Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:31](OC)[N:32]([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:17]([N:18]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
In a round bottom flask containing 10 mL of toluene is added 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butyl ester (3.0 g, 7.9 mmol) and dimethylformamide dimethyl acetal (5.4 mL, 31.6 mmol) under a positive nitrogen flow. The mixture is stirred at 120° C. for 1.5 hour, then cooled to room temperature. The volatiles are removed under reduced pressure and the resulting residue dried in vacuo for 15 h to yield 3.0 g of 6-benzyloxy-3-(dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carboxylic acid tert-butyl ester as a dark oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14]CC)=[O:13])[CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]2
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1Cc2ccc(O)cc2C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
50 g (0.23 mol) of the compound from Example 13 are initially introduced in 780 ml of absolute CH2Cl2 at -78° C. 114 ml (1.2 mol) of boron tribromide in 360 ml of absolute CH2Cl2 are then added dropwise and the mixture is stirred at -78° C. for 30 minutes. It is then stirred at 0° C. for 2.5 h, subsequently cooled to -78° C. again and 690 ml of absolute MeOH are added cautiously. After 15 minutes, the mixture is evaporated, the residue is dissolved in 818 ml of MeOH, 272 ml of 2N NaOH solution are added and the mixture is stirred at 20° C. for 2 h. The methanol is evaporated in vacuo, the aqueous phase is washed with 200 ml of ethyl acetate and then acidified to pH 1-2 using concentrated hydrochloric acid with ice cooling. The aqueous phase is shaken twice with 100 ml of ethyl acetate each time, and the combined ethyl acetate phases are dried over Na2SO4 and evaporated. The residue is recrystallized from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1.Cl>C(O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8])=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(Oc2ccc(N)cn2)c1
Yield: 109.2 %

Procedure:
To a solution of methyl 4-methoxy-3-[(5-nitropyridin-2-yl)oxy]benzoate (26.7 mmol) in ethanol (250 mL) were added iron powder (5.6 g, 0.1 mol) and 6N hydrochloric acid (50 mL) with heating under reflux and vigorous stirring, and the mixture was vigorously stirred under refluxing condition for 1.5 hr. The reaction solution was filtered through celite, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (350 mL), and washed with 1N aqueous sodium hydroxide solution (200 mL×2). The aqueous layer was extracted with ethyl acetate (150 mL×3), and the combined organic layer was washed with saturated aqueous ammonium chloride solution (100 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (8.0 g) as a brownish-red syrup substance.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](I)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: CC(=O)Nc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 59.6 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as tan solid (0.17 g, 60%), m.p. 58°-60° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.C(OCC)C>[CH2:10]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH:5]1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccnc(C)c1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC1CC(=O)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
6.97 g of 4-methoxy-2-methylpyridine was dissolved in 200 ml of acetone and 13.5 g of benzyl bromide was added thereto. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The precipitate was taken up by filtration and the solid matter was dissolved in 60 ml of water. Next, 5.35 g of sodium borohydride was added thereto in portions. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. To the obtained residue was added 5 N hydrochloric acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was made basic by adding potassium carbonate, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 6.84 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:17]=1)[CH:2]=[CH2:3].[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:18]1[N:17]=[C:16]([N:5]2[C:6]3=[N:7][C:8]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)=[N:9][CH:10]=[C:11]3[C:12](=[O:13])[N:4]2[CH2:1][C:2]#[CH:3])[CH:21]=[CH:20][CH:19]=1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(CC(C)(C)O)n1
Reactant: CN(C)C(=O)CN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(CC(C)(C)O)n1

Procedure:
27 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 81-2 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[OH-].[Na+:17].C(=O)([O-])O.[Na+].[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30](Cl)=[O:31])(=[O:26])=[O:25]>O.O1CCCC1>[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12)=[O:31])(=[O:26])=[O:25].[Na+:17]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)CCOC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12

Procedure:
In 50 ml of water is suspended 4.60 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid and, with ice-cooling and stirring, 20 ml of 1N aqueous sodium hydroxide solution is added to the suspension for dissolving the acid. To the solution is added 1.85 g of sodium hydrogen carbonate and, then, a solution of 4.11 g of 2-methylsulfonylethoxycarbonyl chloride in 40 ml of tetrahydrofuran is added dropwise. The mixtrue is stirred with ice-cooling for 2 hours, then adjusted to pH 6.5, washed with ethyl acetate, and concentrated under reduced pressure. The residue is subjected to column chromatography on XAD-II (600 ml). Elution is performed with water and the eluate is concentrated under reduced pressure and freeze-dried to give 3.10 g of sodium 7β-(2-methylsulfonylethoxycarbonylamino)-3-hydroxymethyl-3-cephem-4-carboxylate as light yellow powders.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@H:3]1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=1)=[O:21].[H-].[Na+].Br[CH2:40][C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42]>CN(C)C=O>[C:43]([C:41]([CH2:40][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@@H:3]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=2)=[O:21])[C:2]1=[O:1])=[O:42])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)OC(=O)Cc1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3NC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea (4.93 g) was added to a suspension of 60% sodium hydride (440 mg) in anhydrous N,N-dimethylformamide (50 ml) under ice-cooling, the mixture was stirred for one hour. Bromomethyl tert-butylketone (1.97 g) was added thereto, the resultant mixture was stirred at room temperature for one hour, the reaction mixture was poured into ice-water, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After dried over anhydrous sodium sulfate, the mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby obtain 5.07 g of the title compound (Yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9]([Cl:19])[CH2:10][C:4]=2[CH:3]=1
Reactant: [Cl-]
Reactant: OC1Cc2cc(Cl)ccc2Sc2ccc(F)cc21
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2

Procedure:
58.3 G. of 2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol 300 ml. of benzene and 21 g. of finely pulverized calcium chloride are saturated with hydrochloric acid over a period of 2 hours at 15°. The resulting precipitate is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin as white crystals, having a melting point of 84°-85°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:4][N:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C(#N)C>[CH3:21][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:4][N:3]=1)=[O:33])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCc1cc(N)no1
Solvent: CC#N
Product: CCCCCCCCCCCCc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)no1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A slurry of 3-amino-5-dodecylisoxazole (2.20 g, 8.72 mmol) in acetonitrile (50 mL) was warmed until homogeneous. 2,6-Diisopropylphenyl-isocyanate (1.86 mL, 8.72 mmol) was then added in one portion and the resulting solution was heated under reflux for 6 hours. The resulting solution was cooled (25° C.), concentrated in vacuo, and chromatographed on silica (90:10 to 70;30 hexane:ethyl acetate). The product containing fractions were combined and concentrated to a solid which was washed with cold acetonitrile to yield 0.95 g (23.9%) of the title compound as a white solid, m.p. 101°-107° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([NH:18][C:19](=[O:24])[C:20](Br)([CH3:22])[CH3:21])[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]1[C:5]2[O:25][C:20]([CH3:22])([CH3:21])[C:19](=[O:24])[NH:18][C:6]=2[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(NC(=O)C(C)(C)Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2

Procedure:
6.60 g (16.2 mmol) N-(3-acetyl-5-benzyloxy-2-hydroxy-phenyl)-2-bromo-2-methyl-propionamide and 2.76 g (20 mmol) potassium carbonate are stirred for 1 hour in 70 mL acetonitrile at reflux temperature. The solid is suction filtered, the filtrate is evaporated down and the residue is combined with 30 mL ethyl acetate. After further filtration and after the solvent has been distilled off the crude product is recrystallised from a little methanol.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[CH3:15][N:16]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNN
Solvent: CCO
Product: CN1N=C(c2ccccc2)CC1=O
Yield: 72.7 %

Procedure:
According to General Procedure A; ethyl benzoylacetate (18.4 mL, 95.5 mmol, 1.1 equ.) in ethanol (180 mL) was treated at 0° C. with methylhydrazine (4.57 mL, 86.8 mmol, 1.0 equ.) to give 1-methyl-3-phenyl-1H-pyrazol-5(4H)-one (11.0 g 63.1 mmol, 73%) after purification by crystallization (ethanol) as a light yellow solid. 1H-NMR (400 MHz) CDCl3: 7.67-7.65 (m, 2H), 7.42-7.41 (m, 3H), 3.60 (s, 2H), 3.41 (s, 3H), 13C-NMR (100 MHz) CDCl3: 171.8, 154.2, 131.0, 130.3, 128.8, 125.6, 37.9, 31.4. LC/MS-MS: 175.0→77.2 m/z; GS1 and GS2 at 30, DP=66, CE=43, CXP=4, tR=3.45 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:36]([CH3:35])(=[O:38])=[O:37])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
21.4 g (56.6 mmol) of 2-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 7 was dissolved in 200 ml of methylene chloride, 19.7 ml (141.5 mmol) of triethylamine was added, the temperature was lowered to 0° C., and then, 8.76 ml (113.2 mmol) of methansulfonyl chloride was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with 200 mL of methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and then, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH2:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc2c1OCC2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2c1OCC2
Reaction time: 3 h

Procedure:
The product of Example 48B (4.40 g) in N,N-dimethylformamide (60 mL) at room temperature was treated in one portion with sodium azide (5.37 g), stirred for 3 hours, poured into water and extracted with diethylether (2×100 mL). The organics were dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (5% ethyl acetate/hexane) to provide the title compound. 1H NMR (CDCl3) δ 3.23 (t, 2H), 4.31 (s, 2H), 4.60 (t, 2H), 6.85 (t, 1H), 7.06 (d, 1H), 7.19 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11].[CH3:12][Zn]C>O1CCOCC1>[CH3:12][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11]
Reactant: Nc1ncnn2cc(Br)cc12
Reactant: C[Zn]C
Solvent: C1COCCO1
Product: Cc1cc2c(N)ncnn2c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 79.8 %

Procedure:
To a degassed solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (Intermediate AAE) (316 mg, 1.48 mmol) and Bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.037 mmol) in 1,4-dioxane (10 mL), was added dimethyl zinc (2.97 mL, 5.93 mmol, 2.0 M in toluene). The mixture was allowed to stir at 90° C. for 17 hr and then cooled to 0° C. The reaction was quenched with MeOH (1.0 mL) and partitioned between ethyl acetate (200 mL) and potassium phosphate dibasic pH 10 buffer (100 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. Trituration with Et2O afforded 175 mg (79%) of the desired product. 1H-NMR (DMSO-d6) δ 7.69 (s, 1H), 7.39 (s, 1H), 6.61 (s, 1H), 2.18 (s, 3H); MS [M+H]+=148.9; LCMS RT=1.16.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.C(Cl)Cl>[N:18]([C@@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](c2ccccc2)C1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
A solution of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate (0.8 g) in DMF (10 mL) was treated with sodium azide (0.8 g) and heated at 100° C. for 4 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.5 g of trans-4-azido-2-phenyl-tetrahydro-2H-pyran.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=O)#[N:5]>C(O)C>[NH2:5][C:4]1[NH:3][N:2]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CC#N)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(N)[nH]n3)cc2)CC1
Yield: 80.9 %

Procedure:
2.36 ml (29 mmol) of hydrazine hydrate is added to a solution of 1.6 g (4.86 mmol) of tert-butyl 4-(4-(2-cyanoacetyl)phenyl)piperazine-1-carboxylate dissolved in 30 ml of ethanol. The reaction medium is carried at reflux for 12 hours and then concentrated to a third of its volume. The solid is then triturated, filtered and dried to yield 1.35 g (80%) of tert-butyl 4-(4-(5-amino-1H-pyrazol-3-yl)phenyl)piperazine-1-carboxylate in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:9]1([S:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: ClCCCCCCSc1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCCCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(6-chlorohexyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 437.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25]Br)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1>CC(C)=O>[CH2:16]1[CH2:15][O:14][C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:1]=[C:2]([C:3]4[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=4[CH3:8])[S:13][CH:25]=3)=[CH:23][C:18]=2[O:17]1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc4c(c3)OCCO4)cs2)c(C)s1
Reaction time: 48 h
Yield: 95.1 %

Procedure:
40 mg (0.162 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagent grade acetone. 1-(2H,3H-benzo[e]1,4-dioxin-6-yl)-2-bromoethan-1-one (0.162 mmol; 42 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and allowed to stir for 2 days after which the reaction solution was concentrated in vacuo. The crude product was dissolved in 50 mL of CH2Cl2 and partitioned between 50 mL of 1 N NaOH (aq.). The organic layer was obtained and dried over sodium sulfate and concentrated to afford 60 mg (90% yield) of methyl 4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate.