Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:40])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[C:29]5[CH2:37][CH:36]([CH3:38])[NH:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:35]1[CH:36]([CH3:38])[CH2:37][C:29]2[C:28]([O:27][C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([C:16](=[O:17])[NH:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:7])([F:39])[F:40])[CH:10]=3)[CH:19]=[CH:20]4)=[N:33][CH:32]=[N:31][C:30]=2[CH2:34]1
Reactant: COC(=O)CBr
Reactant: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1
Solvent: CC#N
Product: COC(=O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2CC1C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.15 mL, 1.58 mmol) is added to a solution of 5-(6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 52-B, (0.370 g, 0.792 mmol) and TEA (0.44 mL, 3.17 mmol) in ACN (10 mL). The solution is allowed to stir overnight. The solution is then concentrated and the residue separated directly via FCC (30-100% EtOAc/heptane) to give {6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid methyl ester.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:15]1CC[O:18][CH2:17][CH2:16]1.C(OC(Cl)=O)C(C)C.C(CN)O>C(Cl)Cl>[OH:18][CH2:17][CH2:16][NH:15][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: NCCO
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (1.734 g, 10.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (100 mL) and cooled to 0° C. in an ice bath. The flask was then charged with N-methyl morpholine (1.44 mL, 15.0 mmol) and isobutlychloroformate (1.51 mL, 11.5 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 20 min until the solution became cloudy. At which point freshly distilled ethanolamine (695 uL, 11.5 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature to form N-(2-hydroxyethyl)quinoline-2-carboxamide was formed according to the formula
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:46][CH2:45][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40](C#N)=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1>CCO>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40]([C:5]([NH2:7])=[O:6])=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:45][CH2:46]2)=[O:20])=[N:16][CH:17]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C#N)cn5)ccc42)C3)nc1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.8 %

Procedure:
To a solution of water (30 mL) and urea hydrogen peroxide (165 mg, 1.70 mmol) was added sodium hydroxide (39.8 mg, 0.99 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 6-((R)-1-{7-[2-(5-methoxy-pyridin-2-yl)-acetyl]-2,7-diaza-spiro[3.5]non-2-yl}-indan-5-yl)-nicotinonitrile (11-1c, 379 mg, 0.85 mmol) in 1 mL of EtOH was added dropwise via the funnel over a period of 30 minutes. The solution became cloudy and was stirred overnight while warming to room temperature. After 18 hours, the reaction was concentrated. The crude product was purified on a Biotage (Biotage Inc.) 10 g reverse phase column, eluting with 0-50% acetonitrile in water to give the title compound 12 mg (8%). MS (ES+) 512.0 (M+H)+. 1H NMR (CD3OD) δ 1.61-1.75 (m, 4H), 1.90 (td, 1H), 2.24 (ddd, 1H), 2.83-2.94 (m, 1H), 3.05-3.17 (m, 1H), 3.20-3.27 (m, 2H), 3.48-3.56 (m, 5H), 3.83 (s, 4H), 3.85 (s, 2H), 4.04 (dd, 1H), 7.21-7.29 (m, 1H), 7.30-7.38 (m, 1H), 7.46 (d, 1H), 7.81-7.88 (m, 1H), 7.89-7.95 (m, 2H), 8.13 (d, 1H), 8.27 (dd, 1H), 9.05 (dd, 1H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([C:10]1[S:11][S+:12]=[CH:13][C:14]=1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:9])([CH3:8])[CH3:7].[CH3:20][OH:21]>C(N(CC)CC)C>[CH3:20][O:21][C:10]1([C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][S:12][S:11]1
Reactant: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Reactant: CO
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: COC1(C(C)(C)C)SSC=C1CC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a sample of 136.8 grams of the product prepared as described in Example 2B, i.e., 3-tert-butyl-4-neopentyl-1,2-dithiolium perchlorate, and 180 grams of methanol was added over a 10 minute period 44 grams of triethylamine. The mixture was stirred for 20 minutes. The solvent was removed under diminished pressure and the residue taken up in ether and water. The etheral solution was washed two times with water, dried over anhydrous magnesium sulfate, filtered and distilled under diminished pressure to remove the ether. The product, 3-methoxy-3-tertiarybutyl-4-neopentyl 1,2-dithiole, was isolated as 96 grams (88.8% of theory) of an oil, n.m.r. (CCl4) τ in ppm, 3.81, 1H singlet (vinyl); 6.81, 3H singlet (methoxy); 7.23, 1H doublet (diastereotopic, J=15 cps, neopentyl proton); 7.82, 1H doublet (diastereotopic, J=15 cps, neopentyl proton); 8.63, 9H singlet (t-butyl) and 8.97, 9H singlet (t-butyl).
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21]([O:25][C:26](=[O:33])[C:27]([C:30](Cl)=[O:31])=[N+:28]=[N-:29])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH3:9][O:8][C:6]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:10])[N:1]1[C:30](=[O:31])[C:27]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:33])=[N+:28]=[N-:29])=[O:7]
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)Cl
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 50.6 %

Procedure:
In a flask methyl(s)-(+)-2 pyrrolidone-5-carboxylate (1.0 g, 6.99 mmol) was dissolved in 40 mL THF and cooled to −78° C. LHMDS (8.0 mL, 8.0 mmol) 1.0M in THF was added and the reaction stirred at −78° C. for 25 mins. The chlorocarbonyl-diazo-acetic acid tert-butyl ester (1.7 g, 8.39 mmol, J. Org. Chem. 1994, 59, 1418) was then slowly added and the reaction stirred at −78° C. for 1.5 h, quenched at −78° C. with 5% citric acid and let warm to room temperature. Diluted with EtOAc, seperated, extracted 2× with EtOAc, washed with brine, and dried with magnesium sulfate. Concentrated under vacuum and purified by flash chromatography (10–30% EtOAc/hexanes) to give the product as a viscous yellow oil (1.1 g, 65%). 1HNMR (300 MHz, CDCl3) δ 1.51 (s, 9H) 2.1(m, 1H) 2.2–2.8 (m, 3H) 3.79 (s, 3H) 4.74 (dd, 1H, J 4.0 8.8).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([OH:35])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:35]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 12 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 12% yield: mp 58-61° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.48 (m, 3H), 7.69-7.64 (m, 2H), 7.31-7.18 (m, 3H), 6.21 (br s, 1H), 4.58 (s, 2H), 4.56 (d, J=6.0 Hz, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.62 (t, J=9.0 Hz, 2H), 2.59 (s, 3H); MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[F:17][CH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:20]
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (95 mg, 0.43 mmol) in CH2Cl2/pyridine 9/1 (10 ml) was treated with 4-((S)-2-fluoro-1-methyl-ethyl)benzenesulfonyl chloride (132 mg, 0.55 mmol). Purification by flash column chromatography (CH2Cl2:MeOH, 97:3) gave the title compound (100 mg, 55% for step 31.4 and this step) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][C@@H:18]([C:20]2[CH:31]=[CH:30][C:23]3[O:24][C:25]([CH3:29])([CH3:28])[O:26][CH2:27][C:22]=3[CH:21]=2)[O:17][C:16]1=[O:32].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:28][C:25]1([CH3:29])[O:24][C:23]2[CH:30]=[CH:31][C:20]([C@H:18]3[O:17][C:16](=[O:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:3]=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=4)[CH2:19]3)=[CH:21][C:22]=2[CH2:27][O:26]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCOCCOCc4cccc(NS(C)(=O)=O)c4)C(=O)O3)ccc2O1
Yield: 64.6 %

Procedure:
A solution of (5R)-3-(5-{2-[(3-aminobenzyl)oxy]ethoxy}pentyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (52 mg) in pyridine (4 ml) was treated with methanesulfonyl chloride (13 mg) at 20° C. for 3 h. The mixture was quenched with sat. aqueous sodium bicarbonate (20 ml) and partitioned with DCM. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified using SPE eluting with DCM then EtOAc-PE (3:1). The selected fractions were evaporated in vacuo to yield the title compound (39 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][CH2:8][CH2:9][CH2:10][OH:11]>>[Cl:7][CH2:8][CH2:9][C:10]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:11]
Reactant: O=C(Cl)CCCl
Reactant: OCCCCl
Product: O=C(CCCl)OCCCCl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
101.5 ml (129.6 g, 1.00 mol) of 3-chloropropionyl chloride are added dropwise over about 30 minutes, at 90° C., to 86.1 ml of 3-chloro-1-propanol (97.4 g, 1.00 mol). During the addition, spontaneous evolution of gas occurs, and the reaction temperature drops to about 70° C. When the addition is complete, the reaction mixture is again heated to 100° C. and stirred at this temperature for a further 30 minutes. After cooling, the resultant crude product is purified by distillation.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].[CH3:26]I.Cl>CN(C)C=O>[CH3:26][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC2CNCCN2c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of methyl iodide (11.77 μL, 0.19 mmol). The reaction mixture was stirred overnight. The solution was concentrated, and dichloromethane (1 mL) was added followed by HCl (4M in dioxane, 394 μL, 1.6 mmol). After reaction completion as indicated by LC/MS analysis, the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.35 (d, J=7.80 Hz, 1H), 7.13-7.30 (m, 3H), 3.32-3.47 (m, 3H), 3.17-3.32 (m, 5H) 2.89-3.15 (m, 2H), 2.62 (dd, J=13.22, 7.12 Hz, 1H), 2.12 (d, J=13.56 Hz, 1H); MS (ESI) m/z 231.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
In a 750 ml sulfonating flask, 30.0 g (0.252 mol) of 4-hydroxybenzonitrile, 84.0 g (0.252 mol) of 1-bromooctadecane and 48.7 g (0.353 mol) of finely ground potassium carbonate are introduced into 200 ml of N-methylpyrrolidone (NMP) under a nitrogen atmosphere and heated at 120° C., with stirring. After being stirred for 15 hours, the mixture is cooled to room temperature and poured into 2 liters of water, whereupon a light-beige solid precipitates out, which is filtered off and washed with water. After drying at 60° C. and 150 mbar, there are obtained 90.8 g (97% of theory) of a colourless crystalline solid of formula
Reaction SMILES: [C:1]([CH:4]([C:6]1[C:7]([F:20])=[C:8]([C:17]([OH:19])=[O:18])[C:9](=[C:13]([F:16])[C:14]=1[F:15])C(O)=O)C)(O)=O.CS(C)=O>C(N(CC)CC)C>[CH2:4]([C:6]1[C:7]([F:20])=[C:8]([CH:9]=[C:13]([F:16])[C:14]=1[F:15])[C:17]([OH:19])=[O:18])[CH3:1]
Reactant: CC(C(=O)O)c1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Yield: 94.8 %

Procedure:
A mixture of 4-(1-carboxyethyl)-3,5,6-trifluorophthalic acid (14.9 g, 47.9 mmol), dimethylsulfoxide(100 ml), and triethylamine (30 ml) was heated at 140° C. for 4 days, and the reaction mixture was concentrated to dryness. To the residue was added 1N Hcl (100 ml), and the solution was extracted with ether. The extract was washed with brine, dried over anhydrous sodium sulfate, and then evaporated to yield 9.27 g of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)=[N:18][C:19]=1[NH2:20].O1CCOCC1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[NH:20][C:19]3=[N:18][C:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)=[CH:16][CH:15]=[C:14]3[N:13]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(C1CCCN(c2ccc3nc(COc4ccc(Cl)cc4)[nH]c3n2)C1)N1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)acetic acid (75 μmol) was added into an 8-mL vial followed by a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in anhydrous dioxane (600 μL, 127.5 μmol, 0.21M). Triethylamine (90 μL, 648 μmol) and 1-propanephosphonic acid cyclic anhydride (120 μL, 50% in ethyl acetate, 202 μmol) were added. The vial was capped and the reaction mixture was shaken at 140° C. for 16 h. The solvent was removed by Speedvac and the residue was purified via HPLC to afford the title compound. MS API-ES+ (M+H) 440; HPLC retention time 2.473 min (Method D).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[S:7][CH:6]=[C:5]([C:8](OC)=[O:9])[CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:1][CH:2]([F:12])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1
Reactant: COC(=O)c1csc(C(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1csc(C(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of methyl 5-(difluoromethyl)thiophene-3-carboxylate (267 mg) in THF (5 ml)-MeOH (1 ml) was added NaBH4 (263 mg) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (192 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:37])[C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
2-Methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (4.8 g, 15 mmol) was treated with mCPBA (5.95 g, 25.9 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (5.49 g, 28.8 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. After the amination reaction was stirred for two hours, water was added. Following the work-up procedure, the chromatographic purification was carried out eluting with 90:10 dichloromethane:methanol. The resulting product was triturated with ethyl acetate and isolated by filtration to provide 2-methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 166-169° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].CN(C)[CH:26]=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:1][O:2][CH2:3][CH2:4][O:27][CH3:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved in 65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to the solution was added 1.9 g of 60% sodium hydride with stirring in an ice bath. After removing from the ice bath, the mixture was stirred at a room temperature for 30 minutes, and after addition of 5.4 g of methoxyethoxymethyl chloride with ice cooling, stirred for 15 hours allowing to warm to a room temperature. The reaction mixture was poured on ice, saturated with sodium chloride and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain 13.85 g of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.S(=O)(=O)(O)O>O>[CH:17]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][N:11]3[C:19]=2[C:18]=1[C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=13
Reactant: NN1CCc2ccccc21
Reactant: O=C1CCCCCCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 30.7 %

Procedure:
Following the procedure of Example 1, Step 1, cyclooctanone (6.9 mL, 52 mmol), 1-aminoindoline (7.0 g, 52 mmol) and concentrated sulfuric acid (10 mL) in water (90 mL) provided 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.6 g). MS (ES) m/z 226.2.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=O)[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>CCOCC>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 2 L three-necked round-bottomed flask equipped with an overhead stirrer and reflux condenser, anthranilamide (20.0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) were suspended in 1 L dry ether and heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture was allowed to cool to room temperature, the ether was removed under reduced pressure, and the resulting residue was filtered and washed with water. The resulting solid was then suspended in 600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to room temperature, and it was neutralized with acetic acid, upon which 2-(2-methoxyphenyl)quinazolin-4(3H)-one was precipitated. The product was collected by filtration, washed with water, and dried overnight in vacuo to yield 27 g (73%) of pure 2-(2-methoxyphenyl)quinazolin-4(3H)-one. LC/MS: m/z 253.0 (M+H)+ at 3.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (DMSO) δ 3.86 (s, 3H), δ 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H); 13C NMR (DMSO) δ 55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, 8 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ 157.12, δ 161.35