Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][OH:19])[CH:7]=1)=[O:4].NC1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([CH2:16][CH2:17][CH:18]=[O:19])[CH:7]=1)=[O:4]
Reactant: O=C(Nc1cc(CCCO)cc(C(F)(F)F)c1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: O=CCCc1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 42 %

Procedure:
2,2,2-Trifluoro-N-[3-(3-hydroxypropyl)-5-(trifluoromethyl)phenyl]acetamide (240 mg, 0.76 mmol) prepared by a method similar to that in the above “intermediate aniline: Synthesis 6” was dissolved in dichloromethane (5 mL), and Dess-Martin periodinane (355 mg, 0.84 mmol) was added thereto under ice-cooling. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 14 hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution (30 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2,2,2-trifluoro-N-[3-(3-oxopropyl)-5-(trifluoromethyl)phenyl]acetamide (100 mg, 42%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and phenyl-acetyl chloride (386.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the 2-phenyl-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49](O)=[CH:48][N:47]=1>C1COCC1>[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49]([O:44][C@@H:41]2[CH2:42][CH2:43][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]2)=[CH:48][N:47]=1
Reactant: Oc1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cnc(Cl)c(Br)c2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To 3.15 gm (12 mmol) of PPh3 in 100 mL of dry THF at −20° C. was added 1.89 mL (12 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 1.87 gm (10 mmol) of 1-t-butoxycarbonyl-3-(R)-hydroxypyrrolidine in 20 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 2.08 gm (10 mmol) of 2-chloro-3-bromo-5-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1, hexane:ethyl acetate) to obtain 3.65 gm (65%) of a foamy residue: 1H NMR (300 MHz, CD3OD) δ 8.05 (1H, d, J=2.5 Hz), 7.78 (1H, d, J=2.5 Hz), 5.09 (1H, s), 3.66-3.32 (4H, m), 2.18 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:2].[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CCO>[CH2:1]([N:3]([CH:19]([CH3:21])[CH3:18])[C@H:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:2]
Reactant: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(C(C)C)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of product from example 122A (0.098 g, 0.416 mmol) in EtOH (5 mL) was added acetone (0.031 mL, 0.416 mmol), acetic acid (0.024 mL, 0.416 mmol), and sodium cyanoborohydride (0.039 g, 0.625 mmol), and the resulting mixture and stirred at rt for 8 hrs. The mixture was partitioned between CH2Cl2 and saturated aq. NaHCO3, and the organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-1% MeOH in CH2Cl2 to give the title compound (0.0352 g, 31%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][CH2:59][CH:60](O)[CH2:61][O:62][CH3:63]>O1CCCC1>[CH3:57][O:58][CH2:59][CH:60]([CH2:61][O:62][CH3:63])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: COCC(O)COC
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 50 °C
Reaction time: 13 h
Yield: 116.4 %

Procedure:
A mixture of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g), tributylphosphine (1.6 mL), 1,1′-(azodicarbonyl)dipiperidine (1.7 g), 1,3-dimethoxypropan-2-ol (0.8 g) and tetrahydrofuran (20 mL) was stirred at 50° C. for 13 h. Tributylphosphine (0.82 mL), 1,1′-(azodicarbonyl)dipiperidine (0.83 g) and 1,3-dimethoxypropan-2-ol (0.4 g) were added to the mixture again and the mixture was stirred at 70° C. for 5 h. Furthermore, tributylphosphine (1.64 mL), 1,1′-(azodicarbonyl)dipiperidine (1.66 g) and 1,3-dimethoxypropan-2-ol (0.8 g) were added to the mixture. After stirring at 70° C. for 3 h, the mixture was cooled to 0° C., and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified basic silica gel column chromatography (ethyl acetate/hexane=20/80 to 85/15, volume ratio) to give the title compound (1.79 g, 84%) as an orange oil, MS 463 (MH−).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:49][CH2:48]3)(=[O:46])=[O:45])=[C:40]([CH:50]3[CH2:52][CH2:51]3)[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:60][CH2:61][CH2:62][CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65]1)C1C=CC=CC=1.[OH-].[Na+]>ClCCl.N1C=CC=CC=1.[Cl-].[Na+].O.O>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:49][CH2:48]3)(=[O:45])=[O:46])=[C:40]([CH:50]3[CH2:51][CH2:52]3)[CH:39]=2)/[C:35]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][CH2:62][CH2:61][OH:60])[N:65]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccn(CCCOCc2ccccc2)n1
Reactant: O=C(O)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccn(CCCO)n1)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of triphenylphosphine (320 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (217 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]acrylic acid (200 mg) in dichloromethane (5 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 0.5 hour. A solution of 1-[3-(benzyloxy)propyl]-1H-pyrazol-3-amine (141 mg) in dichloromethane (5 mL) and pyridine (0.09 mL) were added thereto at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1). To a solution of the obtained colorless oily substance in trifluoroacetic acid (5 mL) was added 1,2,3,4,5-pentamethylbenzene (823 mg) at room temperature, followed by stirring at room temperature for 48 hours. To a solution of the oily substance obtained by concentration in methanol (4 mL) was added a 1 M aqueous sodium hydroxide solution (1 mL) at room temperature, followed by stirring at room temperature for 30 minutes. Saturated brine was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, chloroform:methanol=1:0-20:1) to obtain (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[1-(3-hydroxypropyl)-1H-pyrazol-3-yl]acrylamide (155 mg) as a white amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:22](=[O:23])[NH:21][C:20]4[CH:24]=[C:25]([N+:28]([O-])=O)[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:19]2[O:18][CH:17]([CH2:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[C:22](=[O:23])[NH:21][C:20]=2[CH:24]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Yield: 98.2 %

Procedure:
In a mixture of methanol (80 ml) and tetrahydrofuran (20 ml) was dissolved 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.03 g). To the solution was added 10% Pd - C (50% wet, 0.6 g) to conduct catalytic reduction. After the absorption of hydrogen finished, the catalyst was filtered off, and the filtrate was concentrated. The residue was crystallized from ethanol to give 1,85 g (98.2%) of 6-amino-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one, m.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:50](C)=O.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:50])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To the solution of 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.16 mmol) and paraformaldehyde (10 mg, 0.32 mmol) in dichloroethane was added Na(OAc)3BH (68 mg, 0.32 mmol) and stirred at RT overnight. Distilled off the solvent to get 95 mg (95.0% yield) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=640.2 (M+1).
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NC5C=CC(C6C=CC(CCCC=O)=CC=6)=CC=5)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([S:71]([C:74]3[CH:75]=[C:76]4[C:81](=[C:82]([CH3:84])[CH:83]=3)[N:80]=[CH:79][C:78]([C:85]([NH2:87])=[O:86])=[C:77]4[NH:88][C:89]3[CH:94]=[CH:93][CH:92]=[C:91]([O:95][CH3:96])[CH:90]=3)(=[O:73])=[O:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[CH3:96][O:95][C:91]1[CH:90]=[C:89]([NH:88][C:77]2[C:76]3[C:81](=[C:82]([CH3:84])[CH:83]=[C:74]([S:71]([C:68]4[CH:67]=[CH:66][C:65]([C:62]5[CH:63]=[CH:64][C:59]([CH2:58][CH2:57][CH2:56][CH2:55][CH:54]=[O:53])=[CH:60][CH:61]=5)=[CH:70][CH:69]=4)(=[O:72])=[O:73])[CH:75]=3)[N:80]=[CH:79][C:78]=2[C:85]([NH2:87])=[O:86])[CH:94]=[CH:93][CH:92]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCCCO)cc5)cc4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCCC=O)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 124, using Intermediate 68 as substrate. ES/MS calcd. for C35H34N3O5S+ 608.2. Found m/z=608.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:41][CH2:40][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][CH2:33]1>C(Cl)Cl>[CH3:39][O:38][C:36]([CH:35]1[CH2:40][CH2:41][N:32]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:33][CH2:34]1)=[O:37]
Reactant: COC(=O)C1CCNCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(C(=O)OC)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added methyl isonipecotate (63 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 575 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([F:26])=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([N:52]1[CH2:57][CH2:56][N:55]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([F:26])=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH3:25])=[CH:19]5)=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH2:54][CH2:53]1)(=[O:51])[CH3:50]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCBr
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline (310 mg of a sample containing triphenylphosphine oxide (approx. 12% w/w), 0.61 mmol) and 1-acetylpiperazine (258 mg, 2.02 mmol) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (202 mg, 67%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([O:18]C)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)[CH2:3][CH2:2]1.[OH-].[Li+]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([OH:18])=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:24]2[CH2:27][C:26]([F:28])([F:29])[CH2:25]2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 5 c), (S)-methyl 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e=396.1 [M−H]−.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([S:12](=[O:22])(=[O:21])[N:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:14])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[CH:15]1([N:13]([CH3:14])[S:12]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:23])=[O:2])(=[O:22])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 3-(Cyclohexyl-methyl-sulfamoyl)-4-methoxy-benzoic acid methyl ester (1.50 g, 4.39 mmol) in 1,4 dioxane (40 ml) is treated with 2 N NaOH (10 ml) and the resulting solution is stirred at room temperature for 21 hours. The solvent is removed in vacuo and ice cold 2 N HCl (25 ml) is added and the white solid which forms is extracted into DCM (150 ml). The organic layer is washed with water, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid; [M−1]− 326.
Reaction SMILES: Cl.C([N:5]1[C:14]2[C:9](=[C:10]([NH:16]C(=O)C)[CH:11]=[CH:12][C:13]=2[Cl:15])[C:8](=[O:20])[CH:7]([NH:21]C(=O)C)[CH2:6]1)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:21][CH:7]1[C:8](=[O:20])[C:9]2[C:14](=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH2:16])[NH:5][CH2:6]1
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(NC(C)=O)CN2C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)c2c1C(=O)C(N)CN2
Temperature: 110 °C

Procedure:
8 ml of 6N hydrochloric acid was added to 514 mg of the compound prepared in (2) above, and the mixture was heated at 110° C. for 1.5 hours while stirring. After cooling chloroform was added to it, followed by the addition of 50 ml of 1N aqueous solution of sodium hydroxide while stirring. The chloroform layer was extracted, the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The product was concentrated to produce 260 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][S:6][C:7]1[N:12]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])[CH:10]=[CH:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][S:6][C:7]1[N:12]=[C:11]([CH2:13][CH:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])[CH:10]=[CH:9][N:8]=1
Reactant: O=C1NC(=S)SC1=Cc1ccnc(SCc2ccc(Cl)c(Cl)c2)n1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)SC1Cc1ccnc(SCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A suspension of 5-[2-(3,4-dichloro-benzylsulfanyl)-pyrimidin-4-ylmethylene]-2-thioxo-thiazolidin-4-one in toluene was heated to 80° C. in the presence of 2,6-dimethyl-1,4-dihydro-3,5-pyridine carboxylate (1.1 eq.) and activated silica gel. The suspension was filtered and rinsed with EtOAc. The filtrate was evaporated in vacuum and the resulting residue was redissolved in EtOAc and washed with 1N aq. HCl solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the crude product. Flash chromatography afforded pure product.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=O)C.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:19]>C(O)C>[ClH:19].[C:12]1([CH:11]=[C:8]2[C:7](=[O:10])[C:6](=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:5][NH:4][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reaction time: 8 h

Procedure:
14 g (0.1 mole) of N-acetyl-4-piperidone and 32 g (0.3 mole) of benzaldehyde in 150 ml of ethanol are cooled to 15° and treated dropwise with 33 ml of concentrated HCl, refluxed for 6 hours, and stored overnight at room temperature. The light yellow solid is filtered, washed with ethanol, then with ether and air-dried, weight 26 g (83%), mp. 273°-275°(dec.).
Reaction SMILES: [C:1](OCC)(=[O:3])[CH3:2].[H-].[Na+].[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.Cl>C1C=CC=CC=1.O.CO>[C:1]([CH:15]1[CH2:16][CH:11]([O:10][CH3:9])[CH2:12][CH2:13][C:14]1=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC1CCC(=O)C(C(C)=O)C1
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To 2.5 g of ethyl acetate was added 1.12 g of 60% sodium hydride and, a solution of 1.78 g of 4-methoxycyclohexanone in benzene was added to the mixture. After reacting at 40° C. for 3 hours, methanol was added to decompose an excess of sodium hydride, which was poured into water. The mixture was neutralized with hydrochloric acid ahd extracted with ether to give 1.02 g of 2-acetyl-4-methoxycyclohexanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][O:10][C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1onc(-c2ccc(F)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(F)cc2)c1CBr
Yield: 109.5 %

Procedure:
Ethyl 3-(4-fluorophenyl)-4-methylisoxazole-5-carboxylate (8.6 g, 34.5 mmol), NBS (6.8 g, 38.0 mmol), and benzoyl peroxide (0.84 g, 3.45 mmol) were added to 200 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo to give 12.4 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=9.21 (s, 1H), 7.75-7.85 (m, 2H), 7.22-7.32 (m, 2H), 4.66 (s, 2H), 4.54 (q, 2H, J=7.0 Hz), 1.41 (t, 3H, J=7.0 Hz).