Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][OH:54].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][O:54][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: CO
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.192 mmol), Cu(I)I (0.0365 g, 0.192 mmol), 1,10-phenanthroline (0.0346 g, 0.192 mmol), methanol (0.389 mL, 9.59 mmol) and KF on Al2O3 (40%; 0.195 g, 1.34 mmol) in toluene (4 mL) was stirred at 110° C. for 20 hours. The reaction was cooled to room temperature. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated to dryness. The resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(3-methoxy-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.098 g, 96%) as a solid. MS APCI (+) m/z 530.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.06 (s, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.20 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.38 (s, 2H), 3.98 (s, 3H), 3.71 (s, 3H), 3.29 (m, 4H), 2.94 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14][O:15][CH:16](Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[C:4]([CH3:13])=[C:5]([CH3:12])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:3]=[O:2]
Reactant: COc1cc(C)c(OC)c(C)c1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C=O)c1C

Procedure:
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was dissolved in CH2Cl2 (60 ml) and stirred with ice-cooling. After addition of 14.4 g (50×2.5 mmole) of dichloromethyl methyl ether, 13.8 ml (50×2.5 mmole) of titanium tetrachloride dissolved in CH2Cl2 (30 ml) was added dropwise over 15 minutes. After stirring for further 15 minutes with ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crashed ice (about 200 g) and stirred vigorously for 30 minutes. The CH2Cl2 layer was washed with water (3 times), and dried (MgSO4), from which CH2Cl2 was evaporated off. The residue was recrystallized from isopropyl ether/hexane (1:1), to give 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was concentrated, and the residue was purified with silica gel (60 g) column chromatography (eluted with isopropyl ether), to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. Yield 9.88 g (95%), m.p. 85°-86° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:23](Cl)(=O)[C:24](Cl)=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH:24]4[CH2:23][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)OC2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-(2-chloro-4-carboxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (525 mg) in dichloromethane (5 ml) were added oxalyl chloride (0.36 ml) and N,N-dimethylformamide (0.03 ml), and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. Dichloromethane (5 ml) was added and dissolved, and trimethylamine (698 mg), 4-dimethylaminopyridine (10 mg) and cyclohexanol (1.38 g) were successively added under ice-cooling. The mixture was stirred under ice-cooling for 30 min and at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added for partitioning. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane (20 ml) was added to the residue and the mixture was heated. The black insoluble matter was removed by filtration and the filtrate was allowed to cool. The precipitated crystals were collected by filtration, dried under reduced pressure and by heating to give the objective compound (533 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]1[NH:12][C:10](=[O:11])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(Cc2ccccc2)C(=O)N1c1cc(F)ccc1F
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2,5-Difluorophenylisocyanate (1.55 g, 10.0 mmol) in methylene chloride (25 mL) was added dropwise to a suspension of phenylalanine (1.65 g, 10.0 mmol) in methylene chloride (50 mL) containing triethylamine (1.4 mL, 1.01 g, 10.0 mmol). The solution was allowed to stir overnight, and was then concentrated. The residue was taken up into 6N HCl and heated to reflux for 3 hours. The cooled solution was extracted with ethyl acetate (3×), and the combined extracts were washed with water (2×), dried (over MgSO4), filtered and concentrated to give 2.7 grams. Purification by column chromatography gave 2.5 grams of 5-benzyl-3-(2.5-difluorophenyl)imidazolidine-2,4-dione.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[K+].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>O.C(O)CCC>[ClH:9].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21](=[N:2][OH:3])[NH2:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: NO
Reactant: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: NC(COc1ccc(Oc2ccc(Cl)cc2)cc1)=NO
Yield: 157.8 %

Procedure:
A suspension of 5.37 g (0.0772 mol) of hydroxylamine hydrochloride and of 7.72 g (0.0772 mol) of potassium bicarbonate in 8 ml of water is added, all at once, to a suspension of 10 g (0.0385 mol) of 4-(4-chlorophenoxy)-phenoxy-acetonitrile prepared as indicated in Example 29a), in 24 ml of n-butanol. The mixture is heated to the reflux temperature for 1 hour, the butanol is driven off, the residue is taken up in water and the insoluble matter is extracted with diethyl ether. The organic phase is washed with water, dried over dry sodium sulphate and evaporated, and the residue obtained is purified by washing with hot diisopropyl ether to give 10 g of brilliant white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([O:20]C)[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([OH:20])[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)C=Cc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 83.1 %

Procedure:
A solution of 8-Chloro-4-[2-(ethoxycarbonyl)ethenyl]-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.1009 g) in tetrahydrofuran (2.3 mL) was treated with a solution of lithium hydroxide monohydrate (0.0126 g) in tetrahydrofuran (2.3 mL) and water (0.5 mL) at room temperature. The solution was stirred at room temperature under argon for 68 hours. It was then added to 0.05N hydrochloric acid (10 mL). The resulting solid was filtered off, washed with water, and air-dried to give a light tan solid (0.0803 g). The solid was dissolved in hot ethanol (5 mL). The solution was filtered and treated with water (2 mL). The crystals were filtered off at room temperature, washed with aqueous ethanol (1:1, v:v) and dried under vacuum to give a light tan solid (0.054 g); mp 177.5°-178.4° C.; 1H NMR (d6 -DMSO) 7.74 (d,1, J=16), 6.74 (d,1, J=16) for trans olefin protons; MS: m/z=276 (base peak), 322 (M+1). Analysis for C15 H12ClNO5 : Calculated: C, 56.00; H, 3.78; N, 3.99; Found: C, 56.55; H, 3.78; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([OH:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:24][C:18]1[C:17]([CH3:25])=[C:16]([NH:15][C@@H:11]([C:10]2[O:7][C:6]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)=[N:8][N:9]=2)[C@@H:12]([OH:14])[CH3:13])[CH:21]=[CH:20][C:19]=1[C:22]#[N:23]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
To a 500 mL round bottom flask was added 4-chloro-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 4a) (880 mg, 2.09 mmol, 1.0 equiv.) and anhydrous THF (209 mL). After being flushed with nitrogen, p-toluenesulfonic acid (439 mg, 2.3 mmol, 1.1 equiv.) was added and the solution was stirred for 10 min at room temperature. Then PS-BEMP (2.85 g, 6.27 mmol, 3.0 equiv.) was added. The reaction was stirred at room temperature for 8 h. The contents of the flask were filtered over Celite® in a ground glass fritted funnel and the Celite® was rinsed with several portions of acetone. The solvent was removed in vacuo to yield a yellow solid. The product was purified via flash chromatography (0→50% EtOAc/hexanes, 110 g of silica gel; TLC Rf=0.51, 100% EtOAc, vanillin stain) to provide the desired product as an off-white solid (150 mg, 18%). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.01 (d, J=8.79 Hz, 2H), 7.62 (d, J=8.79 Hz, 2H), 7.49 (d, J=8.54 Hz, 1H), 6.86 (d, J=8.54 Hz, 1H), 5.68 (br. d, J=8.31 Hz, 1H), 5.12 (dd, J=3.91, 8.55 Hz, 1H), 4.82 (br. d, J=5.29 Hz, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.35 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H16Cl2N4O2 [M]+ 403.26. found 403.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 75.1 %

Procedure:
Raney nickel 2800 (21.9 g) was added to a degassed solution of the unsaturated ester 30 (20.0 g) in MeOH (100 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Completion of hydrogenation was determined by NMR. Flash chromatography (20-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 31 (15.1 g, 75%). 1H NMR (400 MHz, DMSO-d6): 12.8 (br, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 4H), 3.59 (s, 3H), 2.84 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H) 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN1CCCC1.Cl[C:19]1[C:20]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:19]1[C:20]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Agent: CN1CCCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2, 6-lutidine and 0.9 ml of N-methylpyrrolidine to 360 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it was returned to room temperature, water was added, the precipitated solid was filtered out and washed with water and diethyl ether, and the collected solid was dried to obtain 112 mg of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c2ccccc21
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCn1cc(C=C[N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1-Ethyl-1H-indole-3-carbaldehyde (I-38b: 5.2 g, 29.885 mmol), nitromethane (46.81 mL, 866.66 mmol) and ammonium acetate (1.17 g, 15.241 mmol) were taken in a reaction flask. The flask was refluxed for 16 hours under nitrogen atmosphere. The reaction was monitored by TLC (25% ethylacetate in hexane). The reaction mixture was cooled to room temperature and the reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford 4.8 g of the product (75% yield).
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH2:6]Cl)=[O:4])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>>[CH2:1]([S:3]([CH2:5][CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCS(=O)CCCl
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)CCN1CCCCC1
Yield: 59.5 %

Procedure:
Heat 2-chloroethyl ethyl sulfoxide (1.0 g, 7.1 mmol) and piperidine (2 mL, 20 mmol) at 60° C. for 2 hours. Treat with 5N sodium hydroxide, extract with ethyl acetate (3×50 mL) and dry (MgSO4). Concentrate in vacuo to yield 800 mg orange oil. Purify by silica gel chromatography (50% ethyl acetate/methanol) to yield 560 mg (42%) of the title compound as a yellow oil. 438E-25 MDL 101135
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CN[C:11](NC)=[O:12]>ClC1C=CC=CC=1Cl>[N:7]1[C:11](=[O:12])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: CNC(=O)NC
Reactant: Nc1ccccc1N
Solvent: Clc1ccccc1Cl
Product: O=C1N=c2ccccc2=N1
Temperature: 172 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
216 Parts of o-phenylenediamine and 193.6 parts of N,N'-dimethyl urea are heated in 1000 parts of o-dichlorobenzene for 2 hours to 172° C. Methylanine evolves at 130° C. The suspension is stirred for a further 4 hours at 172° C, then cooled to room temperature and filtered by suction. The filter cake is washed with 800 parts by volume of ethanol and suspended in 1000 parts of water. This suspension is filtered by suction, washed with 100 parts of water and the filter cake is dried at 100° C, giving 250.8 parts (93.6% of theory) of benzimidazolone. The melting point of the product is between 312° and 315° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1ccn1nccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 6, 0.140 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) in pyridine (4 mL) and DCM (3 mL) was stirred at room temperature overnight. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60%. The resultant glass was triturated with ether to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.103 g) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4].[CH3:21]OS(OC)(=O)=O>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[N:13]([CH3:21])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: CNC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(Sc2ccccc2)c2ncccc2n1C

Procedure:
Treat 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methylamide Ia-33 (1.0 equiv) in DMF with dimethylsulfate (1.5 equiv) as described in General Synthetic Procedure V to provide Ia-29 as an ivory colored solid, MS Obs 298.09 (M+1).
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:17][NH2:18])[CH:13]=[C:14]([F:16])[CH:15]=1.[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:17][NH:18][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cc(F)cc(F)c1
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc(F)cc(F)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3,5-difluorophenyl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 159-160° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.75 (t, J=5.6 Hz, 1H), 7.40-7.35 (m, 2H), 7.21-6.99 (m, 5H), 4.60 (d, J=15.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.20 (dd, J=10.1, 9.1 Hz, 1H), 3.78-3.71 (m, 1H), 3.56 (dd, J=10.2, 6.8 Hz, 1H), 2.48 (s, 3H), 1.22 (d, J=6.1 Hz, 3H); MS (ES+) m/z 474.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]#[N:19].B1([O-])OO1.O.O.O.O.[Na+]>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:16][N:1]=[C:2]3[C:3]([CH2:17][C:18]#[N:19])=[CH:4][CH:5]=[CH:6][C:7]=23)=[CH:10][CH:11]=1
Reactant: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)onc12
Temperature: 0 °C

Procedure:
Following the procedure of Intermediate 59, 2-amino-3-(4-chlorobenzoyl)benzeneacetonitrile is reacted with sodium perborate tetrahydrate in acetic acid at 70° C. and thereafter mixed with ice-water to obtain the title compound.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][OH:4].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCCC(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
17 g of 2-fluorodecanol and 60 ml of pyridine were charged into a 300 ml three-necked round bottom flask and cooled to 0° C. to which 24 g of p-toluenesulfonyl chloride was added in 15 min. The system was held at 0° C. for 1 hour and then subjected to reaction for 7 hours while being held below 20° C. Then, the mixture was charged into water and acidified with hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with water, dried with magnesium sulfate and then purified by silica gel chromatography with the use of dichloromethane as the eluent to obtain 23 g of 2-fluorodecyl p-toluenesulfonate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>O.C(#N)C>[N:1]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]

Procedure:
Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solution of 2-(2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile (120 mL). The reaction was refluxed for 4 h, cooled, and partitioned between methylene chloride and water. The organic phase was washed with saturated brine, and dried over magnesium sulfate. The title compound was obtained as an oil (22.8 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CC(CC)=O.O>[CH2:1]([C:3]1[N:4]([CH2:25][CH2:24][O:23][CH3:22])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.8 %

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was added and the mixture was heated to reflux and stirred for 70 hours. The mixture was cooled to ambient temperature and water (250 mL) was added. The resultant slurry was warmed to reflux and held at that temperature for 30 min before cooling to room temperature. The resultant precipitate was granulated at room temperature for 3 h, filtered and vacuum dried to afford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid 24.3 g, 74%. Data as reported for Example (g)(i).