Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([C:9]2[N:10]=[CH:11][N:12]3[CH:16]=[CH:15][S:14][C:13]=23)=[O:8])[CH:4]=[C:3]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=1.C([Sn](Cl)(CCCC)CCCC)CCC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Sn].[OH:53][C@@H:54]([C@H:56]1[C:77](=[O:78])[N:58]2[C@@H:59]([C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=3)=[O:65])[C:60](=O)[C@H:61]([CH3:62])[C@H:57]12)[CH3:55].[N:79]1[CH:84]=[C:83]([C:85]([C:87]2[N:88]=[CH:89][N:90]3[CH:94]=[C:93]([Sn:95]([CH2:104][CH2:105][CH2:106][CH3:107])([CH2:100][CH2:101][CH2:102][CH3:103])[CH2:96][CH2:97][CH2:98][CH3:99])[S:92][C:91]=23)=[O:86])[CH:82]=[C:81]([C:108]2[CH:109]=[N:110][CH:111]=[CH:112][CH:113]=2)[CH:80]=1>>[N:79]1[CH:84]=[C:83]([C:85]([C:87]2[N:88]=[CH:89][N:90]3[CH:94]=[C:93]([Sn:95]([CH2:104][CH2:105][CH2:106][CH3:107])([CH2:100][CH2:101][CH2:102][CH3:103])[CH2:96][CH2:97][CH2:98][CH3:99])[S:92][C:91]=23)=[O:86])[CH:82]=[C:81]([C:108]2[CH:109]=[N:110][CH:111]=[CH:112][CH:113]=2)[CH:80]=1.[OH:53][C@@H:54]([C@H:56]1[C:77](=[O:78])[N:58]2[C:59]([C:64]([O:66][CH2:67][C:68]3[CH:69]=[CH:70][C:71]([N+:74]([O-:76])=[O:75])=[CH:72][CH:73]=3)=[O:65])=[C:60]([C:15]3[S:14][C:13]4=[C:9]([C:7]([C:5]5[CH:4]=[C:3]([C:17]6[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=6)[CH:2]=[N:1][CH:6]=5)=[O:8])[N:10]=[CH:11][N:12]4[CH:16]=3)[C@H:61]([CH3:62])[C@H:57]12)[CH3:55]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C(c1cncc(-c2cccnc2)c1)c1ncn2ccsc12
Agent: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(-c4cccnc4)c3)c2s1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6cccnc6)c5)c4s3)[C@H](C)[C@H]12

Procedure:
7-([3,3′]Bipyridinyl-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was synthesized in substantially the same manner as in step c) of Synthesis Example 1, except that 263 mg of 7-([3,3′]bipyridinyl-5-yl)carbonylimidazo[5,1-b]thiazole, 0.316 ml of tri-n-butylstannyl chloride, and 1.72 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting compounds and, due to the unstable nature of the tin compound, the purification by column chromatography on silica gel was not carried out. 4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-([3,3′]bipyridinyl-5-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (80 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 270 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 7-([3,3′]bipyridinyl-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].B1C2CCCC1CCC2.[C:19]([O:23][C:24](=[O:33])[NH:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:33])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:4]=[CH:3][CH2:2][CH2:1][N:5]2[CH:9]=[CH:8][N:7]=[N:6]2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Reactant: C#CCCn1ccnn1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of 1-but-3-ynyl-1H-[1,2,3]triazole (0.76 g, 6.3 mmol) in anhydrous THF (50 ml) was treated with 9-BBN (0.5 M in THF, 27.6 ml, 13.8 mmol) at 0° C. and stirred for 2 h. This mixture was added to a solution of (4-iodo-phenyl)-carbamic acid tert-butyl ester (2 g, 6.3 mmol), [Pd(PPh3)2]Cl2 (0.51 g, 0.63 mmol) and aqueous potassium carbonate (3M, 6.3 ml, 18.8 mmol) in N,N-dimethyl formamide (50 ml) and stirred for 2 h at 70° C. After cooling to room temperature ethyl acetate (100 ml) was added and the solution extracted with water (2×50 ml). The organic layer was concentrated and the crude product purified by flash column chromatography (ethyl acetate/heptane 3:1) and washing with diethyl ether to yield [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester as beige solid (0.65 g, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].O>C(Cl)(Cl)Cl>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:33]
Reactant: O=C(Cl)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cccc(N)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-aminobenzonitrile (10 mmol) in 50 ml of chloroform and triethylamine (11 mmol) is added to a solution of 10 mmol of 3-(2-quinolinylmethyloxy)benzoic acid chloride in 20 ml of chloroform over a period of 10 minutes. The reaction is stirred at room temperature for 2 hours and is poured into water and then extracted into chloroform. The organic solution is dried and evaporated to give 3-(3-(2-quinolinylmethyloxy)benzoylamino)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O[C@H:17]([C@@H:22](O)[CH2:23][C:24]1C=CC=CC=1)[C:18](OC)=O>>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:13][C:22]([CH2:23][CH3:24])([CH2:17][CH3:18])[O:14]1)=[O:15]
Reactant: COC(=O)[C@H](O)[C@@H](O)Cc1ccccc1
Reactant: COC(=O)[C@@H](O)[C@H](O)Cc1ccccc1
Product: CCC1(CC)O[C@H](C(=O)OC)[C@@H](Cc2ccccc2)O1
Yield: 50 %

Procedure:
The substantially same method as described in Example 263 was conducted, except that (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation example 269) was used instead of (2,3-dihydroxy-4-phenylbutanoate (Preparation example 260), to obtain the title compound (1.5 g, 50˜75%)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:16])[C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:16])[C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(Cl)c(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)c(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-5,7-difluoro-3-methylquinoline (0.3 g, 1.06 mmol), 2-(tributylstannyl)-pyridine (0.410 g, 1.12 mmol), palladium tetrakistriphenylphosphine (0.123 g, 0.106 mmol) in toluene (2 mL) to give 4,8-dichloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline as a tan solid. Mass Spectrum (ESI) m/e=325.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.O.[Br:26][CH:27]([CH3:31])[C:28](Br)=[O:29]>ClCCl>[Br:26][CH:27]([CH3:31])[C:28]([N:15]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@:9]1([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:17])[CH3:16])=[O:29]
Reactant: CN[C@@H]1CCCC[C@@]1(O)c1cccc(OC)c1
Reactant: CC(Br)C(=O)Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc([C@]2(O)CCCC[C@H]2N(C)C(=O)C(C)Br)c1
Reaction time: 1 h
Yield: 104.1 %

Procedure:
Crude (1R*,2R*)-1-(3-methoxyphenyl)-2-methylaminocyclohexanol (4.7 g, from Example 6) was dissolved in dichloromethane (50 cm3) containing triethylamine (2.8 cm3, 2.02 g). The solution was cooled to 10° in a bath of cold water and treated dropwise with 2-bromopropionyl bromide (2.33 cm3, 4.32 g). The mixture was stirred for 1 hr. while cooling and was then concentrated under reduced pressure to an oily solid. This was partitioned between N hydrochloric acid (50 cm3) and ether (50 cm3), and the aqueous phase was extracted with further ether (3×20 cm3). The ether extracts were dried (Na2SO4) and evaporated, leaving crude (1R*,2R*)-2-(2-bromopropionyl-N-methylamino)-1-(3-methoxyphenyl)cyclohexanol as a yellow oil (7.7 g).
Reaction SMILES: CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[I-:25].[Na+].Cl>CN(C)C=O.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([I:25])[CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(F)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
Chloramine-T trihydrate (50 g, 178 mmol) was added to a stirred, cooled (0° C.) solution of 4-fluorophenol (20 g, 178 mmol) and sodium iodide (26.7 g, 178 mmol) in dimethylformamide (250 mL). The mixture was stirred at 0° C. for 1 h., and poured into water (1000 mL). The mixture was acidified with hydrochloric acid (1M) and extracted with ether (4×200 mL). The combined organic fractions were washed with aqueous sodium thiosulfate (5%, 3×100 mL), water (2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The reside was purified by flash column chromatography on silica gel, eluting with hexane/CH2Cl2 to give the title compound as an off-white solid (7.8 g, 18%). 1H NMR (360 MHz, CDCl3) δ 5.08 (1H, s), 6.90-7.01 (2H, m), and 7.37 (1H, dd, J 7.6, 2.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:16][CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:18](=[O:20])[CH3:19])[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(-c2cn3ccsc3n2)ccc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(-c2nc3sccn3c2C(C)=O)ccc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of 6-(4-fluoro-3-methoxyphenyl)-imidazo[2,1-b]thiazole (1.0 g, 4.03 mmol) and acetic anhydride (25 ml), heated to 140° C., was added 43 μl of concentrated sulfuric acid. The reaction mixture was heated at 140° C. for 1 hour. The reaction was monitored by HPLC. After one hour, only 10% product was observed. Another 43 μl of concentrated sulfuric acid was added and the mixture was kept at 140° C. for 4 hours. The reaction mixture was then poured onto 50 ml of ice, and diluted with 50 ml of water and the resulting mixture was extracted two times with 100 ml each of ethyl acetate. The combined extracts were washed with two portions of 50 ml of water and two portions of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown solid. The product, -[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone, was purified by flash chromatography (gradient 25%-50% ethyl acetate in hexanes) and obtained as a pale yellow solid (1.12 g, 96%). 400 MHz 1H NMR (DMSO-d6) δ 8.44 (d, J=4.3 Hz, 1H), 7.56 (d, J=4.3 Hz, 1H), 7.43 (dd, J=8.2, 2.0 Hz, 1H), 7.34 (dd, J=11.7, 8.6 Hz, 1H), 7.21 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 3.89 (s, 3H), 2.14 (s, 3H). LCMS: 291 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][C:3]=1[O:12]C.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][C:3]=1[OH:12]
Reactant: COc1cc2cc(C)[nH]c2cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)c(F)cc2[nH]1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 6-fluoro-5-methoxy-2-methylindole (1.23 g, 6.86 mmol), (prepared as described for the starting material in Example 237), in methylene chloride (15 ml) cooled at −30° C. was added a solution of boron tribromide (3.78 g, 15.1 mmol) in methylene chloride (2 ml). After stirring for 90 minutes at ambient temperature, the mixture was poured onto ice and diluted with methylene chloride. The pH of the aqueous layer was adjusted to 6. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (8/2) to give 6-fluoro-5-hydroxy-2-methylindole (905 mg, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:4].[CH3:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C(OCC)(=O)C>[CH3:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:41])[NH:1][CH2:2][C:3]([N:5]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[O:4])[CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1C(=O)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)N2CCCc3ccccc32)c1
Yield: 45.6 %

Procedure:
Using a procedure similar to that described in Example 27, but starting with tert-butyl 2-{2-amino-N-[2-(1,2,3,4-tetrahydro-1-quinolyl)carbonylphenyl]acetamido}acetate (2 g) and 3-methylphenyl isocyanate (0.63 g), and after recrysallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-[2-(1,2,3,4-tetrahydro-1-quinolyl)carbonylphenyl]acetamido}acetate (1.2 g), m.p. 160° C., is obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:1]([NH:5][S:6](/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)CC(O)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)NS(=O)(=O)/C=C/c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
A mixture of N-tert-butyl-2-hydroxy-2-(4-pyridyl)ethane-sulfonamide (6.62 g), acetic anhydride (13.2 ml) and pyridine (26.4 ml) was stirred at room temperature for 1.5 hr. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.58 ml), and the mixture was stirred in an oil bath at 100° C. for 40 min. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated brine. Th aqueous layer was extracted with ethyl acetate and organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give (E)-N-tert-butyl-2-(4-pyridyl)ethenesulfonamide (3.91 g) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:12][NH:13][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)NN)n1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carbohydrazide (1.0 g, 4.6 mmol) and 2-phenylacetyl chloride (0.61 mL, 4.6 mmol) were dissolved in 20 mL pyridine. The solution was stirred at 60° C. for 3 h. Upon cooling to room temperature, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc 3 times. The combined organic layers were washed with 2 N HCl and H2O, dried over magnesium sulfate and concentrated under vacuum. Flash chromatography was required to obtain 0.442 g (26% yield) of product as a white solid. MS (M+H)+ 337.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=1.CN(C(ON1[N:33]=[N:32][C:27]2C=[CH:29][CH:30]=[CH:31][C:26]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NN1CCCCC1.O>CN(C=O)C>[N:32]1([NH:33][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:9][C:10]=2[CH3:16])=[O:15])[CH2:29][CH2:30][CH2:31][CH2:26][CH2:27]1
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)NN1CCCCC1
Reaction time: 0.02 h
Yield: 83.1 %

Procedure:
To 1 g of 2-(2-chloro-phenyl)-5-methyl-1H-imidazole-4-carboxylic acid in 10 ml of DMF was added 1.36 g of TBTU and 3.6 ml of Hünigs' base and the reaction mixture was stirred for 1 minute. Then 0.46 ml of 1-aminopiperidin was added and the reaction mixture was stirred for 1.5 hour at room temperature. After such time the reaction mixture was poured onto 200 ml of water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were then washed with water (2×100 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to yield an oil which crystallized on standing. The residue was then triturated with heptane, the solid was filtered and dried to yield 1.12 g of the title compound, MS (ISP) 319.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:6])=[O:5])[CH3:3].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>>[CH3:3][N:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:6])=[O:5])[CH3:1]
Reactant: CN(C)S(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)N(C)C)cc23)CC1
Yield: 72.8 %

Procedure:
Beginning with 1.17 gm (4.89 mMol) 5-(N,N-dimethylamino)sulfonylamino-1H-indole and 0.78 mL (6.4 mMol) 1-methyl-4-piperidone, 1.19 gm (72.6%) of the title compound were recovered as a pale yellow powder.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][C:18]([C:27]#[N:28])=[CH:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][C:18]([C:27]#[N:28])=[CH:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(Cn2cncc2CCCO)c(-c2ccccc2)c1
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCCCl)c(-c2ccccc2)c1

Procedure:
To a solution of SOCl2 (0.382 mL, 5.24 mmol) in CH2Cl2 (20 mL) at 0° C. is added 6-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile in portion and the resulting white suspension is refluxed for 1.5 h. The mixture is cooled in ice and partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated to give an oily foam.
Reaction SMILES: P(O)(O)(O)=O.[S:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH:8]=[C:7]1B(O)O.[CH3:18][C:19]1[CH:23]=[N:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[C:20]=1OS(C(F)(F)F)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:18][C:19]1[CH:23]=[N:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[C:20]=1[C:7]1[S:6][C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH:8]=1
Reactant: Cc1cccc(-n2ncc(C)c2OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cc2cnccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(-n2ncc(C)c2-c2cc3cnccc3s2)n1
Yield: 108.5 %

Procedure:
An oven-dried three-neck round-bottom flask equipped with reflux condenser and gas inlet valve was charged with thieno[3,2-c]pyridine-2-boronic acid trihydrogen phosphate (1.0 g), trifluoro-methanesulfonic acid 4-methyl-2-(6-methyl-pyridin-2-yl)-2H-pyrazol-3-yl ester (1.16 g), potassium phosphate tribasic (2.3 g), 1,4-dioxane (30 mL), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.60 g), and 1,1′-bis(diphenylphosphino)ferrocene (0.40 g) and the stirring mixture was brought to reflux under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with ethyl acetate (250 mL) and the solution was treated with activated carbon and filtered through Celite. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel chromatography. Elution through a 120 g RediSep flash silica cartridge on a Biotage system with 100% heptane to 100% ethyl acetate over 1800 mL followed by 100% ethyl acetate until material with the desired mass elutes afforded an oil (1.2 g); MS (APCl+) m/z 307 (MH+). The product was further purified by dissolving in acetonitrile (30 mL) and dividing into two equal portions. After filtration, the solutions were sequentially purified by prep HPLC (Waters prep HPLC system; Stationary phase: Waters DeltPak C18 5 μm, 100 Angstrom, 300×50 mm I.D., P/N 011801, WAT 011801, No. 330009125W; Mobile phase 90:10 to 50:50 water-acetonitrile with 0.1% formic acid over 30 minutes). The combined fractions were concentrated under reduced pressure to an aqueous solution, removing the acetonitrile. The clear aqueous solution was treated with saturated aqueous potassium carbonate to give a cloudy white suspension. The suspension was allowed to stand at room temperature overnight. The solid white precipitate that had formed was collected by vacuum filtration and was dried in the vacuum oven (77° C.) overnight to afford the title compound as a white solid (0.506 g). melting point 157-158° c.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:23]>C(Cl)Cl>[Br:23][CH2:20][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(-c2ccccc2OC(F)(F)F)noc1C1CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of (5-cyclopropyl-3-(2-trifluormethoxy-phenyl)-isoxazol-4-yl)-methanol (2.19 g, 7.32 mmol) in anhydrous methylene chloride (50 mL) at 0° C. is added PBr3 (0.83 mL, 8.7 mmol) and the mixture is stirred for 3 hours. The mixture is then poured into 100 mL of ice water and extracted with DCM (2×). The combined DCM layers are washed with brine, dried (MgSO4) and concentrated under reduced pressure to provide crude residue. The residue is purified via flash chromatography (120 g silica) eluting with a gradient of 0 to 60% ethyl acetate in heptane to provide the title compound (2.1 g, 79%) as an oil.