Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CO>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Product: Cc1ccc2nc(Cl)nc(NCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 2,4-dichloro-6-methylquinazoline (700 mg, 3.29 mmol), tert-butyl N-(2-aminoethyl)carbamate (2.6 g, 16.4 mmol) and methanol (35 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography to afford 1.0 g of the product as a white solid (yield was 91%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)[C:3]=1[CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Temperature: 60 °C
Yield: 55.9 %

Procedure:
To a solution of methyl [2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.233 g; 0.5 mmol) in methanol (5 mL) was added a solution of sodium hydroxide 5 N (1 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.125 g (56%) of the title compound as a light yellow solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=O)C.[C:16](Cl)(=[O:28])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>Cl>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:16]([N:4]2[CH2:9][CH2:8][CH:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2)=[O:28])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(C(=O)O)C1CCN(C(C)=O)CC1
Agent: Cl
Product: CCC(C(=O)O)C1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of (1-acetyl-4-piperidinyl)butyric acid (11.6 g, 54.4 mmol) and concentrated hydrochloric acid (30 ml) was refluxed for 16 hours, at the end of which time the hydrochloric acid was distilled off under reduced pressure. The residue was washed with ether and dissolved in 5N-NaOH/H2O (30 ml), followed by addition of ether (30 ml). To this mixture with ice-bath cooling was added p-nitrobenzyl chlorocarbonate (11.7 g, 54.3 mmol) in small portions, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4, and the solvent was distilled off under reduced pressure. The residual oil was treated with ether to provide the title compound (13.5 g) as colorless powders.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([NH:28][C:29]1[CH:40]=[CH:39][C:32]2[NH:33][C:34]([C:36]([OH:38])=O)=[N:35][C:31]=2[CH:30]=1)(=[O:27])[CH3:26].[NH2:41][CH2:42][C:43]1[C:44]([F:60])=[C:45]([O:50][C:51]2[CH:52]=[C:53]([CH:56]=[C:57]([Cl:59])[CH:58]=2)[C:54]#[N:55])[C:46]([Cl:49])=[CH:47][CH:48]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[C:25]([NH:28][C:29]1[CH:40]=[CH:39][C:32]2[NH:33][C:34]([C:36]([NH:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([O:50][C:51]4[CH:52]=[C:53]([C:54]#[N:55])[CH:56]=[C:57]([Cl:59])[CH:58]=4)[C:44]=3[F:60])=[O:38])=[N:35][C:31]=2[CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)nc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 5-(acetylamino)-1H-benzimidazole-2-carboxylic acid (0.035 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.031 g, 0.241 mmol) in DMF (1 mL). After stirring at RT overnight, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to give the title compound (0.007 g, 8.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.03 (s, 1H), 9.48 (s, 1H), 8.11 (m, 1H), 7.74-7.90 (m, 1H), 7.43-7.67 (m, 4H), 7.35-7.44 (m, 1H), 7.26-7.34 (m, 1H), 4.55 (s, 2H), 2.05 (s, 3H). MS: m/z 512 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)(Cl)(Cl)Cl>[CH:10]1[C:11]2[N:12]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OCCOCCn1c2ccccc2c2ccccc21
Reactant: C=C(C)C(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)OCCOCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
1.05 g (4.12 mmol) 4 and 0.65 g (6.22 mmol) methacryloyl chloride were dissolved in 15 ml of carbon tetrachloride. After the addition of 2.6 g activated molecular sieves (3 Å), the mixture was heated to reflux for 24 h. After cooling down to room temperature, it was filtered over basic alumina using 20% THF in CCl4. Evaporating the solvent yielded 0.8 g (60.1%) of a viscous yellow oil. Rf=0.44 (EtOAc/hexanes: 2/8). 1H NMR (CDCl3, 500 MHz, 20° C.): d 8.10 (t, 2H, J=7.76 Hz), 7.44 (m, 4H), 7.23 (m, 2H), 5.99 (s, 1H), 5.51 (s, 1H), 4.49 (t, 2H, 5.95 Hz), 4.19 (t, 2H, J=4.75 Hz), 3.88 (t, 2H, J=5.95 Hz), 3.59 (t, 2H, J=4.75 Hz), 1.88 (s, 3H). 13C NMR (CDCl3, 125 MHz, 20° C.): d 167.3, 140.6, 136.0, 125.8, 125.7, 122.9, 120.3, 119.0, 108.8, 69.5, 69.3, 63.7, 43.2, 18.2.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(O)(=O)C.ClCCl.CO>[C:20]([O:10][C:9]([C:7]1[S:6][C:5]2[CH:12]=[CH:13][C:2]([OH:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cc2cc(O)ccc2s1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(OC(=O)c1cc2cc(O)ccc2s1)c1ccccc1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
To a suspension of 1168 mg (6.01 mmol) 5-Hydroxy-benzo[b]thiophene-2-carboxylic acid (Misra, T., et al., Spectrochim. Acta Part A 57 (2001) 2795–2808) in 30 ml dichloromethane were added 1186 mg (15 mmol) pyridine. The mixture was cooled to 0° C. and a solution of 1968 mg (14 mmol) benzoyl chloride in 15 ml dichloromethane was added within 0.5 h. The reaction mixture was warmed to room temperature and added to 5% aqueous citric acid. The aqueous phase was extracted twice with dichloromethane, the solvent of the organic phases was removed and the residue was chromatographed on silica gel (dichloromethane/methanol 19:1 and then dichloromethane/methanol 19:1 with 2% acetic acid) to yield 1180 mg (3.96 mmol) O-Benzoyl-5-hydroxybenzothiophene-2-carboxylic acid (2) as colorless crystals, mp. 235–236° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13]CC(O)C[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17]>[C].[Pd].C(C(CCCC)CO)C>[CH2:16]([CH:18]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:19][OH:1])[CH3:15].[CH3:13][C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[CH2:9].[C:18]1([CH:16]([CH3:17])[CH3:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Solvent: CCCCC(CC)CO
Product: CC(C)c1ccccc1

Procedure:
A 300-ml four-necked glass flask was charged with 38.0 g (0.20 mole) of 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol, 0.4 g of 5% palladium carbon, 59.1 g (0.50 mole) of α-methylstyrene and 100 ml of 2-ethylhexanol. The mixture was reacted at 160° C. for 4 hours in a nitrogen atmosphere. The reaction mixture was hot filtered at 150° C. to recover the palladium-carbon. 2-Ethylhexanol, α-methylstyrene and cumene formed were distilled off from the filtrate under reduced pressure. 37.2 g of white crystals of 4,4'-biphenol were obtained. The product had a purity of 98.6% based on liquid chromatography, a p-phenylphenol content of 0.9% and a yield converted to a purity basis of 98.5%. High purity 4,4'-biphenol useful as the raw material of high-temperature resistant resins and other intermediates can be obtained in high yield according to this invention.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:19])[C:13]3[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.CO>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:12]=2[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Yield: 61.5 %

Procedure:
A dispersion of 8-benzyloxy-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (22.0 g, 56.3 mmol) and 10% palladium on carbon (7.5 g) in 50:50 ethanol/methanol (300 mL) was shaken under hydrogen pressure on a Parr apparatus at 50 psi (3.4×105 Pa) for three days. The reaction mixture was filtered to remove the catalyst, which was washed with hot ethanol/methanol (3 L). The filtrate was concentrated under reduced pressure. The resulting solid was triturated with methanol and isolated by filtration to provide 10.4 g of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C[O:20][CH2:19]C1.C([Li])(CC)C.Cl>C1(C)C=CC=CC=1.CN(C)C=O.CCCCCC.C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: C1CCOC1
Reactant: CCCc1ccc(-c2cccc(F)c2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(C=O)c(F)c2)cc1
Temperature: -74 °C
Reaction time: 2 h

Procedure:
In a reaction vessel under a nitrogen atmosphere, 27.0 g of 3-fluoro-4′-propylbiphenyl (T-1) and 270 ml of THF were put, and cooled to −74° C. Thereto, 141 ml of cyclohexane and n-hexane solution of 1.07 M sec-butyllithium was added dropwise in a temperature range of −74° C. to −65° C., and stirred for another 120 minutes. Subsequently, 19.5 ml of N,N-dimethylformamide (DMF) was added dropwise in a temperature range of −74° C. to −67° C., and stirred for another 60 minutes. The reaction mixture obtained was returned to 25° C., and then poured into 300 ml of 0.1 N hydrochloric acid solution and mixed. Then 300 ml of toluene was added, and allowed to be separated into an organic layer and an aqueous layer, and extraction was carried out. Then the organic layer obtained was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel; heptane/toluene (=1/1 by volume)) to obtain 29.6 g of 3-fluoro-4′-propylbiphenyl-4-carbaldehyde (T-2). The yield based on compound (T-1) was 97%.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C[C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>O.CO>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][O:9][CH3:7])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C

Procedure:
To 10 ml of carbon tetrachloride were added 2.72 g of 7-ACA, 15 g of antimony pentachloride and 1.40 g of methanol. The mixture was cooled at 10° C. for 80 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 150 ml of water. Then, the mixture was adjusted to pH 7.7 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid, and then concentrated by evaporation under reduced pressure so that a precipitate was formed. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.61 g. The yield of the desired product was 25 %.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].Cl.[F:8][C:9]1([F:34])[CH2:11][CH:10]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1)[CH2:18][CH2:17]2.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([CH2:3][C:4]([NH:33][C@H:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:12][CH:10]4[CH2:11][C:9]4([F:34])[F:8])[CH:15]=3)[CH2:20]2)=[CH:26][CH:27]=1)[CH3:32])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)CC#N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C

Procedure:
1.70 mg (20.0 μmol) Cyanoacetic acid, 4.09 mg (10.0 μmol) (S)-1-{4-[6-(2,2-difluoro-cyclopropylmethoxy)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-phenyl}-ethylamine hydrochloride (example XXXIII.1) and 6.88 μL (40.0 μmol) DIPEA in 0.5 mL ACN are stirred at r.t. Then 4.18 mg (15.0 μmol) CIP are added and the resulting mixture is stirred at r.t. over night. The reaction is quenched by the addition of 25 μL aq. K2CO3 solution (c=3 mol/L), filtered over basic aluminum oxide and concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:17]>>[NH2:17][C:7]1[C:6]2([F:16])[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: N
Reactant: FC12CCCC1c1cc(Br)ccc1NC2=S
Product: NC1=Nc2ccc(Br)cc2C2CCCC12F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
75 mg (0.25 mmol) of 8-bromo-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 20 ml of 7 M methanolic ammonia solution. After 1.5 hours of stirring at room temperature, the batch is concentrated by evaporation in a vacuum and the residue is purified by column chromatography on silica gel with ethyl acetate: 60 mg of product, melting point 220° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Cn2nccc2CBr)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nccc2Cn2nc(I)c3c([N+](=O)[O-])cccc32)cc1
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (1.55 g, 5.37 mmol) in DMF (20 mL) was added 5-(bromomethyl)-1-(4-methoxybenzyl)-1H-pyrazole (1.51 g, 5.37 mmol) and K2CO3 (1.11 g, 8.06 mmol). The reaction mixture was stirred overnight, diluted with EtOAc (100 mL), washed with H2O and brine (10 mL), and then concentrated under reduced pressure. Silica gel chromatography (Hexanes/EtOAc 5:1) provided the desired product (2.35 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[CH2:7][C:6]=2[CH:14]=1.C([O-])(=O)C.[Na+]>[Pd].O1CCCC1>[O:12]=[S:9]1(=[O:11])[CH:8]([CH3:13])[CH2:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: CC1Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O

Procedure:
2,2 g of 6-bromo-3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are hydrogenated in the presence of 0.7 g of sodium acetate and 0.3 g of 5% palladium on carbon catalyst at 20° C. and 1 bar in 45 ml of tetrahydrofurane. The catalyst is removed, the solvent evaporated, the residue taken up with a mixture of water and ethyl acetate. The organic phase is separated, washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The residue is crystallised from acetonitrile, affording 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide with a melting point of 204°-205° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[S:13][CH:14]=1)=[O:7].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH:17]([O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:18]2)[S:13][CH:14]=1)=[O:7]
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1ccco1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (426 mg, 1.72 mmol) (obtained as described in Reference Example 67(2)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.16 ml, 2.07 mmol) and triethylamine (0.29 ml, 2.07 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (20:1) as the eluant to afford 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (481 mg, yield 78%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]2[CH2:13][CH:14]([CH2:17]OS(C)(=O)=O)[CH2:15][CH2:16][CH:9]2[CH2:8]1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.O>[N:23]([CH2:17][CH:14]1[CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH:9]2[CH2:16][CH2:15]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCC2CN(c3ncccn3)CCN2C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution containing methanesulfonic acid 2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1 eq., see subpart (b) above) and sodium azide (2 eq.) in DMF was stirred at around 90° C. for 24 hours. The solution was cooled to room temperature, diluted with water, and extracted with methylene chloride. The combined organic layers was washed with brine, dried over Na2SO4, filtered, and concentrated to give the corresponding azide as yellow oil. This material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[N:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(=O)Oc1cccc2c1CCCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCCc2c(OC(C)=O)cccc21
Yield: 99 %

Procedure:
6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine (252 mg) was dissolved in DMF (5 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (509 mg) and methyl bromoacetate (0.22 ml) were added to the solution at room temperature. After disappearance of the raw materials was confirmed, water (20 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=1/1) to obtain the object compound ml (333 mg, yield 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a mixture of tert-butyl-3-bromobenzoate (65 g, 0.25 mol), 4-tolyl boronic acid (41.3 g, 0.30 mol) and sodium carbonate (150 g) in a mixture of toluene (500 mL) and water (50 mL), tetrakis-triphenylphosphine palladium(0) (14.5 g, 0.05 mol) was added and the reaction mixture was refluxed overnight. Cooled to RT, toluene layer was separated. The organic layer was washed with water, brine, dried. The solvent was removed under vacuum to give tert-butyl-3-(4-tolyl)benzoate (62 g, 90%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCOC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of tert-butyl 4-(tetrahydrofuran-3-yl)benzoate (350 mg, 1.41 mmol) was added trifluoroacetic acid (2 mL) in dichloromethane (10 mL) and then stirred at room temperature for 0.5 hour. Solvent concentration gave final desired product 4-(tetrahydrofuran-3-yl)benzoic acid (200 mg, 74%) as a white solid. LRMS (M−H+) m/z: calcd 192.08. found 192.