Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: OCc1ccccc1-c1nccs1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1nccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred solution of (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol) in THF (15 mL) was added phthalimide (1.12 g, 7.65 mmol), triphenylphosphine (2.0 g, 7.65 mmol). The mixture was cooled in an ice-water bath and diisopropyl azodicarboxylate (3.1 g, 15.3 mmol) was added dropwise. After the addition, the mixture was stirred at 0° C. for 30 min, and at rt for 18 h. The mixture was then filtered and the filtrate was evaporated. The residue was purified by column chromatography to yield 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (1.1 g) as a white solid. To a stirred solution of 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (400 mg, 1.25 mmol) in ethanol (10 mL) was added dropwise hydrazine hydrate (160 mg, 3.1 mmol). The mixture was heated at 70° C. for 1 h. After cooling to rt, the mixture was filtered, and the filtrate was evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanamine (190 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])O[C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2].C[N:38](C)C=O>N>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:38][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)OCCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Agent: N
Product: CC(=O)OCCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1

Procedure:
A solution of 115 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 1 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The cooled mixture was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1). Crystallization from ethyl acetate/petroleum ether gave 13 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 272°-274° C.
Reaction SMILES: S(Cl)(Cl)=O.C1(C2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C1(C2C=CC(C(Cl)=O)=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][CH:41]=[C:40]2[O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][C:51]=1[F:57].[C:58]1([C:64]2[CH:69]=[CH:68][C:67]([C:70]([N:72]=[C:73]=[S:74])=[O:71])=[CH:66][CH:65]=2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][CH:41]=[C:40]2[O:49][C:50]1[CH:56]=[CH:55][C:53]([NH:54][C:73]([NH:72][C:70](=[O:71])[C:67]2[CH:68]=[CH:69][C:64]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:65][CH:66]=2)=[S:74])=[CH:52][C:51]=1[F:57]
Reactant: O=C(N=C=S)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C(O)c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(-c5ccccc5)cc4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-phenylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-phenyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-phenyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-phenyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 92%). Mass spectrometry value (ESI-MS, m/z): 554 (M++1)
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([NH:27][C@H:28]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:57][CH2:56][CH2:55][C@H:49]1[C:50]([NH:52][CH2:53][CH3:54])=[O:51])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])=[O:36])[CH2:29][S:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH2:3][OH:4].[CH3:58][C:59]([CH2:61][C:62]([OH:64])=[O:63])=[O:60].[NH2:65][C@H:66]([C:72]([NH:74][C@H:75]([C:82]([NH:84][C@H:85]([C:96](NN)=[O:97])[CH2:86][C:87]1[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[NH:89][CH:88]=1)=[O:83])[CH2:76][C:77]1[N:81]=[CH:80][NH:79][CH:78]=1)=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[OH:70]>>[NH2:65][C@H:66]([C:72]([NH:74][C@H:75]([C:82]([NH:84][C@H:85]([C:96]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([NH:27][C@H:28]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:57][CH2:56][CH2:55][C@H:49]1[C:50]([NH:52][CH2:53][CH3:54])=[O:51])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])=[O:36])[CH2:29][S:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:6])[CH2:3][OH:4])=[O:97])[CH2:86][C:87]1[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[NH:89][CH:88]=1)=[O:83])[CH2:76][C:77]1[N:81]=[CH:80][NH:79][CH:78]=1)=[O:73])[CH2:67][CH2:68][C:69](=[O:70])[OH:71].[CH3:58][C:59]([CH2:61][C:62]([OH:64])=[O:63])=[O:60]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: NNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Agent: CC(=O)CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O

Procedure:
In analogy to Example 7(e) 469.5 mg (0.5 mol) of H-Ser-Tyr-D-Leu-Cys(But)-Arg-Pro-NH-C2H5 -diacetate were reacted with Glu-His-Trp-NH-NH2, worked up and purified over Dowex 1 × 2 (acetate form) and carboxymethyl cellulose. Since the substance was not yet completely pure it was purified in analogy to Example 1(a) on Sephadex LH 20.
Reaction SMILES: II.C[Si](C)(C)[Si](C)(C)C.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][CH:21]3[CH2:27][CH:26]4[N:28](C(OCC)=O)[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.CO>ClCCCl>[CH:23]12[NH:28][CH:26]([CH2:25][CH2:24]1)[CH2:27][CH:21]([NH:20][C:16]1[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=1)[NH:11][N:12]=[CH:13]3)[CH2:22]2
Reactant: CCOC(=O)N1C2CCC1CC(Nc1ccc3[nH]ncc3c1)C2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Solvent: ClCCCl
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of iodine (0.488 g, 1.92 mmol) in hexamethyldisilane (0.560 g, 3.83 mmol) was heated at 110° C. and stirred until the purple solution became colorless. The solution was cooled to room temperature, followed by adding thereto a solution of the ethyl 3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.200 g, 0.637 mmol) obtained in Example 14 in 1,2-dichloroethane (6 ml), and the resulting mixture was heated at 50° C. and stirred for 7 hours. The mixture was cooled to room temperature and methanol was added thereto to quench the mixture. Then, the solvent was distilled off under reduced pressure and a 1N-aqueous sodium hydroxide solution was added to the residue. The solvent was distilled off under reduced pressure and the residue was dried up and then purified by a silica gel chromatography (eluent: chloroform/methanol/30%-aqueous ammonia=100/10/1) to obtain N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (0.0893 g, 58%).
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][CH:55]=[N:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[OH:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][CH:55]=[N:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][C:30]=1[C:31]([OH:33])=[O:32])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cnco2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
Thioanisole (2.3 mL) and trifluoroacetic acid (7.7 mL) were added to the obtained tert-butyl 2-(2-(benzyloxy)-5-(oxazol-5-yl)benzamido)-4-phenylbenzoate (0.21 g), followed by stirring at room temperature for 9 hours and 40 minutes. The solvent was evaporated under reduced pressure, and methanol was added to the residue. The solid substance was collected by filtration to obtain 0.12 g of 2-(2-hydroxy-5-(oxazol-5-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:20][CH:21]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][OH:23].[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:23][CH2:22][CH:21]([CH3:20])[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(CO)CCC(C)(C)C
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(COCC(C)CCC(C)(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (7.0 g, 25.6 mmol) is partly solved in dioxane (190 mL) at 80° C. 2,5,5-Trimethyl-hexan-1-ol (124.1 g, 731 mmol) and sodium hydride (1.7 g, 42 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 80° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.8 g of 2-(2H-Benzotriazol-2-yl)-6-(2,5,5-trimethylhexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1C=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[OH:12])=[O:5])[CH3:2].ClC1C=CC(C=O)=[N:29]C=1>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][N:29]=1)[OH:12])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(Cl)cn1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cn1

Procedure:
The title compound was obtained in analogy to the procedure described for intermediate B but using 5-chloro-2-formylpyridine. After completion, the reaction mixture was diluted with EtOAc and extracted with a saturated NaHCO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flas chromatography (heptane/EtOAc, 100:0→0:100) to give the title compound. tR: 1.00 min (LC-MS 2); ESI-MS: 402.0/404.0 [M+H]+ (LC-MS 2).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.[N:27]1([CH2:32][CH2:33]O)[CH:31]=[CH:30][N:29]=[N:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:33][CH2:32][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: OCCn1ccnn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCn1ccnn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A solution of diethyl azodicarboxylate (1.15 ml, 7.3 mmol) in methylene chloride (2 ml) was added in portions to a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (1 g, 4.9 mmol), (prepared as described for the starting material in Example 1), 2-(1,2,3-triazol-1-yl)-ethan-1-ol (663 mg, 5.9 mmol), (J. Antib. 1993, 46, 177), and triphenylphosphine (1.92 g, 7.3 mmol) in methylene chloride (150 ml). After stirring for 10 minutes at ambient temperature, triphenylphosphine (256 mg, 0.98 mmol) was added followed by diethyl azodicarboxylate (154 μl, 0.98 mmol). The reaction mixture was stirred for 30 minutes and the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/ethyl acetate/methanol (45/50/5). The fractions containing the expected product were combined and evaporated under vacuum. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline (470 mg, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](Cl)(=[O:13])[CH3:12]>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C=O)c(O)c1
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C=O
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a 0-5° C. solution of 2-hydroxy-4-methylbenzaldehyde (15 g, 110 mmol) in 250 mL of DCM was added TEA (30.7 ml, 220 mmol) followed by dropwise addition of acetyl chloride (8.65 g, 110 mmol) over 15 min. The reaction was stirred at 0-5° C. for 30 min. The reaction mixture was concentrated under reduced pressure. To this residue 100 mL of 1N HCl was added. The crude mixture was extracted with EtOAc×2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil, 2-formyl-5-methylphenyl acetate (18 g). 1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H), 2.40 (s, 3H), 7.13 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 10.01 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH3:29])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]>ClCCl.C(OCC)C>[CH3:29][N:8]([CH2:7][CH2:6][Cl:3])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane was added to a solution of 3.37 g of Intermediate XIII in 20 ml of dichloromethane, and the mixture was stirred for 4 hours at ambient temperature. Removal of the solvent gave an oil which was taken up in diethyl ether. The title compound precipitated as a white solid which was filtered off for use without further purification. m.p. (118) 126°-128° C. (diethyl ether).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][CH3:8])[CH2:3][C:4](=O)[CH3:5].[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:5][C:4](=[N:15][S@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[CH2:3][C@@H:2]([CH3:1])[CH2:7][CH3:8]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC[C@H](C)CC(C)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)CC(C)=N[S@@](=O)C(C)(C)C
Yield: 63.4 %

Procedure:
A mixture of (S)-4-methyl-hexan-2-one (1.6 g, 14 mmol), (S)-2-methyl-propane-2-sulfinic acid amide (1.7 g, 14 mmol) and titanium(IV) ethoxide (6.4 g, 28 mmol) in THF (30 mL) was refluxed for 10 hours. Then the reaction mixture was poured into brine (150 mL). The mixture was filtered. The filtrate was extracted by EtOAc (3×70 mL). The EtOAc phase was removed under reduce pressure and the residue was purified by a silica gel column (Hexane/EtOAc 3:1) to give the titled compound (1.93 g, 63% yield) as a colorless oil: 1H NMR (CDCl3) δ 2.24 (m, 2H), 2.27 (s, 3H), 1.85 (m, 1H), 1.22 (m, 2H), 1.20 (s, 9H), 0.85 (m, 6H); MS (APCI) (M+1)+ 218.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:12][C@@H:13]1[C@@H:18]([OH:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:19][C@H:18]1[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][C@@H:13]1[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2Cl)[C@@H](F)C1
Temperature: 0 °C
Yield: 63 %

Procedure:
A mixture of 2-chloro-1-fluoro-4-nitrobenzene (2.0 g, 1.1 eq, 11.5 mmol) and tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.3 g, 1.0 eq, 10.5 mmol) was taken in annhydrous THF (50 mL) and stirred at 0° C. KOtBu (2.1 g, 1.8 eq, 18.9 mmol) was added to the above solution at 0° C. and the heterogeneous mixture was warmed to room temperature. Then the reaction mixture was refluxed overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the crude mixture and pardoned with aqueous saturated NaHCO3 (50 mL) solution. The layers were separated and the organic layer was washed with aqueous saturated NaHCO3 (50 mL) solution and brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated to leave cude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:1 to 2:8) as eluent gave the desired product in 63% yield.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:26]=[C:27]([NH:28][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(Oc2cccc(N)c2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cccc(Oc2cccc(NC(=O)c3ccn4c3CSC4c3cccnc3)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 60° and 65° C., to a solution of 3-(3-methoxyphenoxy)aniline (6.45 g) and triethylamine (6.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 4 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 65° C. The residue is dissolved in methylene chloride (350 cc). The solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (750 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (12 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(3-methoxyphenoxy)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (4.5 g) in the form of cream-coloured crystals, m.p. 130° C., is thereby obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[CH:43]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:43][C:31]3[CH:32]=[C:33]([C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=4)[CH:34]=[CH:35][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(-c2ccc(O)cc2)ccc1F
Product: Oc1ccc(-c2ccc(F)c(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-fluoro-4′-hydroxy-biphenyl-3-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 579.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 73 %

Procedure:
Prepared as described in the Nitro Reduction section using 6-iodo-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.45 g, 1.23 mmol) and tin (II) dichloride dihydrate (1.39 g, 6.16 mmol) in EtOH (25 ml) to give the title compound (0.301 g, 73%) as a yellow solid, after work-up and flash chromatography (4:1 EtOAc/DCM).