Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4](=[O:16])(=[O:15])[NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[Na].Cl[CH2:19][C:20](=[O:22])[CH3:21]>CO>[CH2:19]([N:3]1[C:2](=[O:1])[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4]1(=[O:16])=[O:15])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:20]([CH3:21])=[O:22]
Reactant: O=C1NS(=O)(=O)c2c1ccc1ccccc21
Reactant: CC(=O)CCl
Agent: [Na]
Solvent: CO
Product: CC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
46.6 gm (0.2 mol) of 3-oxo-naphth[2,1-d]isothiazoline -1,1-dioxide were added to a solution of 5.3 gm (0.23 gm-atom) of sodium in 150 ml of methanol and the majority of the alcohol was distilled off. The residue was taken up in 50 ml of dry dimethyl sulfoxide. 23.2 gm (20 ml; 0.25 mol)of chloroacetone were added dropwise over a period of 10 minutes, and the resulting mixture was stirred at room temperature for 30 minutes and was then heated at 120° C for 2.5 hours. The dimethyl sulfoxide was then partly distilled off in vacuo, a solution of 25 gm of sodium acetate in 250 ml of water was added to the residue, accompanied by exterior cooling, and the resulting mixture was thoroughly stirred. The precipitatewhich had formed was suction-filtered off and washed first with water and then with a small quantity of ice-cold ethanol. The crude product (52.3 gm; 90% of theory) thus obtained, m.p. 163°-165° C, may be used as such in the next reaction step. Pure 2-acetonyl-3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide, recrystallized from ethanol, melted at 164°-165° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C1COCC1>[S:1]1[C:5]([CH:21]([OH:22])[C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc3ccccc3s2)cc1

Procedure:
α-(2-benzo[b]thienyl)-4-methyoxybenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles. 1.0 g), t-BuLi (1.7 m, 10.4 mmoles, 6.1 ml), 4-methoxy-benzaldehyde (8.9 mmoles, 1.1 ml) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.75 g (87%) of a yellow solid.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:19][C:20](=[O:21])[CH3:22]
Reactant: CC(C)=O
Reactant: Cc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1ccccc1C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
In a 250 ml single neck flask was charged 12.0 g (100 mmoles,1.0 eq) of o-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.8 g of 4-(o-tolyl)-3-buten-2-one as a faintly yellow oil in 86.3% yield.
Reaction SMILES: [N:1]([CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14]C)=[O:13])[N:6]2[C:5]1=[O:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17]
Reactant: COC(=O)C1CCCN2CC(N=[N+]=[N-])C(=O)N12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC1CN2CCCC(C(=O)O)N2C1=O
Yield: 67 %

Procedure:
0.95 g of methyl 2-azido-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5carboxylate (racemte B) and 1.05 g of triphenylphosphine in 20 ml of dioxane were stirred at room temperature for 1 hour and the mixture was then evaporated. The residue was treated with 40 ml of 2N aqueous ammonia at 50° C. for 2.5 hours and the precipitated triphenyl phosphine oxide was removed by filtration. Evaporation then yielded 0.53 g (66%) of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) in the form of a white solid which, after recrystallization from aqueous methanol, melted at 228°-230° C. (decomposition).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([CH:28]([OH:43])[CH:29]([NH2:42])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH3:40])[CH:34]=[C:33]([F:41])[CH:32]=2)[CH2:26][O:25][CH:24]([O:44][CH2:45][C:46]([CH2:50][F:51])([CH3:49])[CH2:47][F:48])[CH:23]1[CH3:52])=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH:27]([CH:28]([OH:43])[CH:29]([NH:42][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH3:40])[CH:34]=[C:33]([F:41])[CH:32]=2)[CH2:26][O:25][CH:24]([O:44][CH2:45][C:46]([CH2:50][F:51])([CH3:49])[CH2:47][F:48])[CH:23]1[CH3:52])=[O:21])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCCOc1cc(F)cc(CC(N)C(O)C2COC(OCC(C)(CF)CF)C(C)N2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cc(F)cc(CC(NC(C)=O)C(O)C2COC(OCC(C)(CF)CF)C(C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Add triethyl amine (0.025 mL) and acetic anhydride (0.013 mL) to a solution of 5-[2-amino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(3-fluoro-2-fluoromethyl-2-methyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (67 mg) in dichloromethane (2 mL). Stir at room temperature for 2 hours. Concentrate under reduced pressure and subject to silica gel chromatography, eluting with a linear gradient from hexanes to ethyl acetate to afford 5-[2-acetylamino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(3-fluoro-2-fluoromethyl-2-methyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (49 mg, 68%)
Reaction SMILES: [OH2:1].[Br-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([OH:11])[CH3:10].ClCl>O1CCCC1>[CH3:10][C:9]1[O:11][CH:8]=[CH:7][C:6](=[O:1])[C:5]=1[OH:4]
Reactant: CC(O)c1ccco1
Reactant: O
Agent: ClCl
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O
Yield: 55 %

Procedure:
In a 3-neck round bottom flask equipped with a stirring bar, a gas inlet tube and an addition funnel was added 20 ml of tetrahydrofuran, 50 ml of water and sodium bromide (0.20 mole). The solution was cooled to a temperature of 0° to 20° C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.18 mole) in 20 ml of tetrahydrofuran and this was added dropwise to the rapidly stirred reaction flask while gaseous chlorine (0.40 mole) is added via the gaseous inlet tube. The rate of the alcohol addition was such that a yellow orange color was maintained. The reaction temperature was kept below 20° C. with ice bath cooling. After the alcohol and chlorine had both been added to the reaction flask, the temperature was raised to reflux to distill off the tetrahydrofuran. The isolation procedure of Example 1 was used to isolate 12.47 g of pure maltol (55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:18]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 100.8 %

Procedure:
42 g of 4(4-chlorophenoxy)-phenol and 48 g of allyl bromide were heated at the boil at a reflux condenser, while stirring and adding 50 g of potassium carbonate, in 500 ml of butanol for 4 hours. Inorganic salts were then separated from the reaction solution by suction-filtration, the solvent was vaporized and the residue was distilled under greatly reduced pressure. 50 g of 4(4-chlorophenoxy)-phenyl allyl ether were obtained, boiling point: 173°-175° C. under a pressure of 2-3 mm mercury.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.Br[CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>C(#N)C>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:40][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)OC)cc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
The 4-[(S)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (0.51 g, 1.29 mmol) was dissolved in 10 mL of dry acetonitrile. Sodium iodide (20 mg, 0.13 mmol) was added and the reaction was stirred under nitrogen at room temperature during the addition of triethylamine (0.72 mL, 5.16 mmol), followed by methyl 4-(bromomethyl)benzoate (0.59 g, 2.58 mmol). The reaction mixture was stirred under nitrogen overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over Na2SO4/MgSO4 and concentrated under reduced pressure. The residual light yellow oil was purified by chromatography on silica gel (50% EtOAc in CH2Cl2) to give 0.45 g (0.83 mmol) of methyl 4-{(2R, 5S)-4-[(S)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl}-benzoate as a white amorphous solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:19])[CH2:5]1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:25].CCCCCC>COCCOC>[O-:25][N+:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([CH2:9][N:7]3[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]3=[O:19])=[CH:11][NH:12][C:13]=12
Reactant: CCCC1CC(=O)N(Cc2c[nH]c3ncccc23)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Solvent: CCCCCC
Product: CCCC1CC(=O)N(Cc2c[nH]c3c2ccc[n+]3[O-])C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.9 %

Procedure:
To 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231 (100 mg, 1 eq, 0.39 mmol) dissolved in 1,2-dimethoxyethane (3 ml) is added m-chloroperoxybenzoic acid (111 mg, 1.6 eq, 0.64 mmol). The resulting solution is stirred at room temperature for 20 hours. Hexane (10 ml) is added to the reaction mixture, and the decanted syrup is washed twice with hexane by decantation and dried under vacuum. To the residual solid are added 3 ml of water and a saturated solution of K2CO3 until pH 9. The resulting mixture is extracted with CH2Cl2 and the organic phase is dried over MgSO4. Volatiles are removed under reduced pressure and the residue is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 95/5/05) to give 50 mg of 1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 239.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[CH3:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:1]1[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CNc1ccccc1N
Reactant: O=Cc1cccc(C(=O)O)c1
Product: Cn1c(-c2cccc(C(=O)O)c2)nc2ccccc21
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (428 g, a slight brown solid) from 3-formylbenzoic acid (500 mg, 3.33 mmol) and N1-methylbenzene-1,2-diamine (407 mg, 3.33 mmol) by the similar manner in Intermediate-7.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.C(N(CC)CC)C.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59](Cl)=[O:60].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:59]([C:55]3[O:54][CH:58]=[CH:57][CH:56]=3)=[O:60])=[CH:42][CH:41]=2)=[N:20][CH:19]=[N:18]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1)c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
To a solution of 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol) was added tetrahydrofuran (4.50 mL), triethylamine (0.345 mL, 2.48 mmol), and 2-furoyl chloride (0.058 mL, 0.735 mmol). The mixture was stirred for 16 h at ambient temperature and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0086 g, 5% yield). 1H NMR (DMSO-d6) δ 8.75 (d, 1H), 8.10 (m, 6H), 7.74 (m, 1H), 7.39 (d, 1H), 6.75 (m, 1H). ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:36]([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])=[O:37]>ClCCl.CN(C)C1C=CN=CC=1.CO>[C:36](=[O:37])([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])[O:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH:21]([C:18]2[S:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[N:20][CH:19]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH2:23]1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)Cl
Reactant: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)O[C@@H]1CCN(C(c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccccc2Cl)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (3.00 g, 6.02 mmol) was suspended in 200 mL of anhydrous dichloromethane containing N,N-dimethylpyridin-4-amine (2.20 g, 18.0 mmol). (1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl chloroformate (1.91 mL, 9.00 mmol) was slowly added to the suspension and the resulting mixture was heated to reflux for 16 hours. The resulting pale yellow solution was allowed to cool to room temperature, diluted with 20 mL of methanol, and then evaporated to dryness. The crude reaction mixture was separated on 330 g of silica gel utilizing a gradient of 0-5% methanol in dicholoromethane to yield the pure product as a pale yellow solid (2.0087 g, 2.9529 mmol, 49.1%). ESI-MS m/z calc. 679.3. found; 680.5 (M+1)+; Retention time 3.88 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C1COCC1>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCNc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added N1,N1-dimethylethane-1,2-diamine (310 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the residue was dissolved in dichloromethane and washed with 1 N HCl aq and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (280 mg, 50%) as a purple solid: ESI MS m/z 181 [C9H16N4+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C[O:14][C:15](=O)[C:16]1[C:21]([I:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]2[C:16](=[C:21]([I:22])[CH:20]=1)[C:15](=[O:14])[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH2:24]2
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A mixture of 4-trifluoromethyl-benzyl amine (0.142 mL, 1.0 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.270 g, 0.73 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.84 (s, 2H), 7.10 (d, 1H), 7.42 (d, 2H), 7.60 (m, 2H), 7.66 (d, 1H). GC-MS: m/z 435 (M)+, 416 (M−19)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.[H-].[Na+].CI.[C:28](O)(=O)C(O)=O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([CH3:28])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2cc(OC)ccc2c1
Reactant: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 31.6 g. of diethyl 6-methoxy-2-naphthylmalonate, 2.4 g. of sodium hydride, and 350 ml. of methanol is stirred for one hour; then 24 g. of methyliodide are added and the resulting mixture is refluxed for 2 hours. The cooled mixture is neutralized with aqueous oxalic acid. The product, diethyl 6-methoxy-2-naphthyl-α-methylmalonate, is isolated, hydrolyzed, and decarboxylated by the means of the above described processes to give 6-methoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13]O>OS(O)(=O)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ncccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ncccc12
Yield: 90 %

Procedure:
To a solution of 1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XV) (0.39 g, 2.4 mmol) in dry MeOH (10 mL) was added concentrated H2SO4 (4 drops) and refluxed for 6 h under nitrogen. The solution was cooled and the solvent was evaporated under vacuum. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified on a flash silica gel column (100% DCM→3:97 MeOH:DCM) to produce methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVI) as a white solid (382 mg, 2.16 mmol, 90% yield). 1H NMR (CDCl3) δ ppm 4.08 (s, 3H), 7.38 (m, 1H), 8.63 (dd, J=8.10 Hz, J=1.51 Hz, 1H), 8.72 (dd, J=4.62 Hz, J=1.41 Hz, 1H); ESIMS found for C8H7N3O2 m/z 178.2 (M+H).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Cl[C:7]1[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=[C:9]([Cl:19])[N:8]=1.O>C(O)C>[Cl:19][C:9]1[N:8]=[C:7]([O:1][CH2:2][CH3:3])[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=1
Reactant: CC[O-]
Reactant: CC(C)c1ncc2cc(Cl)nc(Cl)n12
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOc1nc(Cl)cc2cnc(C(C)C)n12

Procedure:
To a stirred solution of sodium ethoxide prepared in ethanol from 0.18 g (7.8 mmole) of sodium metal under nitrogen was added 1.50 g (6.52 mmole) of 5,7-dichloro-3-isopropylimidazo[1,5-c]pyrimidine (from Example 37). After three hours at room temperature the mixture was poured into 50 ml of water and extracted thrice with 30 ml portions of chloroform. The combined extracts were washed thrice with 40 ml portions of water, dried over magnesium sulfate and evaporated to provide crude 7-chloro-5-ethoxy-3-isopropylimidazo[1,5-c]pyrimidine.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH2:3][CH2:1][OH:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCCO)cn3)ccc2n1CC1CCOCC1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Ethanolamine (29 mg, 0.47 mmol) and DIPEA (122 uL, 90 mg, 0.70 mmol) were added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (4.0 mL, 0.23 mmol) (see following step B for preparation). Stirring for 20 min, HATU (117 mg, 0.47 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with H2O (100 mL), and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl saturated aqueous solution (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1-9:1) on silica gel to give 80 mg (71%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.25-2.36 (m, 1 H), 3.24-3.34 (m, 2 H), 3.40 (t, J=5.66 Hz, 2 H), 3.63 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 7.95 (d, J=8.8 Hz, 1 H), 8.02 (dd, J=8.8, 1.8 Hz, 1H), 8.06 (d, J=0.78 Hz, 1 H), 8.35 (d, J=1.17 Hz, 1 H), 8.78 (s, 1 H); MS (ESI) (M+H)+=490.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]([CH3:12])[CH3:10])[CH:7]=1
Reactant: CNC
Reactant: OCc1ccnc(Cl)c1
Solvent: CCO
Product: CN(C)c1cc(CO)ccn1
Temperature: 200 °C
Yield: 94 %

Procedure:
A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and dimethylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200° C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-hydroxymethyl-2-(dimethylamino)pyridine (1 g, 94%) as a yellow oil.