Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[S:26][C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23](=[O:24])[N:18]3[N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:27]1([CH:33]([O:12][C:11]([C:7]2[N:8]3[C@H:3]([S:4][CH2:5][C:6]=2[CH2:14][S:15][C:16]2[S:26][C:19]4=[N:20][C:21]([CH3:25])=[CH:22][C:23](=[O:24])[N:18]4[N:17]=2)[C@H:2]([NH2:1])[C:9]3=[O:10])=[O:13])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Solvent: CC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a suspension of the product obtained in Step 1 (4.9 g) in acetone (40 ml) was added diphenyldiazomethane (8.2 g), and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate ws concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.94 g of the objective compound as yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
60 mg (0.14 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 35 mg (0.22 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reatced according to the General Method 2. Yield: 35 mg (45% of theory)
Reaction SMILES: [NH2:1][CH:2]([CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]([NH:1][CH:2]([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C(N)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)C(c1ccccc1)c1ccccc1)C(Sc1cccc(OC)c1)c1cccc(OC)c1

Procedure:
A solution of 0.94 g (2.7 mmol) of (R,S; R,S)-2-amino-3-(3-methoxyphenyl)-3-(3-methoxyphenyl-sulfanyl)propionic acid, methyl ester of Example 32, 15 mL of methylene dichloride, 0.69 g (3.2 mmol) of diphenylacetic acid, 0.62 g (3.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC), and 0.02 g (0.16 mmol) of 4-dimethylaminopyridine (DMAP) is stirred at room temperature for 18 hours. The reaction solution is diluted with 100 mL of methylene dichloride, washed with 80 mL of 1N sodium hydroxide and then 80 mL of 1N hydrochloric acid, dried (magnesium sulfate), and evaporated. The residue is purified via silica gel chromatography eluting with 25% ethyl acetate-hexane to give the product as an inseparable mixture of diastereomers; wt 1.10 g (90%);
Reaction SMILES: [ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:44]=1)(=[O:23])=[O:22]>>[ClH:1].[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:32]([C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[CH:19][CH:18]=3)=[C:31]([C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[S:30][C:29]=2[CH:44]=1)(=[O:22])=[O:23]
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Agent: Cl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCOCC3)cc2)cc1

Procedure:
The process of Example 7 was used to prepare the above product, starting with 7.2 g. of 4-(2-morpholinoethoxy)benzoic acid, hydrochloride, and 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene. A yield of 4.25 g. of recrystallized product was obtained, of which 1.25 g. was purified by chromatography as explained in Example 7 above to obtain 0.9 g. of highly purified product, m.p. 197°-200°.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C@@H:20]([C@H:23]1[CH2:27][O:26][C:25]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[O:24]1)[CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[CH2:12]([O:19][C@@H:20]([C@H:23]1[CH2:27][O:26][C:25]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[O:24]1)[CH:21]=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
15.0 g of pyridinium chlorochromate and 10.0 g of crushed 3A molecular sieves were added to a solution of 5.50 g (0.019 mol) of β(R)-benzyloxy-1,4-dioxaspiro[4,5]-decane-2(R)-ethanol in 200 ml of dichloromethane. The mixture was stirred at room temperature for 20 hours, then diluted with 200 ml of diethyl ether and filtered. The filtrate was evaporated to give 4.30 g of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]1[S:10](=[O:12])(=[O:11])[O:9][CH2:8][CH2:7][CH2:6]1>CO>[CH2:1]([NH:4][CH:5]([S:10]([OH:12])(=[O:11])=[O:9])[CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: O=S1(=O)CCCCO1
Reactant: C=CCN
Solvent: CO
Product: C=CCNC(CCC)S(=O)(=O)O
Yield: 36.3 %

Procedure:
A solution of 57 g of allylamine and 136 g of butanesultone in 1 l of methanol was stirred a room temperature for 48 h. After evaporation, washing of the residue with ether and drying under vacuum, 70 g of N-allyl-aminobutane sulphonic acid were obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[OH:4].[OH-].[K+].I[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH2:34][C:35]([NH2:37])=[O:36])[CH:21]=1)([OH:4])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:9]=[CH:8]2
Reactant: NC(=O)CI
Reactant: OC(c1ccc2c(cnn2-c2cccnc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3cccnc3)c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a chilled (0° C.) solution of 45 mg (0.11 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(1-pyridin-3-yl-1H-indazol-5-yl)ethanol in 5 mL of DMF was added 13 mg (0.17 mmol) of powder KOH followed by 31 mg (0.17 mmol) of iodoacetamide. The mixture was stirred over night at room temperature, poured onto ice water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, adsorbed on to silica gel and purified by Combiflash chromatography using EtOAc/hexanes (0-80% gradient, product eluted at 40% EtOAc) to provide a colorless film. The material from the column was crystallized from EtOAc-hexanes to afford 20 mg (39%) of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]([OH:8])[CH3:7])=[O:5].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:8][C@@H:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])(=[O:19])=[O:18]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)OS(C)(=O)=O
Temperature: 20 °C
Yield: 96.6 %

Procedure:
To a solution of (L)-ethyl lactate (124 g, 1.05 mol) and triethyl amine (126 g, 1.25 mol) in toluene at 10-15° C. was added methanesulfonyl chloride (124 g, 1.08 mol) dropwise for about 2 hours. The mixture was allowed to warm to about 20° C. and the solid was filtered off. The solution was washed with water and dried, concentrated to afford the product (S)-ethyl 2-(methylsulfonyloxy)propanoate (199 g, yield 96.7%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C@@H:15]([OH:36])[CH2:14][CH:13]=1)(=O)C.[OH-].[K+]>ClCCl>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([OH:36])[CH2:14][CH:13]=4)[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH2:27][C:26]=2[CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3C1=CC[C@@H]2O
Yield: 94.2 %

Procedure:
2.16 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17β-ol is saponified with 38 ml of 1N methanolic potassium hydroxide solution overnight at room temperature. The reaction mixture is poured into ice cold saturated common salt solution, the precipitate is suctioned off, taken up in dichloromethane, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 1.86 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),14-tetraen-17β-ol is obtained as foam.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:10]2[Cl:29].[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[OH:37])[CH:8]=2)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Reactant: Cn1cncc1C(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.49 mL, 1.2 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (0.500 g, 1.23 mmol, Intermediate 5: step d) in dry THF (20.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (230.9 mg, 1.233 mmol, Intermediate 6: step b) in dry THF (1.5 mL) was added dropwise. The reaction was stirred for 2 minutes, then moved into an ice bath for 7 minutes, and finally allowed to warm to ambient temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water/brine and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc), followed by reverse phase chromatography (ACN/H20+0.05% TFA). Product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54 (d, J=3.9 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.84 (dd, J=9.5, 7.7 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=14.1, 5.4 Hz, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.22 (d, J=1.1 Hz, 1H), 3.51 (q, J=14.6, 7.3 Hz, 4H), 3.25 (s, 3H), 1.05 (t, J=7.0 Hz, 6H); MS m/e 514.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([C:14]1[CH:29]=[C:28]([C:30](=[NH:33])[NH:31]O)[CH:27]=[C:26]([CH3:34])[C:15]=1[O:16][CH2:17][C@@H:18]([OH:25])[CH2:19][NH:20][C:21](=[O:24])[CH2:22][OH:23])[CH3:13]>>[CH2:12]([C:14]1[CH:29]=[C:28]([C:30]2[N:33]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=3)[O:10][N:31]=2)[CH:27]=[C:26]([CH3:34])[C:15]=1[O:16][CH2:17][C@@H:18]([OH:25])[CH2:19][NH:20][C:21](=[O:24])[CH2:22][OH:23])[CH3:13]
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3cc(C)c(C=O)s3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.92 min; [M+1]+=460.17; 1H NMR δ 1.22 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.65 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.20-3.28 (m, 1H), 3.39-3.47 (m, 1H), 3.70-3.80 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.76 (s, 2H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:44])=[O:3])=[CH:10][CH:11]=4)[N:19]=3)=[CH:25][CH:26]=2)[CH:31]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C

Procedure:
Under nitrogen, 2-(4-{2-[2-(3′,5′-bis-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}-phenoxy)-2-methyl propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 H and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (N2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.1 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.08 (d, 2H), 8.01 (s, 2H), 7.83 (s, 1H), 7.62 (d, 2H), 6.88-6.76 (m, 4H), 4.17 (t, 2H), 2.98 (t, 2H), 2.40 (s, 3H), 1.52 (s, 6H); MS (EI) 594.2 (M+H)+.
Reaction SMILES: [C:1]([CH:5]([C:9]([F:11])=[O:10])[C:6]([F:8])=[O:7])([F:4])([F:3])[F:2].[CH2:12](N(CC)CC)C.S(OC)(OC)(=O)=O>CCOCC>[CH3:12][C:5]([C:1]([F:4])([F:3])[F:2])([C:6]([F:8])=[O:7])[C:9]([F:11])=[O:10]
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CC(C(=O)F)(C(=O)F)C(F)(F)F
Reaction time: 3 h
Yield: 48.9 %

Procedure:
A solution of 17.6 g (0.10 mol) of CF3CH(COF)2 in 25 ml of ether was cooled at 0°C and stirred while 9.2 g (0.10 mol) of triethylamine was added dropwise in 15 minutes. Then 25.2 g (0.20 mol) of dimethyl sulfate was added all at once, and the mixture was allowed to stand at 25°C for 3 hours. Distillation gave 9.3 g (49%) of methyltrifluoromethylmalonyl fluoride, bp 62°-65°C. Redistillation gave an analytical sample, bp 64°-65.5°C; ir and nmr spectra were taken on a similarly prepared sample; ir (CCl4): 5.37 (COF) and 7.5-8.5 μ (CF); nmr (CCl4): 1H at 1.92 ppm (broadened singlet, CH3); 19F at 37.8 (quartet, JFF = 10 Hz into quartets, JHF = 1 Hz, 2, (COF) and -71.1 ppm (triplet, JFF = 10 Hz, into quartets, JHF = 0.8 Hz, 3, CF3).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH3:21].[Li+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])(=[O:30])=[O:31])=[CH:25][CH:24]=1)[CH3:19]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CN(C)Cc1ccc(S(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN(C)C)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv), lithium 4-((dimethylamino)methyl)benzenesulfinate (3.075 g, 15.00 mmol, 1.50 equiv) and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water (150 mL) was added and the resulting solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 0.9 g (16%) of methyl 4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoate as a light yellow solid. LC-MS: (ES, m/z): 429 [M+H]+, 175, 120.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.C1COCC1>[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC(c2ccccc2)c2ccccc21
Yield: 50 %

Procedure:
Keeping the temperature at -5° C., to a suspension of 5.0 g (0.131 moles) of LiAlH4 in 300 ml of ethyl ether, 35 g (0.168 moles) is added of 3-phenyl-1-indanone dissolved in 50 ml of THF. The oil obtained by evaporating ether (40 g), is dissolved in 300 ml of toluene containing 20 g of Sio2 and kept refluxing for 2 hours, with formed water being distilled off. The resulting mixture is filtered, the solvent is evaporated and by distillation 18 g is obtained (yield of 50%) of 1-phenylindene boiling at 95-100° C./0.2 mm Hg.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[N:10]([CH2:19][C:20]#[CH:21])([Si:15]([CH3:18])([CH3:17])[CH3:16])[Si:11]([CH3:14])([CH3:13])[CH3:12].I[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:10]([CH2:19][C:20]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[Si:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Si](C)(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#CCN([Si](C)(C)C)[Si](C)(C)C
Yield: 177.9 %

Procedure:
A reactor with a capacity of 40 mL, equipped with a magnetic stirrer was filled, under argon atmosphere, with 0.0085 g (0.015 mmol) of [{Ir(μ-Cl)(CO)2}2], and then with 25 mL of anhydrous and deoxidized toluene and 0.7 g (5.4 mmol) of NEt(i-Pr)2. The whole mixture was stirred until the starting iridium(I) complex was dissolved, and then 0.598 g (3 mmol) of (Me3Si)2NCH2C≡CH and 0.96 g (4.8 mmol) of ISiMe3 were added to the resulting mixture. The reaction was carried out at a temperature of 80° C. until complete conversion of (Me3Si)2NCH2C≡CH. After the reaction was completed, in order to remove the catalyst from the reaction mixture the solvent was evaporated at a reduced pressure along with any residual unreacted substrates, and then anhydrous pentane was added to the residue. The resulting suspension was filtered and the resulting deposit was rinsed with two portions of a solvent. The solvent was initially evaporated from the filtrate, and the residual product was distilled by means of the “trap-to-trap” technique at a reduced pressure to obtain 1.45 g of 1-(N,N-bis(trimethyl-silyl)amino)-3-trimethylsilylprop-2-yne, obtained with a yield of 96%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH3:28]>>[CH2:27]([N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[CH3:28]
Reactant: CCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CCN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and ethyl bromide, to give the desired product as white solid (78%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[C-]#N.[Na+].[CH3:15][N:16](C)C=O>O>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:11]=[CH:10][C:6]1=2
Reactant: BrCc1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc2sccc2c1
Yield: 55 %

Procedure:
In a round bottom flask was placed 5-bromomethyl-benzo[b]thiophene (5.27 g, 23.20 mmol), sodium cyanide (1.59 g, 32.49 mmol) and N,N-dimethylformamide (50 mL) and it was stirred for 24 h at 25° C. After this time, the reaction mixture was dissolved in water (30 mL) and extracted with ethyl acetate (3×30 mL), dried over sodium sulfate and purified on an AnaLogix Intelliflash system (120 g column, 3% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to afford benzo[b]thiophen-5-yl-acetonitrile (2.23 g, 55%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]I>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and MeI (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).