Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Br

Procedure:
A solution of 2-bromo-3-methyl-benzoic acid (21.5 g, 100 mmol) in 500 mL of methanol and 8 mL of concentrated sulfuric acid is refluxed overnight. Methanol is removed under reduced pressure, the residue is taken up in ether, washed with sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CO>[C:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:14])[CH3:13]
Reactant: COc1cc(CO)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: COc1cc(CO)ccc1NC(C)=O
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of 4-amino-3-methoxybenzyl alcohol (900 mg) in methanol was added acetic anhydride (1.8 g) under ice cooling, and the mixture was stirred for 1 hour at the same temperature. After evaporation, the residue was dissolved in ethyl acetate, and the solution was washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-acetamido-3-methoxybenzyl alcohol (840 mg) as solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
55% Sodium hydride (1.41 g, 32.1 mmol) was suspended in tetrahydrofuran (300 ml). To the suspension was added 5-(4-chlorophenyl)-4-(pyridin-4-yl)pyrazole (8.21 g, 32.1 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the resulting mixture was added (2-trimethylsilylethoxy)methyl chloride (5.68 ml, 32.1 mmol) dropwise under ice cooling, and the mixture was stirred at room temperature overnight. At the end of this time, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=3:1), to give the title compound (11.12 g) as a pale brown oil (yield 90%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[C:8]([C:12]1[CH:13]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C(C)=CC=CC=1>O>[C:19]([C:16]1[CH:15]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][N:28]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])=[O:26])[CH:13]=[C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:17]=1[OH:18])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(CCC(=O)NN2C(=O)C=CC2=O)cc(C(C)(C)C)c1O
Yield: 86.5 %

Procedure:
A mixture of maleic anhydride (4.9 g, 50.0 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (15.2 g, 50.0 mmol) and 250 ml of xylene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. The solvent was then removed on a rotary evaporator. The residual mass was extracted with 100 ml of tetrahydrofuran and the extract was added to 500 ml of hexane to precipitate the product. The product was collected by filtration and air dried. 16.1 g of a solid material was obtained having a melting range of 90°-94° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), tetrahydropyran-3-one (187 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as an oil (101 mg, 36%). 1H NMR (CDCl3, 300 MHz): δ 4.24-4.07 (m, 2H); 4.06-3.96 (m, 2H); 3.43-3.32 (m, 2H); 2.78-2.63 (m, 4H); 2.25 (s, 3H); 1.77-1.60 (m, 8H); 1.46 (s, 9H).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[S:51]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[C:60]2[CH:65]=[CH:64][C:63]([NH2:66])=[C:62]([N+:67]([O-])=O)[CH:61]=2)=[O:52])=[CH:40][C:39]=1[N+:70]([O-])=O>>[NH2:67][C:62]1[CH:61]=[C:60]([C:54]2[CH:55]=[C:56]([F:59])[CH:57]=[CH:58][C:53]=2[S:51]([C:45]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([NH2:37])=[C:39]([NH2:70])[CH:40]=2)=[O:52])[CH:65]=[CH:64][C:63]=1[NH2:66]
Reactant: Nc1ccc(-c2cc(F)ccc2S(=O)c2ccc(F)cc2-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(-c2cc(F)ccc2S(=O)c2ccc(F)cc2-c2ccc(N)c(N)c2)cc1N
Yield: 91 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-amino-3-nitrophenyl)-4-fluorophenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]#[N:19])(=[O:28])=[O:27])[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1S(=O)(=O)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) in 2 ml CH2Cl2 was added triethylamine (308 mg, 3.05 mmol) and 2-cyanobenzene-1-sulfonyl chloride (205 mg, 1.02 mmol). The reaction mixture was stirred overnight at room temperature. After completion the reaction mixture was concentrated under reduced pressure and the product was purified on SiO2 using 0% to 50% ethyl acetate in heptane as the eluent to give 3-bromo-1-(2-cyanophenylsulfonyl)-1H-indazole (360 mg) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[S:14]([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 80 %

Procedure:
To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 ml) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m).
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH2:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:7]([C:9]4[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 69 %

Procedure:
To a sealed vial is added 2-[3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]propan-2-ol (60 mg, 0.13 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aqueous Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Ar at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-7% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (42 mg, 68%). LCMS (ESMS): m/z 469.50 (M++1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([OH:23])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([O:23][CH3:26])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)(c2cc(F)cc(OCc3ccccc3)c2)CCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC(C)C1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A mixture of (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.45 g) and dimethylformamide (5 ml) cooled in an ice bath, sodium hydride (0.068 g of a 55% w/w dispersion in mineral oil) was added and the mixture was stirred for 45 minutes. Methyl iodide (0.11 ml) was added and the mixture was stirred for 15 minutes. The ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil, (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran (0.33 g, 71%);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2ccccc12
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1c(-c2cnnc(Cn3ccnc3C)c2)ccc2ccccc12

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(1-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22].O>CS(C)=O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:19][CH2:20][CH2:21][OH:22])[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCCl
Reactant: Oc1cccc2cccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCCOc1cccc2cccnc12
Temperature: 70 °C

Procedure:
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tertbutoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was stirred for 1 hr at room temperature. 3-Chloro-1-propanol (242.0 g, 0.25 mole) was added and the solution was heated overnight at 70° C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80° C. overnight to give 35.67 g (70.3%) of light brown solid, m.p. 126°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH2:15][CH3:16])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:15]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH:21]=[CH:25][CH:24]=[CH:23]3)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:6](=[O:18])[C:7]1=[O:17])[CH3:16]
Reactant: COC1CCC(OC)O1
Reactant: CCn1c(=O)c(=O)[nH]c2cc(N)c([N+](=O)[O-])cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(=O)[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc21
Yield: 374.7 %

Procedure:
4.0 g (16 mmol) of 6-amino-1-ethyl-7-nitro-2,3(1H,4H)-quinoxalinedione, 2.4 g (18 mmol) of 2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap for 3 h. The mixture was then concentrated under reduced pressure, and the residue was treated with methanol. The precipitate was filtered off with suction to yield 18 g (3%) of the product. Melting point 248°-250° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Li+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClC(Cl)C>[CH3:13][C:7]1[CH:12]=[CH:11][C:10]([C:14]([CH3:15])=[O:16])=[CH:9][CH:8]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an agitated mixture of aluminium chloride (20 g., 0.15 mole) and lithium chloride (3.18 g., 0.075 mole) and dichloroethane (20 ml) at -15° C. wash slowly added toluene (4.6 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mole) in dichloroethane (10 ml). The reaction mixture was left at -15° C. for one hour then allowed to warm up to room temperature overnight. After working up as described in Example 1, the 4-methylacetophenone obtained (7.17 g.), had a 1H NMR estimated purity of about 95%. 1H NMR showed less than 2% ortho isomers.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:18][B:19][F:20].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([O:33][CH3:34])[C:31]=1F)[N:28]([C@@H:35]1[CH2:37][C@@H:36]1[F:38])[CH:27]=[C:26]([C:39]([OH:41])=[O:40])[C:25]2=[O:42]>CS(C)=O>[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]([C:31]2[C:30]([O:33][CH3:34])=[C:29]3[C:24]([C:25](=[O:42])[C:26]([C:39]([OH:41])=[O:40])=[CH:27][N:28]3[C@@H:35]3[CH2:37][C@@H:36]3[F:38])=[CH:23][C:22]=2[F:21])[CH2:5]1.[F:18][B:19][F:20]
Reactant: N[C@@H]1CNCC12CC2
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Agent: F[B]F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@@H](N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 91 %

Procedure:
(7S)-7-Amino-5-azaspiro[2.4]heptane dihydrochloride (615 mg; 3.32 mmol) and triethylamine (1.40 ml) in dimethylsulfoxide (5 ml) was stirred for 20 minutes at room temperature. 6,7-Difluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid difluoroboron chelate (1.00 g; 2.77 mmol) was added thereto, and the resultant mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and purified water (50 ml) was added thereto. The pH of the resultant mixture was adjusted to 7.0 with aqueous 1N NaOH solution, and the aqueous layer of the mixture was taken up with chloroform (100 ml×5). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was purified through recrystallization from ethanol, to thereby yield 1.14 g of the title compound as pale yellow crystals (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.ClC1C(Cl)=CC(NC2C3C(=CC(F)=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.C([Si](C)(C)[O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71]OCCOCCO)(C)(C)C.[K]>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][OH:60])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCOCCOCCO
Agent: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Agent: [K]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Yield: 56 %

Procedure:
Compound 29c was prepared as described hereinabove for Compound 29a, using Compound 25 (0.596 gram, 1.6 mmol), 2-[2-(2-{2-[2-(2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy}-ethoxy]-ethanol (Compound 28c, 0.957 gram, 2.4 mmol), and potassium trimethylsilonate (0.621 gram, 4.74 mmol) dissolved in DMSO (37 ml). The crude residue was purified by silica gel column chromatography, using a mixture of 2% methanol in dichloromethane as eluent, to obtain Compound 29c (0.568 gram, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (26 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (78 mg). 1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine (1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 136 part a to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine (32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine (25.2 g, 59%). Oxidative cleavage using a 4% solution of osmium tetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried out in a mixture of THF and water (10:1, 60 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 61 to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g, 56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g). 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cu][C:13]#[N:14].CN(C)C=O.C(OCC)(=O)C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
A mixture of 7.7 g (0.040 mol) of 2,5-dichloronitrobenzene and 4.0 g (0.044 mol) of copper (I) cyanide in 4.0 ml (0.05 mol) of N,N-dimethylformamide was refluxed for 3.5 hours. The reaction mixture was poured slowly into 39 ml (0.40 mol) of ethyl acetate and followed by stirring for 10 hours at room temperature. The precipitate was filtered and washed with 3 ml of ethyl acetate. After concentration of the combined filtrate, the residue gave 4.6 g (63.0%) of 4-chloro-2-nitrobenzonitrile purified by the procedure of Example 1.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]([OH:25])=[O:24])=[O:17])[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(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[N:18]1([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:24]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (5.00 g, 14.8 mmol) in methylene chloride (59 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (7.77 mL, 44.5 mmol) and tert-butyl 2-bromoacetate (4.34 g, 22.2 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, and the organic layer was extracted with methylene chloride. The resulting organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (S)-1-((9H-fluoren-9-yl)methyl) 2-(2-(tert-butoxy)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (Fmoc-Pro-HOGly-OtBu) (Compound SP631) (6.40 g, 14.2 mmol, 96%).