Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[C:19](O)=[O:20]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[C:19]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:20]
Reactant: Cc1cc(-c2ccccc2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1cc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (31, 0.22 mmol) and 3-methyl-1,1′-biphenyl-4-carboxylic acid (D58) (55 mg, 0.26 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91(dd, 1H), 8.14 (m, 3H), 7.86 (d, 1H), 7.78 (br, 1H), 7.66 (d, 1H), 7.62 (d, 2H), 7.53 (m, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.36 (dd, 1H), 2.63 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:53]>C(Cl)Cl>[Br:53][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(4-(hydroxymethyl)phenyl)docosa-4,7,10,13,16,19-hexaenamide (0.5 mmol) was taken up in 5 mL of CH2Cl2 and cooled to 0° C. Triphenylphosphine (0.5 mmol) and carbon tetrabromide (0.5 mmol) were added and the resulting reaction mixture was slowly warmed to room temperature. After 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue can be purified by silica gel chromatography to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(4-(bromomethyl)phenyl)docosa-4,7,10,13,16,19-hexaenamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH:17][CH3:18])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29](O)=[O:30])=[O:23].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:25]=[C:24]([CH:34]=[CH:33][CH:32]=3)[C:22]([O:21][CH3:20])=[O:23])=[C:12]([NH:17][CH3:18])[CH:11]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1N
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Yield: 61.9 %

Procedure:
The reaction and post-treatment were carried out according to Example (16e) using 4-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N2-methylbenzene-1,2-diamine produced in Example (17c) (4.13 g, 15.9 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.68 g, 17.5 mmol), triethylamine (4.44 mL, 31.8 mmol), pivaloyl chloride (1.96 mL, 15.9 mmol) and dichloromethane (80 mL) to obtain the title compound (4.44 g, 64%) as a white powder.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccc2[nH]cnc2c1
Yield: 66 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid (400 mg, 2.50 mmol) and benzylamine furnished the product (410 mg, 66%).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)=[O:2].[BH4-].[Na+]>CO>[CH3:17][O:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:6]([CH2:5][CH2:4][CH2:3][CH2:1][OH:2])[CH:15]=1
Reactant: COc1cc(CCCC=O)c(OC2CCCCO2)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCCCO)c(OC2CCCCO2)c2ccccc12
Reaction time: 0.5 h

Procedure:
The starting 2-(3-formylpropyl)-4-methoxy-1-[(tetrahydro-2H-pyran-2-yl)-oxy]naphthalene (0.587 g) is dissolved in 5 ml methanol. This solution is placed under a nitrogen atmosphere and then cooled to 0°-5° C. and solid sodium borohydride (0.10 g) is added in one portion. Vigorous gas evolution ensues and after stirring for 30 min TLC analysis indicates the reduction is complete. The reaction is quenched with saturated aqueous ammonium chloride and then poured into water. The pH is adjusted to 2-3 (10% aqueous sodium bisulfate) and the mixture extracted with ether. The pH of the aqueous phase is raised to 7 (saturated aqueous sodium bicarbonate), excess solid sodium chloride is added and the mixture reequilibrated. The organic extract is dried with magnesium sulfate, filtered and concentrated to give the crude product as an orange colored oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[CH2:10]([CH:13]([C:16]#[N:17])[C:14]#[N:15])[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:13]([CH2:8][N:6]1[CH:7]=[C:3]([Cl:2])[CH:4]=[N:5]1)([C:16]#[N:17])[C:14]#[N:15])[CH:11]=[CH2:12]
Reactant: ClCn1cc(Cl)cn1
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cc(Cl)cn1
Yield: 72.5 %

Procedure:
1.43 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.01 g of allyl malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.22 g of allyl [(4-chloro-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (20), hereinafter) shown by below formula.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[CH:16]=[CH:15]4)[C:10]([C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([O:31]CC4C=CC=CC=4)=[CH:24][C:23]=3[O:39]CC3C=CC=CC=3)=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CCO.[Pd]>[N:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[CH:16]=[CH:15]4)[C:10]([C:22]3[CH:27]=[C:26]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:31])=[CH:24][C:23]=3[OH:39])=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)c1cc(-c2nnc(Cn3ccnc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(Cn3ccnc3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O

Procedure:
Intermediate (D) obtained above was subjected to Pd (10%) catalyzed hydrogenation in 10 mL EtOH for 24 hours. Removal of Pd/C and solvent gave 5-[3-imidazol-1-ylmethyl-5-(2,4-dihydroxy-5-isopropyl-phenyl)-[1,2,4]triazol-4-yl]-1-methyl-1H-indole (E) as light brown solid (0.07 g, 0.16 mmol, 80%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 11.06 (s, 1H); 9.75 (s, 1H); 7.63 (d, J=8.1 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H); 7.52 (d, J=3.0 Hz, 1H); 7.28 (s, 1H); 7.03 (dd, J=8.1 Hz, 2.1 Hz, 1H); 6.94 (d, J=1.2 Hz, 1H); 6.84 (d, J=1.2 Hz, 1H); 6.51 (d, J=3.0 Hz, 1H); 6.37 (s, 1H); 6.33 (s, 1H); 5.27 (s, 2H); 3.86 (s, 3H); 2.78 (hept, J=6.6 Hz, 1H); 0.55 (d, J=6.6 Hz, 6H). ESMS calcd. for C24H25N6O2 (M H)+: 429.3. Found: 429.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:2].[NH2:22][NH2:23]>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[NH:23][N:22]=1)=[O:21])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCCO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1cc(CCCO[Si](C)(C)C(C)(C)C)[nH]n1
Yield: 2.1 %

Procedure:
A solution of 7-(tert-butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester (1.627 g, 51.4 mmol) and hydrazine (17 mL, 55 mmol) in EtOH was heated at reflux for 6 h. The reaction was concentrated in vacuo. Purification by flash chromatography (6:4 hexanes:EtOAc) provided the title compound (333 mg). 1H NMR (400 MHz, CDCl3) δ6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t, 2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s, 6H); MS 313 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[O:9][N:8]=1)C.[OH-].[Na+]>CO>[C:4]([CH2:5][O:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[O:9][N:8]=1)([OH:16])=[O:3]
Reactant: CCOC(=O)COc1cc(C(=O)OC)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cc(C(=O)O)on1
Yield: 86 %

Procedure:
Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[NH:14][C:13]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[CH2:40]([O:39][C:37]([N:14]1[CH:15]([CH2:17][CH3:18])[CH2:16][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])[C:12]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:13]1=2)=[O:38])[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: CCC1CC(NC(=O)OCc2ccccc2)c2c(C)nn(C)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1c2c(c(C)nn2C)C(NC(=O)OCc2ccccc2)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
(6-Ethyl-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-yl)-carbamic acid benzyl ester (0.35 g, 1.08 mmol) obtained in step (ii), dry THF (5 mL) and potassium carbonate (0.45 g, 3.2 mmol) were charged to a flask under a nitrogen atomsphere. This mixture was stirred at room temperature for about 0.5 h, after which time ethyl chloroformate (0.47 g, 3.2 mmol) was added drop-wise. This reaction mixture was then stirred for about 4 h, water was added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×20 mL), dried over sodium sulphate, and concentrated under vacuum to afford the title compound (0.375 g, 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:35][CH2:36][OH:37]>>[CH3:33][N:2]([CH3:1])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:35][CH2:36][OH:37])[C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1
Reactant: OCCBr
Product: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1CCO
Yield: 68.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-((R)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (43 mg, 0.095 mmol) and 2-bromo ethanol (13 mg, 0.105 mmol) gave 7-cyclopentyl-2-{5-[(R)-4-(2-hydroxy-ethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (32 mg, 68%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Br.O>O1CCCC1>[CH3:21][O:22][CH2:23][N:11]([CH2:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1.00 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.22 g of 60% sodium hydride at room temperature for 30 minutes. 0.78 g of methoxymethyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.90 g of methyl N-methoxymethyl-N-(3-phenylbenzyl)carbamate as a pale yellow transparent viscous liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:17](=O)[CH3:18]>CO.[Pd]>[CH2:17]([NH:2][C@H:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:18]
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CC=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 110.6 %

Procedure:
To a solution of (R)-tert-butyl 2-amino-2-phenylacetate hydrochloride (0.25 g, 1.026 mmol) in MeOH (10.26 mL) was added 10% Pd/C (0.080 g, 1.026 mmol). The resulting mixture was cooled to 0° C., and acetaldehyde (0.576 mL, 10.26 mmol) was added. The resulting mixture was stirred at 0° C. for 10-15 mins, the ice bath was removed, and the mixture was placed under a hydrogen balloon and stirred at rt for 45 mins. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo to give the title compound (0.267 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at 100° C. over night. The reaction mixture was filtered through a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1.8 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.I[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]([CH2:9][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCCCI
Product: CCCCN(CCCC)c1ccc(OC)cc1
Yield: 91.7 %

Procedure:
4-Methoxyaniline (10.5 g) in iodobutane (50 g) was heated under reflux overnight. Excess iodobutane was distilled off and final traces were removed in vacuo. The residue in DMF (dimethyl formamide) (50 mL) was treated with DABCO (1,4-diazobicyclo[2.2.2]octane) (20 g) and the mixture heated under reflux for 2 hours. Most of the DMF was then evaporated and the residue taken up in ethyl acetate, washed well with water, and dried (Na2SO4). After evaporation of the solvent the above procedure was repeated with iodobutane (50 mL) (overnight) followed by treatment with DABCO (10 g). After work-up, the resulting oil was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give 4-methoxy-N,N-dibutylaniline (9.2 g).
Reaction SMILES: [Na].[Cl:2][CH2:3][C:4]#[N:5].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]([OH:18])=O)[CH2:12][CH2:11][CH2:10]2>CO>[Cl:2][CH2:3][C:4]1[NH:5][C:16](=[O:18])[C:15]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=2)[N:6]=1
Reactant: N#CCCl
Reactant: Nc1cc2c(cc1C(=O)O)CCC2
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous methanol (36 ml) was added into a 250 ml round-bottomed flask that contained sodium (0.081 g) under argon. To this stirred solution chloroacetonitrile (1.56 g, 20.7 mmol) was added and stirring was continued for 30 min at room temperature under argon. 5-Amino-6-carboxyindane (European Patent Application 0602851A1; 3.19 g, 18.0 mmol) was then added and the reaction mixture was diluted with more methanol (42 ml). After the reaction mixture being stirred for 1 hour at room temperature, more anhydrous methanol (25 ml) was added and stirring was continued for 1 hour at room temperature and then for a further 1 hour at 80° C. under argon. The reaction mixture was then allowed to cool to room temperature; the white precipitate was collected by filtration, washed with methanol, water and dried in vacuo over P2O5 (3.15 g, 75%), mp 270-272° C.; 1H-NMR (DMSO-d6) 2.07 (m, 2H, 7-CH2), 2.98 (m, 4H, 6-CH2 and 8-CH2), 4.52 (s, 2H, 2-CH2), 7.50 (s, 1H, 9-H), 7.93 (s, 1H, 5-H), 12.37, (s, 1H, N3—H). MS (FAB, m/z) 235 (M+H)+;
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH2:21][OH:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[C:36](=[O:37])([O:38][CH3:39])[O:22][CH2:21]/[CH:20]=[CH:19]/[C:10]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:23][O:24][CH3:25]
Reactant: COC(=O)Cl
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/CO)c(COC)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/COC(=O)OC)c(COC)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-ol (44 mg) and diisopropylethylamine (20 mg) in DCM (1 ml) was added methyl chloroformate (13.5 mg) and stirred for 2 hours at room temperature. The solvent was dried up and the residue was purified with silica gel column chromatography (CHCl3-MeOH 0-2%). (2E)-3-[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-yl methyl carbonate was obtained as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:17])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[Cl:17]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1Br
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1Br
Temperature: 80 °C
Yield: 62 %

Procedure:
6-bromo-7-methoxyquinazolin-4(3H)-one (53 mg, 0.21 mmol) was taken into thionyl chloride (1.5 mL) followed by addition of catalytic DMF. The mixture was heated to 80° C. for 2 h then concentrated. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give 6-bromo-4-chloro-7-methoxyquinazoline (36 mg, 62% yield) as a brown solid. MS (EI) for C9H6BrClN2O: 275 (MH+).
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1F)[CH:10]=[O:11]>CS(C)=O>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[S:3]([CH3:2])(=[O:5])=[O:4])[CH:10]=[O:11]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1F

Procedure:
Methane sulfinic acid sodium salt (20.1 g, 200 mmol) is added to a stirred solution of 3,4-difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 ml) at 75° C. After 2 hours the reaction is poured onto ice-water (200 ml). The precipitate is filtered, washed with water and dissolved in chloroform (400 ml). The organic extract is washed with water (2×200 ml), dried over MgSO4 and the solvent is removed in vacuo to give the titled compound as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:31])[C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])([C:9]([OH:31])=[O:8])[CH2:15][CH2:14]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid benzyl ester (2.36 g, 5.57 mmol), 5% Palladium on charcoal catalyst (250 mg), and glacial acetic acid (3 ml) in methanol (75 ml), was hydrogenated at 51 p.s.i. overnight, in a Parr shaker. The reaction mixture was then filtered through a pad of Celite and the pad washed several times with methanol. The combined filtrates were then concentrated in vacuo to the product, a white solid. 30 mg of this material was recrystallized from toluene to afford fine white crystals m.p. 176°-179° C. dec.