Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13].[CH2:14]1[O:20][C@@H:19]2[O:21][C@H:15]1[C@@H:16]([OH:24])[C@H:17]([OH:23])[C@H:18]2[OH:22].N.[Na].[NH4+].[Cl-]>C1COCC1>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13].[O:20]=[CH:14][C@@H:15]([C@H:16]([C@@H:17]([C@@H:18]([CH2:19][OH:8])[OH:22])[OH:23])[OH:24])[OH:21]
Reactant: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Agent: N
Agent: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
1.09 g (1.41 mmol)of 1,6-anhydro-4-O-benzyl-2-deoxy-2-[1D-(1N,2,4/3)-2,3,4-tri-O-benzyl-5-C-benzyloxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 3) was dissolved in THF (20 ml) and liquid ammonia (~100 ml) was added at -78° C. Sodium (0.42 g) was added and the reaction mixture was stirred for 30 minutes at this temperature. NH4Cl(2 g) was then added and ammonia and THF were evaporated at room temperature. The residue was acetylated in pyridine (5 ml) and acetic anhydride (5 ml). Excess of acetic anhydride was quenched by the addition of methanol. The reaction mixture was evaporated and dissolved in dichloromethane (100 ml) and washed sequentially with 5% HCl solution (2×100 ml), saturated NaHCO3 solution (2×100 ml) and water (2×100 ml) before evaporation to a syrup. The syrup was purified by chromatography on silica gel using toluene:ethylacetate (3:1) as eluent to provide 1,6-anhydro-3-4-di-O-acetyl-2-deoxy-2-[1D-(1N,2,4/3)-(2,3,4-tri-O-acetyl-5-C-acetoxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 4) (613 mg, 75.8%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1
Reactant: COc1ncccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 54% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11](F)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])[CH3:2].[NH2:23][CH:24]1[C:28]2([O:32][CH2:31][CH2:30][O:29]2)[CH2:27][NH:26][CH2:25]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11]([N:26]3[CH2:25][CH:24]([NH2:23])[C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: NC1CNCC12OCCO2
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(N)C4(C3)OCCO4)c(F)cc2c1=O
Yield: 44.6 %

Procedure:
Following the procedure of Step 1 Example 80, starting with 0.750 g (2.4 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and substituting 0.521 g (3.6 mmol) of 9-amino-1,4-dioxa-7-azaspiro[4.4]nonane, from Step 6 Example 208, for the spiro compound of that example, and heating at 40° C. instead of 65° C. for 288 hours instead of 48 hours, the crude product was obtained. The compound was dissolved in methylene chloride which was washed with 2×100 mL of water then dried over anhydrous sodium sulfate, then the solvent was removed by evaporation under vacuum. The product was purified with HPLC, eluting with 60% increasing to 65% methanol/water. The solvent was removed by evaporation under vacuum to afford 0.466 g of the title compound, NMR (CDCl3) d 1.12 (m, 4H), 1.40 (t, 3H, J=7.5 Hz), 3.45 (m, 5H), 3.62 (m, 1H), 3.78 (m, 2H), 3.84 (m, 1H), 3.98 (m, 1H), 4.07 (m, 4H), 4.38 (q, 2H, J=7.5 Hz), 7.83 (dd, 1H, J=15, 1.5 Hz), 8.50 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:3][O:4][C:5](=[O:35])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[C:42]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=1)(=[O:45])[CH:43]=[CH2:44]>ClCCl>[C:42]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:62]=[CH:61][C:57]([C:58]([O:1][C@H:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:3][O:4][C:5](=[O:35])[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:34])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[O:59])=[CH:56][CH:55]=1)(=[O:45])[CH:43]=[CH2:44]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](O)c3ccccc3)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
0.56 g (2.7 mmole) of N,N-dicyclohexyl carbodiimide were added to a solution of 1.5 g (2.7 mmole) of (R)-4-(4-(6-acryloyloxyhexyloxy)benzoyloxy)cinnamic acid 2-hydroxy-2-phenyl-ethyl ester (21), 0.8 g (2.7 mmole) of 4-(6-acryloyloxy-hexyloxy)-benzoic acid (5) and 0.03 g (0.27 mmole) of 4-N,N-dimethylaminopyridine in 20 ml of dichloromethane, and cooled in an ice-water bath. After 3 h the ice-water bath was removed. The mixture was stirred at room temperature for two days. Then the mixture was filtered through a silica pad and the solvent was evaporated. After crystallization from ethanol, 1.2 g of the product (53%) were obtained with mp 97° C.
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19](Cl)=[O:20]>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:2]([F:3])([F:4])[F:1])=[CH:7][CH:8]=1)=[O:20]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)C=Cc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: O=C(C=Cc1ccc(Cl)c(Cl)c1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
p-Aminophenyl trifluoromethyl ether (0.7 g) pyridine (30 ml) and 3,4-dichlorocinnamoyl chloride (1 g) in dioxane (5 ml) were agitated and heated 3 hours at 80°-90° in a suitable flask fitted with a reflux condenser. The reaction mixture was then poured into 2 l. of ice-water containing conc. hydrochloric acid (50 ml). The crude product was filtered, washed with water and dried. It was recrystallized first from a blend of toluene (50 ml) and hexane (60 ml) and then from toluene (16 ml) and hexane (60 ml).
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:34][CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([CH3:43])[C:37]([CH3:45])([CH3:44])[CH2:36]1.O>CC(N(C)C)=O.C(O)CCC>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH:35]5[CH2:36][C:37]([CH3:44])([CH3:45])[N:38]([CH3:43])[C:39]([CH3:42])([CH3:41])[CH2:40]5)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c4c(nnc5c(F)cccc54)c3=O)cc2)CC1(C)C
Reaction time: 8 h

Procedure:
4-(6-fluoro-3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoyl chloride (100 mg, 0.29 mmol) was dissolved in anhydrous DMA (2 ml). Diisopropylethylamine (75 mg, 101 μl, 0.58 mmol) was added followed by 4-amino-1,2,2,6,6-pentamethylpiperidine (49 mg, 0.29 mmol). The mixture was stirred overnight. Water (5 ml) and n-butanol (5 ml) were added. The phases were separated. The organic phase was washed with water (2×5 ml) and the solution was concentrated under vacuum. The title compound was isolated as a dark red solid (50 mg, 0.105 mmol, 36%). LCMS: m/z [M+H]+ 477.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]3[CH:25]=[CH:24][N:23]=[C:14]3[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7]1)(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]3[CH:25]=[CH:24][N:23]=[C:14]3[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Temperature: 25 °C

Procedure:
To the solution of 0.2 g of 5-(4-carboethoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminum hydride are added at once and the mixture is refluxed under nitrogen for 48 hrs. The mixture is cooled to room temperature, stirred with 0.2 ml of 30% sodium hydroxide, and filtered. The filtrates were evaporated to dryness and the product is purified to give 5-(4-methylpiperazino]-imidazo[2,1-b][1,3,5]benzothiadiazepine, melting at 145°-7°, and identical to compound obtained in example 1.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([S:21][CH3:22])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:23][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:3][C:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([S:21][CH3:22])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:23])[CH3:2]
Reactant: C[Mg]Br
Reactant: CSc1ncc(C#N)c(-c2cnc3c(C(C)=O)cccn23)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(C#N)c(-c2cnc3c(C(C)(C)O)cccn23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of the 4-(8-acetylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [156-1] was dissolved in 5 mL of tetrahydrofuran, then 577 μL of methylmagnesium bromide (0.84M tetrahydrofuran solution) was added in an ice-cold condition, and stirred overnight at room temperature. 200 μL of methylmagnesium bromide was further added and stirred at room temperature for 4 hours, then a saturated aqueous solution of ammonium chloride was added to terminate the reaction. The reaction solution was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by preparative thin-layer chromatography, to obtain 18 mg of 4-[8-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [157-1] as a brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[C:17]([CH3:22])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:17]1[C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:32]4[CH2:33][C@@H:28]5[CH2:34][C@H:31]4[CH2:30][O:29]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:23]([F:26])([F:25])[F:24])=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1noc(C)c1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(C)c1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 56.2 %

Procedure:
200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 178 μl (1.28 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:21])[CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:20][C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:21])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: Cc1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)CC2(C)C
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline (348.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (104.8 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 371.2.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH2:16][CH2:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[N:23][C:22]=1[CH2:21][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][CH2:16][CH2:17][CH3:18])[C:3]([OH:2])=[O:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester (preparation 6) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-2-propoxy-propionic acid as light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
A suspension of 5-bromo-1H-indazole (200 mg, 1.02 mmol), cesium carbonate (661 mg, 2.00 mmol), and iodomethane (156 mg, 1.10 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 h. The mixture was partitioned between 5% lithium chloride and ethyl acetate, the aqueous layer was extracted with ethyl acetate (2×), the combined organic extracts were washed with 1 N sodium hydroxide, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) gave 5-bromo-1-methyl-1H-indazole (150 mg, 70% yield) as an orange solid. MS (EI) for C8H7BrN2: 212 (MH+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6]Br.P(Br)(Br)Br.[C:12]1([CH2:18][CH2:19][CH2:20][N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[NH:23][C:22]2=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>C(OCC)(=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:24]2[N:23]=[C:22]([Br:6])[N:21]([CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)Br
Agent: N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2nc(Br)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A reaction vessel was charged with POCl3 (1500.0 g, 9.78 mol). Br2 (184.9 g, 1.157 mol) was then added in one portion at ambient temperature. The reaction mixture was cooled to 10° C. and then PBr3 (313.0 g, 1,157 mol) was added over 25 min. under vigorous stirring. The temperature of the reaction mixture increased to 20° C. After addition, stirring was continued for another 1.5 h, maintaining the temperature in the range of 10–20° C. The formed PBr5 precipitated as a yellow solid. The reaction mixture was warmed to 25° C. and 1,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-imidazol-2-one (150.0 g 0,386 mol) was added in one portion. After addition, the reaction mixture was heated to about 30° C. and stirring was continued for 24 h. The suspension changed to a dark solution. The POCl3 was distilled off under vacuum at a temperature below 35° C., to yield a viscous oil. This oil was added to a mixture of ethyl acetate (1000 g) and aqueous ammonia (25 w %, 1000 g) over about 1.25 hours, with cooling. The resulting two phases were separated, the aqueous phase was extracted with ethyl acetate (500 g) and the combined organic phases were washed with water (200 g) at 70° C. The organic phase was concentrated to approximately 30% of the original volume. To the warmed reaction mixture, was then added triethylamine (600 g) and an additional amount of the solvent (about 150 g) was removed in vacuo, resulting in the crystallization of the desired product. The reaction mixture was cooled to 0° C. and stirred for 12 h. The product was filtered off, washed with triethylamine (50 g) and dried at 40° C. under vacuum, to yield the crude product.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)=O.N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>CS(C)=O>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:18])[CH:10]=1
Reactant: COc1cc(F)ccc1CO
Agent: O=S(=O)([O-])O
Agent: O=S(=O)=O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1cc(F)ccc1C=O
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Triethylamine (0.84 ml, 6.03 mmol) was added to a solution of 4-fluoro-2-methoxybenzylalcohol (310.8 mg, 1.99 mmol) in DMSO (7 ml). Pyridine sulfur trioxide (938.6 mg, 5.90 mmol) was added portionwise to the mixture checking raise of the temperature. The mixture was stirred for 1 hour. The mixture was added to 5% KHSO4 aqueous solution, extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (293.3 mg; 96%).
Reaction SMILES: C(Cl)Cl.[NH:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:25][O:26][CH2:27]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>[CH3:25][O:26][CH2:27][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 250 ml of methylene chloride, 25 g (0.20 mol) of thymine and 109 ml (0.44 mol) of bistrimethylsilylacetamide were added under a nitrogen flow, and stirred for 2.5 hours at room temperature. To this mixture, 24 g (0.30 mole) of chloromethyl methyl ether and 0.59 g (1.6 mmol) of tetrabutylammonium iodide were added and heated under reflux for 1.5 hours. Then, the reaction mixture was added with 400 ml of methanol and 100 ml of water slowly and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1-(methoxymethyl)-thymine. Then, 119 ml of lithium diisopropylamide (0.25 mol) solution in tetrahydrofuran (2.1M) was added to 335 ml of tetrahydrofuran under a nitrogen flow at -70° C., to which a suspension of 17.0 g (0.10 mol) 1-(methoxymethyl)thymine in 107 ml of tetrahydrofuran was added dropwise over 30 minutes. After stirring for 2.5 hours at -70° C., the reaction mixture was added with a solution of 43.6 g of diphenyl disulfide in 49 ml of tetrahydrofuran dropwise over 20 minutes and allowed to react for 20 minutes. The reaction mixture was added with 35 ml of acetic acid, brought to room temperature and then added with 1 l of ethyl acetate. The mixture was washed with water (100 ml×5) and saturated solution of sodium hydrogencarbonate (twice), dried on magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 20 g of the target compound (Yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][C:47]1[C:48]2[N:61]=[C:60]([NH2:62])[S:59][C:49]=2[C:50]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[N:51][CH:52]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:62][C:60]1[S:59][C:49]2[C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[N:51][CH:52]=[C:47]([O:46][CH3:45])[C:48]=2[N:61]=1)=[O:8]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1OC

Procedure:
From 3,4-dimethoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 431 (M+H+, 100).