Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].ClC1C=CC=C(C(OO)=[O:58])C=1>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[O:18])[CH2:13][S:14](=[O:58])[C@H:9]12)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)n3ccnc3)CS[C@H]12)c1csc(NC=O)n1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)n3ccnc3)CS(=O)[C@H]12)c1csc(NC=O)n1
Yield: 79.7 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-imidazolyl)carbonyloxymethyl-3-cephem-4-carboxylate (syn isomer)(13.5 g) in tetrahydrofuran (200 ml) was added m-chloroperbenzoic acid (5.8 g) with stirring under ice-cooling, followed by stirring for an hour at 5° C. The reaction mixture was evaporated and the residue was pulverized in diethyl ether, collected by filtration, washed with ethyl acetate and diethyl ether and then dried to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-imidazolyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer)(11.0 g).
Reaction SMILES: [C:1]([N:20]1[C:28]2[CH:27]=[C:26]([NH:29]C(=O)OC)[N:25]=[CH:24][C:23]=2[C:22]([NH:34][C:35](=[O:44])[O:36][CH2:37]C2C=CC=CC=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:29][C:26]1[N:25]=[CH:24][C:23]2[C:22]([NH:34][C:35](=[O:44])[O:36][CH3:37])=[N:21][N:20]([C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:28]=2[CH:27]=1
Reactant: COC(=O)Nc1cc2c(cn1)c(NC(=O)OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a 50 mL round bottom flask charged with benzyl methyl (1-trityl-1H-pyrazolo[4,3-c]pyridine-3,6-diyl)dicarbamate (126 mg, 0.216 mmol) in ethyl acetate (4 ml) and methanol (4 ml) was added palladium on carbon (45.9 mg, 0.043 mmol). The flask was evacuated and back-filled with hydrogen gas using an attached balloon. This procedure was attempted a further two times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The palladium was filtered off by passing the reaction mixture through celite and washing through with ethyl acetate (20 mL). The volatiles were removed in vacuo to afford crude methyl (6-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (95 mg, 0.211 mmol, 98% yield) as a white solid. MS ESI calc'd. For C27H24N5O2 [M+H]+ 450. found 450.
Reaction SMILES: [ClH:1].Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[ClH:29].[ClH:1].[ClH:29].[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:20]2[CH2:19][CH2:18][NH:17][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:21]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1cc(N2CCCCC2)ccc1[C@H]1CNCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCCCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine trihydrochloride obtained in Reference Example 3 (199 mg, 0.561 mmol) and triethylamine (427 μl, 306 mmol) in tetrahydrofuran was refluxed for 15 minutes. After cooling to room temperature, 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (122 mg, 0.510 mmol) was added portionwise and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and aqueous sodium bicarbonate, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting residue was washed with diethyl ether. Hydrogen chloride in ethyl acetate (4N) was added to a solution of the resulting solids in ethyl acetate, and the precipitate was collected by the filtration and dried to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-piperidin-1-yl-phenyl)-piperazin-1-yl)-3H-pyrimidin-4-one trihydrochloride (267 mg, 0.479 mmol, 94%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[Br:10]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:10])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
A solution of 0.2 g of 2-chloro-4-(hydroxymethyl)pyridine in 2.5 ml of dichloromethane is added dropwise to a solution of 0.706 g of dibromotriphenylphosphorane in 9.5 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3×50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (8/2) (v/v) at a flow rate of 8 ml/minute. The fractions between 8 and 24 ml are concentrated under reduced pressure. 0.1 g of 2-chloro-4-(bromomethyl)-pyridine is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11].FC(F)(F)C(O)=O.COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](CC1C=CC(OCC2C=CC=CC=2)=CC=1)N.[C:76]([O:80][C:81]([NH:83][C@H:84]([C:94](O)=[O:95])[CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:82])([CH3:79])([CH3:78])[CH3:77].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:94](=[O:95])[C@H:84]([CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:77])[CH3:78])=[O:82]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester trifluoroacetic acid salt by neutralizing to litmus with triethylamine in the cold and then adding 1.4 ml. (10 mmol) of additional triethylamine (pH 8.5). The cold solution is treated with 2.95 g. (10 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 1.35 g. of 1-hydroxybentriazole and 2.2 g. of dicyclohexylcarbodiimide. The mixture is stirred for two and one-half hours at -5° C. and overnight at room temperature. The mixture is filtered, the solid rinsed with dimethylformamide and the filtrate evaporated at 40° C. under reduced pressure. The residue is dissolved in 50 ml. of ethyl acetate and 200 ml. of ether and washed three times with 5% sodium bicarbonate solution and with saturated salt solution, dried over magnesium sulfate and evaporated. The residue is crystallized from a minimum of methanol by adding ether; 6.6 g. The product is recrystallized from methanol-ether; 6 g.; m.p. 67°-71° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][C:5]([CH2:12][O:13][CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>ClC1C=CC=CC=1Cl>[CH3:14][O:13][CH2:12][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:25](=[O:26])[C:19]3[N:15]2[C:16]([CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[N:17][CH:18]=3)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCc1cc(-n2ccnc2C2CCOC2)c(N)cc1C(=O)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: COCc1cc2c(cc1C(=O)OC)[nH]c(=O)c1cnc(C3CCOC3)n12
Temperature: 120 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 6.00 g of methyl 5-amino-2-(methoxymethyl)-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate, 5.87 g of 1,1′-carbonyldiimidazole, and 30 mL of 1,2-dichlorobenzene was stirred at 120° C. for 3 hours. After air-cooling, the precipitate was collected by filtration. The obtained solid was washed with methanol and air-dried to obtain 4.54 g of methyl 8-(methoxymethyl)-4-oxo-1-(tetrahydrofuran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(F)cc21
Yield: 96.4 %

Procedure:
1,1-Dimethylethyl N-((7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (590 mg, 1624 μmol) was stirred in TFA (3 mL, 40386 μmol) at room temperature for 15 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (481 mg). MS (m/e)=308.1 (M+H)+. Calculated for C15H14FNO5 307.09.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[CH3:18][O-:19].[Na+]>CO>[Cl:17][C:4]1[C:3]([CH2:2][O:19][CH3:18])=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: [Na+]
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution comprising 12.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate prepared in Reference Example 3(1) and 100 ml of methanol, 50 ml of a methanol solution containing 1.7 g of sodium methoxide was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. Then, dilute hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 9.5 g of the desired product as a crude product. The crude product was purified by silica gel column chromatography (eluted with benzene) to obtain 7.5 g of a purified product as an oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][O:24][CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CCNCCOC
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)ethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine, MS: 419 (MH+, 1Cl).
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10]([O:12]CC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:1]1([C:8]2[N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[N:25]=[C:10]([OH:12])[C:9]=2[C:15]2[C:16]([F:23])=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Oc1nc2nccn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (342 mg, 1.0 mmol), 2-aminoimidazole (Helv. Acta. Chim. 76, 2066 (1993))(83 mg, 1.0 mmol), and 0.5 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 1.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acide (×2) and saturated sodium chloride, dried over magnesium sulfate, and concentrated to give crude 5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-7-ol as a dark oil (294 mg).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[O:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][NH2:44]>CN(C=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:44][CH2:43][C@@H:39]4[CH2:40][CH2:41][CH2:42][O:38]4)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: NC[C@@H]1CCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). (S)-(tetrahydrofuran-2-yl)methanamine was added and the reaction mixture was stirred at 80° C. for 3 h. The solvent was evaporated under reduced pressure and the crude used in the subsequent step without purification. MS (ES+) m/z 493.3 (M+H)+
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16]Br.C(OCC)(=O)C>CC(N(C)C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16][O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#Cc1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
876 mg (2 eq) of sodium hydride is added gradually at 0° C. under nitrogen to a solution of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0° C. before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl bromide. The mixture is placed under stirring for 2.5 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The organic phases are isolated, dried and concentrated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68% of 5-(3,5-difluorobenzyloxy)nicotinonitrile in the form of a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.[Br:23]Br>C(O)(=O)C.ClCCl>[Br:23][C:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[C:6]([F:18])=[CH:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[CH:3][C:2]=2[F:1])[NH:15][CH:16]=1
Reactant: BrBr
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1.05 g (3.45 mmol) of N-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide are dissolved in 35 ml of glacial acetic acid and, using an ice bath, cooled to about 10° C. 4.8 ml (4.8 mmol) of a 1M solution of bromine in dichloromethane are added, and the mixture is stirred at 20° C. for about 30 min, resulting in the precipitation of a solid. The solid is filtered off with suction and washed with ethyl acetate. The mother liquor is neutralized using conc. aqueous sodium hydroxide solution and extracted with ethyl acetate. The crystals that were filtered off with suction are dissolved in 3 ml of DMF. The mixture is diluted with ethyl acetate and extracted three times with 1N sodium hydroxide solution. The combined organic phases are dried over magnesium sulfate. The solvent is removed under reduced pressure. The product is reacted without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:17]([CH3:22])([CH2:20]O)[CH2:18]O)[CH3:16]>>[CH2:15]([C:17]1([CH3:22])[CH2:20][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:18]1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CCC(C)(CO)CO
Product: CCC1(C)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
4-Nitrobenzylphosphonic acid and 2-ethyl-2-methyl-1,3-propanediol were treated in the same manner as in Reference Example 20 to yield 5-ethyl-5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 184°-185° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[N:13]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:17][C:14]1[CH:15]=[CH:16][N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[N:13]=1
Reactant: CN(CCn1ccc([N+](=O)[O-])n1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(CCn1ccc(N)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 783.3 %

Procedure:
To a solution of 206d (4.5 g, 1.7 mmol) in ethanol (40 mL) was added Fe (4.7 g, 8.5 mmol) and NH4Cl (900 mg, 17 mmol). The reaction mixture was stirred at room temperature for 4 hours. It was then evaporated and purified by silical-gel column eluting with 2:1 petroleum ether/ethyl acetate to give 206e as a brown solid (3.2 g, 80%). MS: (M+H)+ 241.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25](S(C)(=O)=O)[C:24]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CO>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:30])=[O:31])[NH:25][C:24]([C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one (780 mg, 1.27 mmol) in THF/methanol (15 mL/15 mL) was added Cs2CO3 (1.25 g, 3.83 mmol) in one portion. The mixture was allowed to stir at rt for 4 h and concentrated in vacuo to afford the crude product 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one. It was used for the next step reaction without further purification. To a solution of crude 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one, 2-(Boc-amino)ethyl bromide (2.8 g, 12 mmol), tetrabutylammonium iodide (235 mg, 0.63 mmol) in CH2Cl2/toluene (2 mL/4 mL) was added 40% NaOH aqueous solution (20 mL). The mixture was allowed to stir at rt for 20 h. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with H2O (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2/Methanol (95/5) to provide tert-butyl (2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate (300 mg, 35% yield for two steps).
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:14])[CH2:10][N:11]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]([CH2:8][CH:9]([OH:14])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC(O)COc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COc1ccccc1
Yield: 107.6 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 1.17 g of 3-phenoxy-2-hydroxypropylazide (prepared as described in Preparation 14), 0.46 g of lithium aluminum hydride and 20 ml of anhydrous tetrahydrofuran were used, to give 1.09 g of the title compound, melting at 82° C. to 84° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:32]([C:27]2[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a solution of 3-nitroaniline (28.8 g, 209 mmol, 1 equiv) in THF (1000 mL, 35 volumes), was added triethylamine (70 mL, 500 mmol, 2.4 equiv). 3-Nitroaniline can be obtained from Aldrich, Milwaukee, Wis. A solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (71.3 g, 250 mmol, 1.2 equiv) in THF (250 mL, 3.5 volumes) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 48 hours. The slurry was then filtered through diatomaceous earth and the filtrate was concentrated. Water (700 mL, 24 volumes) was added and the slurry was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum at 40° C. to provide 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-nitro-phenyl)-amide (80.7 g, 100%) as a pale yellow powder.