Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:18][CH3:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42]>CN(C)C=O.C(Cl)CCl>[C:40]([C@@H:41]([NH:42][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:18][CH3:19])[CH:10]=1)[CH2:43][CH2:44][S:45][CH3:46])([O:39][CH3:38])=[O:47]
Reactant: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step F (0.27 g) in dimethylformamide (10 mL) was added hydroxybenzotriazole (0.16 g), EDC (0.19 g), N-methylmorpholine (0.40 mL), and (S) methione methyl ester hydrochloride (0.203 mg). After stirring for 2 h the solution was concentrated in vacuo and the residue was partitioned with water and ethyl acetate. The ethyl acetate layer was washed with saturated sodium hydrogen carbonate, 2% potassium hydrogen sulfate and saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to yield the title compound. 1HNMR (300 MHz, CDCl3) δ 7.70 (2H, s), 7.40 (2H, m), 6.95 (1H, d, J=7 Hz), 4.94 (1H, q, J=7 Hz), 4.45 (2H, s), 3.81 (3H, s), 2.82 (3H, d), 2.59 (2H, m), 2.30 (1H, m), 2.13 (1H, m), 2.12 (3H, s), 1.46 (9H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.[N+:18]([O-])([OH:20])=[O:19].[N+]([O-])(O)=O.S(=O)(=O)(O)O>C(#N)C>[N+:18]([C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: COCc1c([N+](=O)[O-])ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred, 0° suspension of 11.20 g. (6.0 × 10-2 moles) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in acetonitrile (150 ml.) is added dropwise 83.0 g. (6.6 × 1012 moles of nitric acid) of a 5% nitric acid/sulfuric acid solution. The mixture is allowed to stir at 0° for 45 minutes, warmed to room temperature and stirred an additional two hours. The mixture is poured into 700 ml. of ice water, the organic layer separated, the acidic aqueous solution washed with methylene chloride (2 × 100 ml.) and filtered. The aqueous solution is made basic (pH 8) by the dropwise addition of 40% sodium hydroxide, the basic solution stirred for 30 minutes and the precipitate filtered under suction. The yellow solid is washed with water, then acetone and dried under high vacuum. The solid is suspended in water (350 ml.), the solution saturated with hydrogen chloride, heated to boiling and filtered. Saturated sodium chloride solution (100 ml.) is added, the mixture cooled and the precipitate isolated yielding the title product as a yellow powder.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@H:57]1[CH2:62][N:61]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:60][CH2:59][O:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:61]4[CH2:60][CH2:59][O:58][C@@H:57]([CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:62]4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OC[C@H]1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CCO1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCO[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 63.8 %

Procedure:
The title product (77 mg, 66%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 51.7 mg, 0.10 mmol) and 4-((R)-4-((R)-2-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)benzenesulfonamide (INTERMEDIATE 98, 72 mg, 0.09 mmol) were used as starting materials. The title product was used in the preparation of EXAMPLE 22 without further purification.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:37])[CH:18]([C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH3:19])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:37][N:17]([CH:18]([C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH3:19])[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:6][CH2:5][C:4]([OH:38])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)N(C)c1ccc(OCC(=O)O)c2ccccc12
Reaction time: 2 h

Procedure:
0.055 g (0.11 mmol) of the above prepared [rac]-[4-(methyl-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethyl}-amino)-naphthalen-1-yloxy]-acetic acid ethyl ester was dissolved in 0:6 ml of THF/EtOH=1/1, treated with 0.33 ml (3 eq.) of 1N NaOH, and kept at 0° C. for 2 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt afforded finally 0.040 g of the title compound as off-white solid of mp. 157-58° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=S.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)[N:11]=1.C(#[N:27])C>>[F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]([NH2:27])[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)[N:11]=1
Reactant: CC#N
Reactant: Nc1ccnc(CCCCc2c[nH]cn2)n1
Reactant: FC(F)(F)CN=C=S
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCc2c[nH]cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2,2,2-trifluoroethyl)isothiocyanate (0.43 g.) and 4-(4-[4-aminopyrimid-2-yl]butyl)imidazole (0.35 g.) was heated under reflux in acetonitrile for 18 hours. It was then evaporated to dryness and the residue purified by medium pressure liquid chromatography using a mixture of CHCl3 /MeOH/aqueous ammonia (s.g. 0.880) 15:1:0.05 v/v/v) as eluant. The appropriate fraction was evaporated to dryness and the residue of the thiourea was dissolved in concentrated ethanolic ammonia (15 ml.) and mercuric oxide (0.2 g.) added. The resulting mixture was stirred at room temperature for 30 minutes, filtered and the filtrate evaporated to dryness. The residue was dissolved in EtOH (10 ml.), treated with a small amount of hydrogen sulphide gas, filtered and the filtrate evaporated to dryness. The residue was crystallised from acetonitrile to give 4-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butyl]imidazole (0.075 g.), m.p. 191°-193°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:19][C:17]1[CH:18]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:3][CH:4]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(Br)cc1
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(-c2cncnc2)cc1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-1-(3,5-difluoro-phenyl)-3-o-tolyl-propan-1-one oxime (example 53) and pyrimidine-5-boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=430.3 ([M+H]+).
Reaction SMILES: [ClH:1].Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][NH2:12])[CH2:4]2.Cl.C(=N)(OC)C.[CH2:19]([N:21](CC)[CH2:22]C)[CH3:20]>CO>[ClH:1].[ClH:1].[CH3:20][C:19]1[N:21]=[CH:22][N:11]([CH:5]2[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]2)[N:12]=1
Reactant: NNC1CN2CCC1CC2
Reactant: CCN(CC)CC
Agent: COC(C)=N
Agent: Cl
Solvent: CO
Product: Cc1ncn(C2CN3CCC2CC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
3-Quinuclidinyl-hydrazine dihydrochloride (D5) (0.78 g, 3.6 mmol) was suspended in dry methanol (30 ml) and methyl acetimidate hydrochloride (0.40 g, 3.65 mmol) added, followed by triethylamine (1.52 ml, 3 eq). The solution was stirred for 3 h at room temperature under N2, and then evaporated to dryness under reduced pressure at a temperature not exceeding 30° C. Anhydrous triethylorthoformate (40 ml) and anhydrous pyridine (4 ml) were added, and the suspension was stirred overnight at room temperature under N2 and then refluxed under N2 for 1.5 h. The mixture was cooled, evaporated to dryness under reduced pressure and the residue was dissolved in saturated aqueous potassium carbonate solution (40 ml). The solution was extracted with ethyl acetate (2×300 ml), the organic extracts dried (Na2SO4), filtered and evaporated to dryness under reduced pressure. The resulting oil was purified by column chromatography using neutral alumina and with gradient elution using ethyl acetate to 2% methanol in ethyl acetate. The resulting clear oil was crystallised as the dihydrochloride salt using diethyl ether/methanol solution and recrystallised in acetone/ether to afford the title compound as white crystals (110 mg, 13%), m.p. >250° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[N:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C(CC(=O)O)CC(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC(CC(=O)O)c1ccc(N=C=S)cc1
Temperature: 40 °C

Procedure:
11.5 g (100 mmol) of thiophosgene is added to 22.12 g (100 mmol) of 3-(4-aminophenyl)-glutaric acid in 300 ml chloroform and heated for 50 minutes at 40° C. It is evaporated to dryness and the residue is crystallized from a little isopropanol/ether.
Reaction SMILES: [NH:1]([C:8]1([CH3:36])[CH:13]([C:14]([O:16]C(C2CC2)C)=[O:15])[N:12]2[C:22](=[O:35])[CH:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:11]2[S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH:1]([C:8]1([CH3:36])[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:22](=[O:35])[CH:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:11]2[S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Nc1ccccc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(Nc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Reaction time: 1 h
Yield: 50.4 %

Procedure:
1-Cyclopropylethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylate (142 mg) was dissolved in ice-cooled trifluoroacetic acid (1.5 ml) and the mixture was stirred for 1 hour under ice-cooling. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate and extracted with 5% sodium bicarbonate aqueous solution. The extract was adjusted to pH2 with 5% hydrochloric acid and back-extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue (amorphous) was dissolved in methanol and to this solution was added water little by little. Precifitates were collected by filtration and dried to give powder of 3-anilino-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid (62 mg), mp 119° to 123° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C1COCC1.O>[S:17]([N:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of glycidyl 4-indolyl ether (compound 1a) (1.0 g, 5.3 mmol) in THF (5 mL) was cooled to 0° C., and sodium hydride in mineral oil (60%, 0.42 g, 10.6 mmol) and tosyl chloride (1.2 g, 6.3 mmol) were added. After being stirred at this temperature for 1 h, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with CHCl3 (3.50 mL). The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with benzene/acetone mixtures to give the glycidyl N-tosyl-4-indolyl ether (compound 1b) (1.5 g, 82%) as a white solid. See FIG. 18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([CH:15]=[C:16]([C:22]([O-])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>C(O)C>[CH2:20]([O:19][C:17]([CH:16]1[C:22](=[O:23])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH:15]1[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:26][CH:25]=1)=[O:18])[CH3:21]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1)C(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)Nc2ccccc2SC1c1ccc(OC)cc1
Yield: 27.4 %

Procedure:
A mixture of 32 g of o-aminothiophenol, 69.6 g of ethyl p-methoxybenzalmalonate and 1.6 g of triethylamine hydrochloride was heated at about 180° C. until no further ethanol was distilled out (for about 4 hours). The resulting mixture was then worked up in the same manner as described in Reference Example 2 (a) and the crystals thus obtained were recrystallized from chloroform-petroleum ether to obtain 25 g of 2,3-dihydro-3-ethoxycarbonyl-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 192° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][CH:26]([CH2:25][C:24]([O:29][CH2:30][CH3:31])=[O:28])[CH2:27][N:22]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Yield: 64 %

Procedure:
A solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.62 g), ethyl but-2-ynoate (1.2 mL) and tributylphosphine (1.1 mL) in a mixed solvent of tetrahydrofuran (30 mL)-toluene (20 mL) was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-35:65). The obtained crystals were crystallized from ethyl acetate-hexane to give the title compound (1.35 g, yield: 64%) as pale-yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:12])[CH:9]([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[C:8]#[N:12]
Reactant: CC(C)C#N
Reactant: Fc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of fluorobenzene (5.85 mL, 62.4 mmol) in 100 mL of anhydrous toluene was added isobutyronitrile (22.5 mL, 250 mmol) followed by 200 mL (100 mmol) of a 0.5 M solution of KHMDS in toluene. The reaction was stirred at 80° C. for 24 hours. The reaction was then allowed to cool to room temperature, diluted with diethyl ether, and washed with water and brine. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography using an ethyl acetate/hexanes gradient to yield 4.57 g (50%) of the objective compound as a brown oil. MS: (ESI, Pos) m/z 168.0 (M+23). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.48 (d, 2H), 7.39 (t, 2H), 7.31 (t, 1H), 1.73 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26](=[O:29])([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:29][CH3:26])[CH:13]=5)[S:6][CH:7]=4)[CH2:22][CH2:21]3)[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2nc(CCl)cs2)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Reactant: C1CNCCN1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(CN3CCN(Cc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)thiazole (240 mg) and piperazine (34 mg) were dissolved in DMF (3 mL), potassium carbonate (166 mL) and potassium iodide (166 mg) were added to the solution, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, chloroform was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (250 mg, 0.604 mmol) was reacted with NH2OTHP following the procedure described in Example 12, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (270 mg) as a light yellow solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccccc1F
Product: Fc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-fluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 320.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.62 (s, 1H); 8.43 (br s, 1H); 8.09 (br s, 1H); 7.86 (m, 1H); 7.13 (m, 2H); 6.85 (d, J=5.3 Hz, 1H; 5.87 (br s, 1H); 4.81 (d, J=6.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:25])[CH:3]=1.CN(C)C(C1SC2C(=NC=CC=2OC2C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[S:48])=CC=2F)C=1)=O>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:8]2[CH:15]=[C:14]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[S:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reactant: Nc1ccc(Oc2ncnc3sc(C(=O)N4CCCC4)cc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3sc(C(=O)N4CCCC4)cc23)c(F)c1
Yield: 17 %

Procedure:
Starting from the compound 210 and following the procedures described above for the synthesis of compound 8a (scheme 1, step 7, example 1), crude title compound 211 was obtained. It was purified by flash chromatography, eluents DCM and DCM-MeOH-Et3N (97.75:2:0.25) followed by trituration with a mixture of MeOH-EtOAc, to afford title compound 211 in 17% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.43 (s, 1H), 11.80 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H, J=11.7/2.3 Hz), 7.53-7.47 (m, 2H), 7.34-7.26 (m, 5H), 3.90 (t, 2H, J=6.7 Hz), 3.83 (s, 2H), 3.55 (t, 2H, J=6.7 Hz), 1.99-1.85 (m, 4H). LRMS (M+1) 536.2 (100%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH3:17])=[C:10]([CH:12](O)[CH:13]([CH3:15])[CH3:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:19]>O=S(Cl)Cl>[ClH:19].[C:1]1([C:7]2[NH:8][C:9]([CH3:17])=[C:10]([CH:12]([Cl:19])[CH:13]([CH3:15])[CH3:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1[nH]c(-c2ccccc2)nc1C(Cl)C(C)C
Product: Cl

Procedure:
27 g of 2-phenyl-4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole are dissolved in 700 ml of chloroform with 44 ml of SOCl2 and refluxed for 5 hours. 2-Phenyl-5-methyl-4-(1-chloro-2-methylpropyl)-1H-imidazole hydrochloride is isolated in quantitative yield.