Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:40])[CH:4]=[C:5]([C:8]([NH:10][N:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([NH:20][C:21]([N:23]3[CH2:26][C@H:25]([NH:27]C(=O)OCC4C=CC=CC=4)[C:24]3=[O:38])=[O:22])(=[O:19])=[O:18])[C:12]2=[O:39])=[O:9])[NH:6][CH:7]=1>CN(C)C=O.[Pd]>[NH2:27][C@H:25]1[CH2:26][N:23]([C:21]([NH:20][S:17]([N:13]2[CH2:14][CH2:15][CH2:16][N:11]([NH:10][C:8]([C:5]3[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:40])[CH:4]=3)=[O:9])[C:12]2=[O:39])(=[O:18])=[O:19])=[O:22])[C:24]1=[O:38]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O
Reaction time: 1 h

Procedure:
4.95 g (8.57 mmol) (S)-[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-carbonyl]amino]tetrahydro-2-oxo-1(2H)-pyrimidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was dissolved in 50 ml N,N-dimethylformamide. After the addition of 2.5 g palladium on carbon, the mixture was hydrogenated for 1 hour. The catalyst was removed and subsequently the filtrate added dropwise to 500 ml isopropanol. The desired product was filtered off, slurried with either and dried in vacuo. Yield 3.03 g, melting range 160°-220° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[S:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:27])=[O:3])=[S:26])=[C:19]([F:25])[CH:20]=1
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=S)NCc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=S)NCc2ccc(Br)cc2F)c(OCC(=O)O)cc1F
Yield: 98.7 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.79 g, 1.53 mmol) in ethanol (7.6 mL, 0.2 M) and treated with aqueous NaOH (2 N, 7.4 mL, 9.15 mmol) in an analogous fashion to Example 45, Step 9 to provide [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid (0.65 g, 98%) as a yellow solid: mp 162–164° C.; Rf 0.41 (20% methanol in methylene chloride); 1H NMR (DMSO-d6, 300 mHz) δ 10.64 (t, J=5.0 Hz, 1 H), 7.61 (d, J=9.0 Hz, 1 H), 7.52 (dd, J1=9.6 Hz, J2=1.7 Hz, 1 H), 7.45–7.36 (m, 2 H), 7.00 (d, J=11.4 Hz, 1 H), 4.89 (bd d, J=5.1 Hz, 2 H), 4.78 (s, 2 H), 2.15 (d, J=1.2 Hz, 3 H); ESI-LC/MS m/z calcd for C17H14BrF2NO3S: 428.98; found 428.0 (M−1)−; Anal. calcd for C17H14BrF2NO3S: C, 47.45; H, 3.28; N, 3.26; S, 7.45. Found C, 47.54; H, 3.19; N, 3.11; S, 7.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH3:42][O:41][C:37]1[CH:36]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:38]=1[O:39][CH3:40])[CH:31]=[CH:32][C:33]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:34]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Product: COc1cc(C=CC(=O)N2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 3,4,5-trimethoxycinnamic acid (65 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.S(Cl)([Cl:28])=O.S(=O)=O>C1C=CC=CC=1>[CH2:1]([Cl:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=S(Cl)Cl
Agent: O=S=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCCl
Temperature: 0 °C
Yield: 81 %

Procedure:
67 gms of oleyl alcohol was dissolved in 75 mls of benzene, 0.15 ml of pyridine were added. The solution was cooled to 0° C. and 46 gms of thionyl chloride was added over 5 minutes with stirring. The solution was heated to reflux temperature for 10 minutes until all sulphur dioxide evolution ceased. It was cooled and extracted with 150 ml of 10% saline solution then with 50 ml of 10% sodium carbonate solution and finally with 100 ml of 10% saline solution. The organic layer was dried over sodium sulphate, evaporated and distilled. The product distilled at 166°-169° C., at 3 torr and yielded 58 gms of oleyl chloride.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[C:19](O)=[O:20])=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH2:19][OH:20])=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc2[nH]c(SC(C)(C(=O)O)c3ccccc3)cc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc2[nH]c(SC(C)(CO)c3ccccc3)cc2c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
A solution (20 ml) of 2-(5-hexyloxy-1H-indol-2-yl)thio-2-phenylpropionic acid (2.81 g) in anhydrous tetrahydrofuran was added dropwise to a suspension (10 ml) of lithium aluminum hydride (0.4 g) in anhydrous tetrahydrofuran, and the mixture was heated and refluxed for 30 minutes. The reaction solution was allowed to cool, and was poured into ice water. The mixture was acidified by adding 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was crystallized by adding n-hexane. The crude crystalline matter was recrystallized from ethanol to give 1.66 g (yield: 61 %) of the product compound as a pale green prism crystal. The melting point was 93.5°-95.5° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:34])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine (63 mg, 0.2 mmol) in dioxane (10 ml) was added diisopropylethylamine (33 μl, 0.2 mmol) and p-tolyl chloroformate (0.2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (60 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Br:27][C:28]1[CH2:32][O:31][C:30](=O)[CH:29]=1>C1COCC1>[Br:27][C:28]1[CH2:32][O:31][C:30](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH:29]=1
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: O=C1C=C(Br)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=C1C=C(Br)CO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. stirred solution of 6-fluorooxindole (370 mg, 2.45 mmol) in anhydrous THF (10 mL) was added 1M LiHMDS/THF solution (4.9 mL, 4.9 mmol). The mixture was stirred at 0° C. for 10 minutes. 4-Bromo-5H-furan-2-one (200 mg, 1.23) was added as a solution in 2 mL of THF. The resulting mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour and quenched with 10 mL of 2M HCl. Methanol (5 mL) was added and the mixture was stirred at 50° C. for 0.5 hour. The mixture was poured into 150 mL of water and then stirred for 30 minutes. The precipitates were filtered, washed with water, and dried in vacuum to give 3-(4-bromo-5H-furan-2-ylidene)-6-fluoro-1,3-dihydro-indol-2-one as a yellow solid. Yield: 228 mg, 63%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)#[N:18]>>[OH:28][C:23]1[NH:24][C:25]2[C:21]([C:22]=1[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][N:7]=1)=[CH:20][C:19]([C:17]#[N:18])=[CH:27][CH:26]=2
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(S(=O)(=O)N4CCOCC4)cn3)c2c1

Procedure:
The title compound was prepared as described for Example 101 using 4-[(6-chloropyridin-3-yl)sulfonyl]morpholine and 5-cyanooxindole. The reaction mixture was quenched with water and the solvents were evaporated in vacuo. Water was added and the mixture was filtered. The solid material was washed with water, methanol, ethyl acetate and diethyl ether to give the title compound. Yield: 44%: MS (ES) m/z 385 (M++1).
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12]C)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[Li+]>C1COCC1>[C:1]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccn(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.16 g (4.31 mmol) methyl N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in 16 ml THF are combined with 10 ml of water and 10 ml of 1-molar lithium hydroxide solution are added. After stirring at ambient temperature for 2 h the mixture is evaporated down i. vac., the residue is combined with water, filtered and the filtrate is adjusted to pH 5 with potassium hydrogen sulphate solution. After total evaporation i. vac. the residue is treated with dichloromethane and a little ethanol, suction filtered and the filtrate is evaporated down completely i. vac.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[C:5]([CH3:12])[N+:4]=1[O-])[CH3:2].C([Br:17])(=O)C>C(O)(=O)C>[Br:17][C:7]1[CH:6]=[C:5]([CH3:12])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Reactant: CC(=O)Br
Solvent: CC(=O)O
Product: CCc1cc(Br)cc(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Ethyl-6-methyl-4-nitropyridine N-oxide (36.4 g) was added to 60 g of acetic acid and the mixture was warmed to give a clear solution which was cooled to 15°-20° C. and treated dropwise, keeping the temperature below 25° C., with 49.2 g of acetyl bromide. After addition was complete, the mixture was stirred at room temperature for 11/2 hours and then slowly warmed to 65°-70° C. and kept in this temperature range for 24 hours. The acetic acid and volatile components were removed in vacuo and 200 ml of chloroform were added to the residue. To the chilled mixture there was added dropwise 58 g of phosphorus tribromide at 10° C. and the mixture was warmed to room temperature and then heated at reflux for 3 hours. An additional 10 g of phosphorus tribromide were added and the mixture was heated for 1 hour, poured onto ice, neutralized with cold 35% sodium hydroxide and extracted three times with 200 ml of methylene chloride. The organic extract was concentrated, 300 ml of diethyl ether were added and the ether solution was dried over magnesium sulfate and concentrated. The crude product was fractionated in vacuo to give 30 g of the title product as a yellow oil; bp13 120°-130° C.
Reaction SMILES: [O-2:1].[Al+3].[O-2].[O-2].[Al+3].[CH3:6][CH2:7][C:8]1[CH2:19][N:17]2[CH2:18][C@H:10]([CH2:11][C@:12]([C:60]([O:62][CH3:63])=[O:61])([C:27]3[CH:32]=[C:31]4[C:33]56[C@@H:44]([N:45]([CH3:46])[C:30]4=[CH:29][C:28]=3[O:58][CH3:59])[C@@:43]([OH:51])([C:47]([O:49][CH3:50])=[O:48])[C@H:42]([O:52][C:53]([CH3:55])=[O:54])[C@:38]3([CH2:56][CH3:57])[CH:39]=[CH:40][CH2:41][N:36]([C@H:37]53)[CH2:35][CH2:34]6)[C:13]3[NH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH2:15][CH2:16]2)[CH:9]=1>>[CH3:6][CH2:7][C@@:8]12[O:1][C@@H:9]1[C@H:10]1[CH2:18][N:17]([CH2:16][CH2:15][C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[NH:26][C:13]=3[C@@:12]([C:60]([O:62][CH3:63])=[O:61])([C:27]3[CH:32]=[C:31]4[C@:33]56[C@@H:37]7[C@:38]([CH2:56][CH3:57])([C@@H:42]([O:52][C:53]([CH3:55])=[O:54])[C@:43]([OH:51])([C:47]([O:49][CH3:50])=[O:48])[C@@H:44]5[N:45]([CH3:46])[C:30]4=[CH:29][C:28]=3[O:58][CH3:59])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[CH2:11]1)[CH2:19]2
Reactant: [O-2]
Reactant: CCC1=C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](OC(C)=O)[C@]3(O)C(=O)OC)C2)C1
Agent: [Al+3]
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
Following the procedure described in the Example 19 but performing the oxidation in the presence of aluminium oxide used in a five-fold amount related to the anhydrovinblastine the title compound is prepared. The quality of the aluminium oxide employed corresponds to the activity grade I or II. The reaction is completed within two hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.O>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][CH2:14][O:15][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])[CH3:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(CCO)S(=O)(=O)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide (1.339 g) in chloroform (15 mL) was stirred in an ice bath, during which tert-butyldimethylchlorosilane (1.04 g) and N,N-dimethyl-4-aminopyridine (84 mg) were added thereto. Triethylamine were added dropwise, and the mixture was returned to room temperature and stirred for 16 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→60:40) to give 4-bromo-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methylbenzenesulfonamide as a colorless powder (1.77 g, 100%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[CH3:16].CN(C)[CH:19]=[O:20]>CCCCC.C1COCC1>[CH3:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:19]=[O:20])[CH:8]=2)[NH:12][N:11]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1n[nH]c2ccc(C=O)cc12
Reaction time: 0.25 h

Procedure:
Tetrahydrofuran (600 ml) was cooled down to −78° C. under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at −78° C., a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-1H-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed −70° C. The mixture was stirred for 30 minutes before N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-1H-indazole-5-carbaldehyde, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:18]=1)[C:10](=[O:17])[C:11]1[CH2:16][CH2:15][CH2:14][C:12]=1[N:13]=2)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C[O-].[Na+]>CO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:14]1[C:12]2[N:13]=[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:18][N:9]3[C:10](=[O:17])[C:11]=2[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3
Reactant: COc1cccc(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C=C2CCc3c2nc2ccc(C(=O)O)cn2c3=O)c1

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 153°-154° C. (3.3 g) was reacted with 3-methoxybenzaldehyde (5.52 g) in methanol (145 g) in the presence of sodium methoxide (2.97 g) under stirring at reflux temperature for 144 hours. After cooling the precipitate was filtered and treated with formic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol to give 2.73 g of 3-(3-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 310°-312° C., NMR (CF3COOD) δ ppm: 3.42 (br) (4H, cyclopentane protons), 4.11 (s) (3H, OCH3), 7.2-7.6 (m) (4H, phenyl protons), 7.61 (br) (1H, =CH--), 8.41 (d) (1H, C-5 proton), 9.11 (d.d) (1H, C-6 proton), 10.20 (d) (1H, C-8 proton).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.14 g, 66%). MS (ISP) 427.0 [(M+H)+]; mp 171° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.[CH:11]1(Br)[CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: BrC1CCC1
Reactant: Brc1n[nH]c2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1nn(C2CCC2)c2cccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg) in DMF (10 ml) were added cyclobutyl bromide (0.19 mL) and Cs2CO3 (395 mg) at room temperature. After stirring overnight at 60° C., the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (181 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[B:16](OC)([O:19]C)[O:17]C.Cl>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[Cl:15][C:9]1[CH:8]=[CH:7][C:12]([B:16]([OH:19])[OH:17])=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(Br)cc1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(B(O)O)ccc1Cl
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.76 M, 2.5 mL) was added dropwise to a solution of commercially available 4-bromo-2-chloroanisole (1.0 g) in toluene (8 mL) and tetrahydrofuran (3 mL) at −78° C., and the mixture was stirred as such for 30 minutes. Thereafter, trimethyl borate (1.0 mL) was added and the mixture was stirred at room temperature for 15 minutes. Dilute hydrochloric acid and ethyl acetate were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→98:2) to give the title compound as a colorless powder (535 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH:11]([F:13])[F:12])[CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH:11]([F:12])[F:13])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(Br)cc(C(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
1-Bromo-3-(difluoromethyl)-5-nitrobenzene (944 mg, 3.60 mmol) was treated with iron powder (804 mg, 23.43 mmol) in a mixture of acetic acid (1.35 ml) and ethanol (25 ml) and stirred at 80° C. for 3 h. The crude was filtered over Celite and the solvent was removed in vacuum. A mixture of a solution of sodium bicarbonate 4% and ethyl acetate was added and the resulting mixture was filtered over Celite. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was remove to give 855 mg (100% yield) of the title compound as a dark solid, that was used in the next step without further purification. Purity 96%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N:13](C(=O)C)[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:6]=1>O1CCCC1.CO>[CH3:2][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(OC)c(N(C(C)=O)c2cc(Cl)cc(Cl)c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OC)c(Nc2cc(Cl)cc(Cl)c2)c1
Reaction time: 72 h
Yield: 23.6 %

Procedure:
Concentrated HCl (45 mL) was added to a solution of 3-[acetyl-(3,5-dichlorophenyl)-amino]-4-methoxybenzoic acid methyl ester (11.46 g, 31.12 mmol) in a mixture of tetrahydro-furan (75 mL) and methanol (75 mL). The reaction was heated to reflux. After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and dried (MgSO4). The ethyl acetate was removed under reduced pressure to give the product (2.4 g); m.p. 134-135° C. after chromatography on silica gel in ethyl acetate followed by recrystallization from ether/hexane 1:9.