Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:23]([C:11]2[C:2]([OH:1])=[CH:3][C:4]3[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=3[CH:10]=2)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and benzoyl chloride (155 mg, 1.10 mmol) followed by stirring at 60° C. for 1 hour. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 27.3 mg (9%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].C(O)(=O)C.O.[CH3:12][C:13]([CH3:15])=O>>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:13]([CH3:15])[CH3:12])=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)NN=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Hydrazinecarboxylic acid methyl ester (5.01 g) were dissolved in acetone (28 mL), and acetic acid (0.0636 mL) was added. The reaction mixture was stirred at room temperature for 24 hours. Water (50 mL) was added, and mixture was extracted three times with DCM (50 mL) and evaporated under vacuum, giving N′-Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g, 89%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)[C:12]=3[N:33]3[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2cccs2)c(F)c2oc(C3CC3)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2cccs2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 12.5 h
Yield: 82.8 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(thiophen-2-yl)-1,3-benzoxazole-4-carbonitrile (I-307) (192 mg, 0.64 mmol) was dissolved in dimethyl sulfoxide (4 ml), and at room temperature, triethylamine (117 μl, 0.84 mmol) and (3S)-3-(dimethylamino)pyrrolidine (106 μl, 0.84 mmol) was added. After stirred under nitrogen atmosphere at 90° C. for 12.5 hours, this was cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7, v/v) to obtain the entitled compound (208 mg, 83%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[C:13]([Cl:24])=[N:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[C:13]([Cl:24])=[N:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)n1
Reactant: Clc1nc2ccccc2o1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)n1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
In xylene (100 ml), 2-chlorobenzoxazole (326 μl, 2.86 mmol) and ethyl (3-amino-2-chloro-6-pyridyl)acetate (557 mg, 2.59 mmol) were heated under reflux for 4 hours under stirring. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3:1, v/v) eluate fractions, ethyl (3-(2-benzoxazolyl)amino-2-chloro-6-pyridyl)acetate (460 mg, 53%) was obtained as a colorless gum.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([CH:10]1[CH2:20][C:19]2[C:21]3[C:16]([N:17]([CH2:22][C:23]4[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=4)[N:18]=2)=[N:15][C:14]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:13][C:12]=3[S:11]1)#[N:9].CC1C=CC(S(OC(C#N)CC2C3C(=NC(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=3Cl)N(CC3C(C)=C(OC)C(C)=CN=3)N=2)(=O)=O)=CC=1>ClCCl>[NH2:33][C:14]1[N:15]=[C:16]2[C:21]3[C:19]([CH2:20][CH:10]([C:8]#[N:9])[S:11][C:12]=3[N:13]=1)=[N:18][N:17]2[CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SC(C#N)C3)c1C
Agent: COc1c(C)cnc(Cn2nc(CC(C#N)OS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C#N)C3)c1C
Reaction time: 1 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (0.25 mL) was added to a mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 4) of Example 3 (30 mg) and dichloromethane (1 mL). Then, the ice bath was removed and the mixture was stirred for one hour. After confirming that the raw material disappeared, the reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried to obtain the title compound (13.8 mg, 71%).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:33])=[C:7]([C:9](=[N:30][O:31][CH3:32])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:34]>>[ClH:34].[NH2:3][C:4]1[S:5][C:6]([Br:33])=[C:7]([C:9](=[N:30][O:31][CH3:32])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.) was treated with conc. hydrochloric acid (0.34 ml.) in a similar manner so that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 850 mg.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:28]>CN(C(OC)OC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:17]=[C:18]([C:19](/[N:21]=[CH:9]/[N:10]([CH3:14])[CH3:11])=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:28]
Reactant: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Agent: COC(OC)N(C)C
Product: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 178.4 %

Procedure:
A solution of combined batches of 1 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxamide (220 mg, 0.52 mmol) in DMF-DMA (15 ml) was stirred at 130° C. for 2 h. When TLC showed no starting material remaining, the mixture was cooled to rt and the solvent was removed under reduced pressure to give the crude product (JS211561-105A1, 220 mg, 89%), as a yellow solid. LC-MS: m/e=474 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[N:10][CH:11]=[CH:12][CH:13]=3.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[N+:10]([O-:26])[CH:11]=[CH:12][CH:13]=3
Reactant: O=c1c2cc(Br)ccc2ccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(Br)ccc2ccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of 2.15 grams (0.0075 mole) of 9-bromo-11-oxo-benzo[5,6]cyclohepta-[1,2-b]pyridine in 40 milliliters of chloroform was added 1.78 grams (0.0082 mole) of m-chloroperbenzoic acid and the resulting solution was stirred at room temperature for about 24 hours. At this time, an additional 0.9 gram of m-chloroperbenzoic acid oxidant was added and the stirring continued for 5 hours, after which time, yet another 0.45 gram of the oxidant was added and the stirring continued overnight at room temperature. The resulting mixture was washed twice with 10 percent aqueous sodium hydroxide and twice with water and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated at reduced pressure to obtain a residue. The latter was triturated with acetonitrile to obtain 1.37 grams of 9-bromo-11-oxo-benzo[5,6]cyclohepta[1,2-b]pyridine N-oxide intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH:20]([N-]C(C)C)(C)C.[Li+].CI.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:20][CH:6]1[C:5](=[O:9])[N:4]2[CH:7]1[CH2:8][C:2]([Cl:1])=[C:3]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12

Procedure:
A solution of benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (56 mg) in anhydrous THF (0.5 ml) is added dropwise over a few minutes to a stirring solution of lithium diisopropylamide (from 31 μl diisopropylamine and 140 μl 1.6N BuLi) in anhydrous THF (3 ml) at -78°. After 15 more mins at -78°, the solution is treated with methyliodide (125 μl) and then allowed to warm to -20° over a period of 30 mins. Saturated aqueous NH4Cl (3 ml) is added and the mixture is allowed to come to room temperature. The mixture is diluted with EtOAc (50 ml), washed with pH 3 phosphate buffer, water, 5% NaHCO3, and brine, dried with magnesium sulfate, and evaporated in vacuo to give benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:1]([N:9]1[CH2:10][CH2:11][CH:6]([OH:5])[CH2:7][CH2:8]1)=[O:3]
Reactant: OC1CCNCC1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add a solution of sodium nitrite (13.8 g, 200 mmol) in water (40 mL) to 4-hydroxy piperidine (10.1 g, 100 mmol) in water (20 mL). Cool the mixture to 0° C. on an ice bath. Add acetic acid (8.6 mL, 150 mmol) dropwise over 20 minutes. After the addition, continue stirring at 0° C. for 30 minutes, slowly warm up to room temperature and stir at room temp for 5 hours. Add sodium carbonate (15.9 g, 150 mmol) in portion to quench the acid. Extract the reaction with ethyl acetate (3×60 mL), combine the organic, dry over sodium sulfate, filter and concentrate to afford the desired product as yellow oil. Yield: 12.9 g, (98%).
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1cc2c(s1)CCNC2)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.84 g of tert-butyldiphenylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldiphenylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, and 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto. The mixture was allowed to react at room temperature (20° C.) for 1.5 hours by further stirring and then left to stand overnight to obtain a reaction mixture.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:55]=[C:54]3[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([O:60]C)=[O:59])[C:53]3=[O:56])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:39]>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:55]=[C:54]3[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([OH:60])=[O:59])[C:53]3=[O:56])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1OC
Yield: 79 %

Procedure:
The compound of example 142 was prepared analogous to compound of example 98 by hydrolysis of compound of example 141.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:13])[NH:24][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:23][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C=O)C=O)cc1OC
Reactant: N=C(N)c1ccccc1
Product: COc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC
Yield: 67 %

Procedure:
(3,4-Dimethoxyphenyl)malonaldehyde acid methyl ester (7.2 g) (30 mmol) and 10 g (42 mmol) of benzamidine are melted at 100° C. The reaction mixture is chromatographed on 250 g of silica gel (0.063-0.2 mm) and the product is eluted with dichloromethane/methanol (9:1 v/v). The eluate is concentrated in a vacuum at 45° C. and the crystalline product is filtered off under suction. The whole is washed with diethyl ether and dried in a high vacuum at room temperature. There are obtained 6.2 g of 5-(3,4-dimethoxyphenyl)-2-phenyl-6(1H)-pyrimidinone as yellow crystals of m.p. 230° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ncccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCOc1ncccc1N
Temperature: 25 °C

Procedure:
To the solution of 2-allyloxy-3-nitropyridine(28.68 mmol) in ethanol (30 ml), Tin (II) chloride (143.4 mmol) may be added. The reaction mixture can be stirred at reflux for 4 hours and then can be cooled to room temperature. NaHCO3 (aq) can be added until pH=7 is achieved. Then the reaction mixture can be extracted with ethyl acetate (3×). The combined organic layer can be dried over MgSO4, filtered and concentrated under reduced pressure to give desired product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:33][CH3:34])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][C:8]1([F:32])[F:31]>CN(C)C=O>[CH3:34][O:33][C:7]1([O:6][CH3:5])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][C:8]1([F:31])[F:32]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2)CC1(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1(F)F
Temperature: 70 °C
Yield: 88 %

Procedure:
The mixture of sodium azide (26.0 mmol) and (R)-{3-[4-(4,4-dimethoxy-3,3-difluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (12.0 mmol) in dimethylformamide was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 88% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][NH:47][CH:48]=2)O1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:44]2[CH:45]=[N:46][NH:47][CH:48]=2)[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Br)cc(OCc2ccccc2)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Product: COc1cc(-c2cn[nH]c2)cc(OCc2ccccc2)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
6-(2-(Benzyloxy)-4-bromo-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (129 mg, 50% pure, 0.12 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.4 mg, 0.24 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(2-(Benzyloxy)-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a yellow solid (14 mg, 22% yield) after HPLC purification. MS (M+1)=527.4.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[ClH:2].[C:7]1([C:13]2[CH:14]=[CH:15][N:16]=[C:17]([CH2:3][CH2:4][CH2:5][NH2:6])[CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCCCl
Reactant: c1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCc1cc(-c2ccccc2)ccn1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
3-Chloropropylamine hydrochloride (13.0 g) and 15.5 g of 4-phenylpyridine were dissolved in dimethylacetamido and heated at 70° C. for 5 hours. Ethyl acetate was added thereto and the precipitated crystals were collected by filtration to obtain 17.5 g of 3-(4-phenylpyridyl)propylamine hydrochloride.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:14]([F:15])=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:14]([F:15])=[CH:13][C:12]([N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(Br)cc(F)c1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(N(Cc3ccccc3)Cc3ccccc3)c(F)c2)CC1

Procedure:
A mixture of the product of Example 16B (490 mg, 1.3 mmol), tert-butyl piperazine-1-carboxylate (258 mg, 1.4 mmol), palladium diacetate (14 mg, 0.06 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (59 mg, 0.09 mmol) and cesium carbonate (848 mg, 2.6 mmol) in 1,4-dioxane (10 mL) was heated at reflux for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum ether/ethyl acetate to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=1[CH3:23])([O-:9])=[O:8].[Cl:28]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N+:7]([C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH2:18][Cl:28])=[CH:16][C:15]=1[CH3:23])([O-:9])=[O:8]
Reactant: Cc1cc(CO)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(CCl)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 165.6 %

Procedure:
Pyridine (79 mL, 0.97 mmol) was added to a stirring mixture of 8b (112 mg, 0.39 mmol) and triphosgene (46 mg, 0.16 mmol) in CH2Cl2 (5 mL) at r.t. After 15 minutes, the reaction mixture was concentrated in vacuo. Flash chromatography (20 g, 5:1 hexanes/ethyl acetate) yielded 9b (81 mg, 68%) as a white solid: 1H NMR (270 MHz, CDCI3) d 2.27 (s, 6H), 4.52 (s, 2H), 5.23(s, 2H), 7.09 (s, 2H), 7.51 (t, J=8.2 Hz, 1H), 7.76 (t, J=7.4 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H); 13C NMR (68 MHz, CDCI3) d 16.4, 46.2, 70.1, 124.9, 128.2, 128.4, 129.5, 131.5, 133.5, 134.2, 134.7, 146.6, 155.6.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 2,4-dichlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H10Cl2N4, 330. Found, 329, 331.