Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[C@@H:47]([NH2:49])[CH3:48]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:49][C@H:47]([C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[CH3:48])=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](N)c1nccs1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4nccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (31 mg, yield 68%).
Reaction SMILES: C[N:2]([CH3:6])[C:3]([NH2:5])=[S:4].C1(C)C=CC=CC=1.[C:14](=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22]>O>[CH3:6][N:2]([C:3](=[S:4])[NH:5][CH3:14])[C:21](=[O:22])[O:23][CH3:24]
Reactant: COC(=O)Cl
Reactant: CN(C)C(N)=S
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)N(C)C(=O)OC
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
420.9 g (4.00 mol) N,N-dimethylthiourea with a purity of 99% were charged to 2000 g toluene. 507 g (4.78 mol) sodium carbonate was added and the suspension heated to 65° C. Afterwards 432.2 g (4.60 mol) methyl chloroformate were dosed in over 5 h at 65° C. The mixture was poststirred at the same temperature over 0.5 h. For work up, demineralized water was added under agitation and the phases separated. The aqueous phase was extracted with 800 g toluene and the organic phases were combined. The product content of the organic solution was determined with 15.15% by quant. HPLC (HPLC-method A; tR=3.6 min), which corresponds to a chemical yield of 90.3%.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH2:6]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:11]#[N:12])[CH3:7].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[CH2:6]([O:8][C:9](=[O:24])[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([C:11]#[N:12])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:7]
Reactant: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C#N)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a sodium ethoxide solution, which was prepared from sodium (2.11 g) and ethanol (400 ml), were added in turn 2-benzyloxycarbonylamino-2-cyanoacetic acid ethyl ester (24.0 g) and ethyl bromoacetate (15.3 g). The resulting mixture was stirred at 25° C. for 3 hours and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform. The extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (31.6 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:37]=[CH:38][CH3:39])([CH:34]=[CH:35][CH3:36])[C:23]1=[O:40].C(N(CC)CC)C>CN(C)C=O>[C:7]([O:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:34]=[CH:35][CH3:36])([CH:37]=[CH:38][CH3:39])[C:23]1=[O:40])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC1(C=CC)C(=O)N(O)C(=O)C1(C=CC)C=CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC=CC1(C=CC)C(=O)N(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)C1(C=CC)C=CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
0.14 mole of triphenylchloromethane and 0.14 mole of N-hydroxy tetrapropenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 90% of N-trityloxy tetrapropenylsuccinimide is recovered.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30](C(Cl)=O)=[CH:29][CH:28]=1)#[N:26].[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH2:41][NH2:42]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:35][CH:34]=2)[C@H:12]([C:22]([NH:42][CH2:41][C:37]2[O:36][CH:40]=[CH:39][CH:38]=2)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)NCc2ccco2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2-furylmethylamine the title compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=443.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH3:10][N:11]([CH3:16])[C:12](=[O:15])[CH:13]=[CH2:14].CC(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:14][CH2:13][C:12]([N:11]([CH3:16])[CH3:10])=[O:15]
Reactant: C=CC(=O)N(C)C
Reactant: Nc1cc(Cl)ccc1S
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of 2-amino-4-chlorobenzenethiol (327 mg, 2.05 mmol), N,N-dimethylacrylamide (203 mg, 2.05 mmol) and HOAc (0.5 ml) in CH2Cl2 (5 ml) was stirred at room temperature for 3 days. The reaction was quenched with NaHCO3 (aq.) and then extracted with CH2Cl2 (2×10 ml). The organic layer was washed with water and brine and concentrated in vacuo. The crude product was purified by chromatography on silica gel (50% ethyl acetate in hexane) to yield the title compound (284 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[CH:29]=[CH:28][N:27]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[C:24]3=[N:25][CH:26]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:21]2[CH:22]=[C:23]3[CH:29]=[CH:28][N:27]([Si:30]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[C:24]3=[N:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)ccc1N
Yield: 65.5 %

Procedure:
7.50 g of methyl 3-amino-6-bromopyridine-2-carboxylate, 12.10 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridine, 8.18 g of sodium hydrogencarbonate and 2.27 g of PdCl2(PPh3)2 in 90 ml of dioxane and 15 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 7 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 25 min), giving 8.40 g of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxylate as white solid (yield 56%, content 92%); MS-FAB (M+H+)=425.2; Rf (Esi1rod method): 3.10 min.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36](C)=[C:37](C)[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH3:41][NH:42][CH:43]=O.[CH3:45]N>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:42]([CH3:41])[C:43]([CH3:45])=[C:37]([CH3:36])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CNC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CN
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously-to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a stirred solution of ethyl 5-nitroindole-2-carboxylate (8) (4.3 g, 19.5 mmol) in 100 mL THF-methanol (1:1, v/v), at room temperature under argon, was added a solution of NaOH (12 g, 300 mmol) in 300 mL water. The resulting deep red-brown solution was stirred for 3 h, then quenched by acidification to pH 1 with dilute HCl. Precipitated product was collected by vacuum filtration and the remaining dissolved product was extracted with THF:ethyl acetate (1:1 v/v). The precipitate was dissolved in THF and this solution was combined with the organic layers from the extractions. Drying over magnesium sulfate, and evaporation of the solvent afforded 5-nitroindole-2-carboxylic acid (3.6 g, 90% yield) as a light brown solid: NMR (acetone d6) 6 7.0-9.0 (m,4H), 6 9.5 (s, 1H), 6 12.5 (s, 1H). To a stirred solution of 5-nitroindole-2-carboxylic acid (3.1 g, 15 mmol) in 150 mL THF, under argon, was added oxalyl chloride (4.8 g, 37.6 mmol) followed by 0.1 mL of DMF which caused a vigorous evolution of gas. After 40 min, the reaction mixture was evaporated to dryness. The resulting solid was redissolved in 100 mL THF and cooled to -23° C. and stirred under argon. A solution of potassium t-butoxide (1.0M in THF, 45 mL, 45 mmol) was then added dropwise over 30 min, and stirring was continued for an additional 20 min. The reaction was quenched with 5 volumes of water, neutralized with dilute HCl, and extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium bicarbonate and water, then dried over magnesium sulfate, filtered, and concentrated to afford 6 (3.24 g, 83% yield) as a brown solid:NMR (acetone-d6) δ1.6 (s, 9H), δ7.4-8.9 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(CBr)n1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), ethyl N-(diphenylmethylene)glycinate (1.76 g, 6.58 mmol, Acros, N.J.) and 5N sodium hydroxide (6.58 mL, 32.9 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (1.86 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[OH:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 71.4 %

Procedure:
A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140 mmol) and methylethylketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from isopropyl ether to give the title compound (14.20 g, 71.4%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH:14]1[CH2:17][NH:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:19]1[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH3:25][C:23]1[N:24]=[C:19]([N:16]2[CH2:17][CH:14]([O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:15]2)[C:20]([NH2:26])=[N:21][CH:22]=1
Reactant: c1ccc(OC2CNC2)cc1
Reactant: Cc1cnc(N)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(N)c(N2CC(Oc3ccccc3)C2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 35.2 %

Procedure:
Potassium carbonate (18.53 mg) was added to a mixture of 3-phenoxyazetidine (20 mg) and 3-bromo-5-methylpyrazin-2-amine (25 mg) in DMF (dry) (1 mL). The mixture was stirred at 120° C. for 4 hr. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (12 mg) as white solid.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2.C=O.O.[C:19](O)(=O)C>C(#N)C>[CH3:19][N:2]([CH3:1])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2
Reactant: [BH3-]C#N
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium cyanoborohydride (8.42 g, 134 mmol) was added into a stirred suspension of 5-aminophthalide (5.0 g, 33.5 mmol) and 37% CH2O/H2O solution (24.9 mL, 335 mmol) in 120 mL of acetonitrile. The mixture was stirred at room temperature for 1 hour, cooled to 0° C. and 120 mL of 10% aqueous acetic acid solution was added. The mixture was then stirred at room temperature for 1 hour, evaporated under low pressure until no acetonitrile remained. The resulting mixture was extracted with ethyl acetate (2×125 mL). The combined organic extracts were washed with saturated NaHCO3 solution (125 mL) and brine (125 mL), dried over Na2SO4 and evaporated to dryness to give a light brown solid, which was triturated with hot MeOH (10 mL) to give the title compound (3.9 g, 66%) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
A solution of the compound of Example 69, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.98 g, 2.98 mmol) in 20 mL CH2Cl2 was treated with triethylamine (1.04, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.363 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL water and 25 mL CH2Cl2 and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from CH2Cl2/hexanes gave 422 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)benzamide as a light yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Cc1ccccc1N
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccccc3C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with o-toluidine according to the procedure from Example 137C substituting o-toluidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (74 mg, 92%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 2.34 (s, 3H), 3.18-3.29 (m, 1H), 3.78 (s, 3H), 6.91 (d, J=7.35 Hz, 1H), 7.00 (d, J=8.09 Hz, 2H), 7.22 (t, J=7.72 Hz, 1H), 7.40 (d, J=8.46 Hz, 2H), 7.50-7.72 (m, 4H), 7.81 (d, J=8.09 Hz, 1H), 8.00 (s, 1H), 8.59 (s, 1H), 8.87 (d, J=8.46 Hz, 1H), 10.13 (s, 1H), 10.21 (s, 1H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[O:2][CH3:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1cc(C)ccc1O
Product: COc1cc(C)ccc1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-methoxy-4-methylphenol (162 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 mmol, prepared in Example 52, Step 2) to give 233 mg (67%) of a yellow solid. HRMS m/z calcd for C18H24N4O3 (M)+ 344.1848, found 344.1839.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:15]OS(=O)(=O)OC.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([O:11][CH3:15])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Br)cc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
A mixture of the 1-(5-bromo-2-hydroxy-3-nitrophenyl)-1-ethanone (17.4 g), dimethylsulfuric acid (12.7 g), potassium carbonate (13.8 g) and acetone (200 mL) was heated to reflux for 15 hours, and then water was added to the mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (16.2 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: OCCNCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N(CCO)CCO
Yield: 90 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 2.9 ml of diethanolamine were used as starting materials. 7.0 g (yield 90%) of the title compound was obtained as a colorless oil. Elemental analysis for C24H41NO3
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][CH:3]1[NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.Cl[C:27]1[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>CS(C)=O>[F:8][C:5]1([F:7])[CH2:4][CH:3]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:2]([NH:1][C:27]2[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)[CH2:6]1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1
Temperature: 120 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-methylpropane-2-sulfonamide (66 mg, 0.26 mmol) in DMSO (650 μl) was added DIPEA (135 μl, 0.77 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 47 mg, 0.26 mmol). The reaction mixture was sealed and heated at 120° C. for 18 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 10-60% ethyl acetate/petrol) to afford the title compound.