azeotroped with toluene (×3) and the resulting oil was triturated (diethyl ether) to give a solid, that was washed with ether and dried to give 2.75 g (97%) of trans 3-(4-amino-cyclohexyl)-propionitrile trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.88 (br s, 3H), 3.01 (m, 1H), 2.37 (t, 2H), 2.08 (m, 2H), 1.89 (m, 2H), 1.59 (q, 2H), 1.49-1.35 (m, 3H), 1.04 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.C[O-].[Na+]>CO>[Cl:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:2][C:3]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COc1cccc(C(=O)O)c1CBr
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1cccc(C(=O)O)c1C=Cc1cccc(Cl)c1

Procedure:
For the synthesis of the title compound, 45.6 g (0.186 mol) of 2-bromomethyl-3-methoxybenzoic acid, 48.8 g (0.186 mol) of triphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0 g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by method I. Purification is carried out by recrystallization from methanol with water.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CN([CH:23]=[O:24])C>C1COCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:23]=[O:24])[CH3:16]
Reactant: CCOC(OCC)c1ccncc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccncc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
BuLi (5.84 mL, 9.35 mmol) was added to a solution of 3-bromo-4-diethoxymethyl-pyridine (2.21 g, 8.50 mmol) in THF (50 mL) at −78° C. After 1 h, DMF (6.58 mL, 85 mmol) was added. The reaction was stirred at −78° C. for 1 hr. It was then warmed to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of 4-diethoxymethyl-pyridine-3-carbaldehyde, which was taken in the next step without further purification. MS (ESI) m/z 210.1 (M+H)+
Reaction SMILES: [OH:1][C@@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C@@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:3]1)(=[O:29])[CH3:28]
Reactant: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-21-methoxy-5α-pregnane-11,20-dione (0.2 g.) in pyridine (1.0 ml.) was treated with acetic anhydride (0.2 ml.) at room temperature for 16 hours. The mixture was then partitioned between ether and 2N-hydrochloric acid and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from acetone/petroleum ether to give 3α-acetoxy-21-methoxy-5α-pregnane-11,20-dione (0.17 g.) as white needles; m.p. 93°; [α]D + 107°, (c 0.7).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](=[C:15]2[S:19][CH:18]=[CH:17][S:16]2)[C:11](=[O:20])[C:10](C)([C:21](OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>C(O)C>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:21])[C:11](=[O:20])[C:12](=[C:15]2[S:19][CH:18]=[CH:17][S:16]2)[C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C)CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-3-methyl-4,6-dioxopiperidine-3-carboxylate (245 mg) is dissolved in ethanol (5 ml), and thereto is added a 10% sodium hydroxide solution (2.5 ml). The mixture is stirred at room temperature overnight. The mixture is acidified with 10% HCl, and poured into water. The aqueous solution is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is dissolved in ethanol (20 ml) and the solution is refluxed for one hour. The mixture is distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:1), and is recrystallized from a mixture of ethyl acetate and n-hexane to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-5-methyl-2,4-dioxopiperidine (138 mg, 69.1%) as pale yellow needles, m.p. 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]([OH:31])[C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:31][CH:15]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([F:1])[CH:12]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)COc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Agent: [H-]
Agent: [Na+]
Product: O=C(O)COc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2-fluoro-phenoxy)acetic acid is prepared from 2-(2-fluoro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]3[NH:20][C:29](=[O:30])[O:22][N:21]=3)[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(N)=NO)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(-c2noc(=O)[nH]2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxamidoxime (124 mg) in tetrahydrofuran (1.7 mL) were added 1,1′-carbonyldiimidazole (57 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (53 μL). This mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 1,1′-carbonyldiimidazole (27 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (25 μL), followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound (116 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 5.55 (2H, s), 6.55-6.70 (2H, m), 6.77 (1H, dd, J=2.4, 8.9 Hz), 7.15 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.9 Hz), 7.35-7.55 (5H, m), 7.75-7.90 (2H, m), 13.07 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(O)=[O:2].Cl.C([N:38]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(=[O:2])[NH2:38]
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(=O)O)c3Cl)c2n1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(N)=O)c3Cl)c2n1
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To a solution of 2-carboxy-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (80 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.3 mg) and 1-hydroxybenzotriazole (30.7 mg) at ambient temperature, and the mixture was stirred for 1.5 hours at the same temperature. To the mixture was added conc. ammonia solution (12 mg) at ambient temperature, and the mixture was stirred for 2 days at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 2-carbamoyl-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (31 mg) as amorphous powder.