Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3F)CC2)c(C)c1
Yield: 46.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 211 and 1-acetylimidazolidin-2-one (236 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (262 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].C(N(CC)CC)C.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>Cl.ClCCl>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A mixture of 2 g of L-alanine ethyl ester in hydrochloride form and 1.83 ml of triethylamine in 30 ml of dichloromethane is stirred at room temperature for 10 minutes. Next, 2.05 g of quinoline-4-carbaldehyde are added. The reaction medium is stirred at room temperature for 15 hours and then concentrated under reduced pressure. 35 ml of ethanol are then added; the solution is cooled to 0° C. and 0.49 g of sodium borohydride is then added portionwise. Stirring is continued for 15 hours at room temperature. The precipitate formed is filtered off; the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column (SiO2, CH2Cl2/MeOH, 95/5 by volume as eluent, Ar). 0.71 g of ethyl (S)-2-[(quinol-4-ylmethyl)amino]propanoate is obtained in the form of a pink oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Reactant: CC(c1cccc(F)c1)N1CCC(N)CC1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cccc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (291 mg, 64%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and 1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (s, 1H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85-2.25 (m, 5H), 1.45-1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([NH:33][C:34](=[O:36])[CH3:35])[CH:31]=3)[CH2:26][O:25][C:21]=2[C:22]=1[O:23][CH3:24]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([NH:33][C:34](=[O:36])[CH3:35])[CH:31]=3)[CH2:26][O:25][C:21]=2[C:22]=1[O:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COc1c(Cl)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Product: COc1c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Yield: 60 %

Procedure:
Prepared as described in Example 18, Part H using (5)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methoxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (5)-tert-butyl(1-((2-acetamido-7-methoxy-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (112 mg, 0.089 mmol, 60% yield) as a brown oil. LCMS (ESI) m/e 486.2 [(M+H)+, calcd for C26H36N3O6 486.2]; LC/MS retention time (Method F): tR=0.91 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=3[CH2:25][N:24](S(C)(=O)=O)[C@H:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:22]2)[N:17]=[CH:16]1>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]2[N:21]([CH2:20][C:18]3[N:17]=[CH:16][NH:15][CH:19]=3)[CH2:22][C@@H:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:24]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH2:25][C:26]=2[CH:31]=1)#[N:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 3 %

Procedure:
Example 383 was prepared as a white solid in 3% yield from 4-nitrobenzene sulfonylchloride and Compound C of Example 248 by the following sequence: Compound C of Example 350, except that the reaction was run at room temperature and no purification was performed; Compound C of Example 380.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([I:13])[C:5]=12.Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:15]3[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:11]=[C:12]([I:13])[C:5]=12
Reactant: N#Cc1cccnc1Cl
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1nc(I)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.825 mmol, 153 mg) was added to a suspension of 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.825 mmol) in DMF (5 mL). After 10 min, 2-chloro-3-cyanopyridine (531 mg) was added and the reaction was heated at 60° C. for 16 h. The resulting dark mixture was poured into ice-water (50 mL) and the solid collected by filtration to afford 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-pyridyl cyanide as a brown solid (1.1 g, 79%); 1H NMR (DMSO-d6, 400 MHz) δ 7.82 (1H, m), 8.29 (1H, s), 8.64 (1H, m) and 8.93 (1H, m); RP-HPLC (Pecosphere, C18, 3 μm, 33×4.6 mm column, 0% to 100% acetonitrile in 50 mM ammonium acetate, buffered to pH 4.5, at 3.5 mL/min) Rt 2.16 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:10]S(O)(=O)=O>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N+:6]([O-:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nccnc1Cl
Product: N#Cc1c(Cl)ncc[n+]1[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
2-Chloro-3-cyano-pyrazine (5.00 g, 35.94 mmol) was dissolved in 35 ml concentrated H2SO4 under nitrogen and cooled to 0° C. To this was added 11.65 g (43.95 mmol) K2S2O8 portionwise. The flask was fitted with a CaCl2 drying tube, the reaction mixture allowed to warm to rt and stir for 24 h. After partitioning between CHCl3 and ice water, the separated aqueous phase was extracted with CHCl3. The combined organics were washed with water, saturated NaHCO3, brine and dried over MgSO4. Concentration gave 2.01 g (36%) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H), 8.38 (d, 1H). MS (DCI/NH3) m/e 173 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:18])=[C:5]2C(O)=O.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:18][C:23]1[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=1)=[CH:5]2
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccc(F)cc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cc(F)ccc4nc3-c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 11 h
Yield: 18 %

Procedure:
6-Fluoro-3-hydroxy-2-phenyl-quinoline-4-carboxylic acid (118 mg), 4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine (310 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture was stirred at 160° C. for 11 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (32 mg, yield 18%).
Reaction SMILES: [CH3:1][C:2](/[CH:9]=[CH:10]/[CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[FH:20]>O1CCCC1>[F:20][C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH2:13][CH:12]([CH3:19])[CH2:11]/[CH:10]=[CH:9]/[C:2]([CH3:1])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: F
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/CC(C)CCCC(C)(C)F
Reaction time: 15 h

Procedure:
One gram of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate is added to a solution of 1 equiv. of dry hydrogenfluoride in dry tetrahydrofuran. The mixture is allowed to stand at 0° for 15 hours and is then washed with water, dried and evaporated under reduced pressure to yield trans ethyl 11-fluoro-3,7,11-trimethyldodeca-2,4-dienoate which can be purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[N:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)[N:3]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1N
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1NC(C)=O
Yield: 61 %

Procedure:
In acetic anhydride, 1.00 g of ethyl 4-amino-2-(4-benzylpiperazino)pyrimidine-5-carboxylate (the compound synthesized in Referential Example 60) was refluxed for 1 hour. After allowing the reaction mixture to cool down, acetic anhydride was distilled off and the resulting viscous oil was purified by silica gel column chromatography to obtain 0.68 g of the above-identified compound (yield: 61%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[CH:19]5[CH:23]([CH2:24][C:12]([C:13]=34)=[CH:11]2)[N:22]([CH3:25])[CH2:21][CH:20]5[C:26](OC)=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[CH:19]5[CH:23]([CH2:24][C:12]([C:13]=34)=[CH:11]2)[N:22]([CH3:25])[CH2:21][CH:20]5[CH2:26][OH:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(CO)C2c3cccc4c3c(cn4S(=O)(=O)c3ccccc3)CC21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the 9-methyl ester (Example 14) (0.365 g) in dry methanol (4 cm3) under anhydrous conditions was added sodium borohydride (0.252 g) causing vigorous effervescence. After 2 hours further sodium borohydride (0.067 g) was added. After the initial effervescence had subsided the reaction was heated to 60° C. Reaction was indicated to be complete and after 4 hours water (4 cm3) was carefully added and the cloudy mixture allowed to cool to room temperature. The product was extracted from the aqueous solution with chloroform, the combined extract washed with water (50 cm3), dried and evaporated under vacuum to yield the title compound as a yellow-white foam, m.p. 124°-127° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])C1C=CC=CC=1>O1CCOCC1.CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2COCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2CO)cc1
Yield: 94.9 %

Procedure:
A mixture of (2R,3S)-2-benzyloxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine (330 mg) and palladium hydroxide (40 mg) in dioxane (5 ml) and MeOH (5 ml) was hydrogenated in hydrogen at 3.5 atm and ambient temperature for 1 day. The catalyst was removed by filtration through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt/n-hexane 60%, then MeOH/AcOEt 1%) to give 253 mg of (2R,3S)-2-hydroxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:14][C:15]2([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1(CO)CCCC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.030 g, 0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 1-amino-1-cyclopentanemethanol (35 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 276 (M+H)+; 1H NMR (DMSO) δ 4.99 (m, 1H), 4.86 (t, 1H), 4.28 (m, 1H), 4.00 (m, 1H), 3.50 (d, 2H), 3.51 (m, 2H), 2.27 (m, 2H), 2.14 (m, 1H), 1.75 (m, 6H), 1.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(CC)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.21, 1.58, 1.80-1.85, 2.51, 3.15-3.17, 3.46-3.56, 3.66-3.76, 4.40-4.45, 5.88, 6.04, 7.21-7.34, 7.47-7.50; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([OH:31])[CH:11]=[C:10]1[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:60][C:61]1[CH:66]=[CH:65][C:64](O)=[C:63]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([CH2:75][CH3:76])=[CH:71][CH:70]=2)[CH:62]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:34]([O:33][CH2:32][C:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([O:31][C:64]2[CH:65]=[CH:66][C:61]([Cl:60])=[CH:62][C:63]=2[CH2:68][C:69]2[CH:70]=[CH:71][C:72]([CH2:75][CH3:76])=[CH:73][CH:74]=2)[CH:11]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCc1ccc(Cc2cc(Cl)ccc2O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Cl)ccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 48 h
Yield: 22 %

Procedure:
In a argon stream, (1S,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxymethyl)cyclohex-2-enol (0.5 g, 0.933 mmol) and triphenylphosphine (367 mg, 1.400 mmol) were added to a THF (6 mL) solution of 4-chloro-2-(4-ethylbenzyl)phenol (345 mg, 1.400 mmol) at room temperature. DIAD (0.276 mL, 1.400 mmol) was added thereto at the same temperature. The reaction mixture was stirred for 48 h. The reaction mixture was concentrated under reduce pressure, and the obtained residue was purified by prepared LC-MS to obtain 157 mg of ((1S,2S,3R,6R)-4-(benzyloxymethyl)-6-(4-chloro-2-(4-ethylbenzyl)phenoxy)cyclohex-4-ene-1,2,3-triyl)tris(oxy)tris(methylene)tribenzene (27).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30])[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
Triethylamine (0.167 mL, 1.2 mmol) was added to O-methyl-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (0.32 g, 1.0 mmol) in dichloromethane (10 mL) and cooled to 0° C. Acetic anhydride (0.103 mL, 1.1 mmol) was added dropwise and the reaction mixture was stirred for 6 hours. The reaction was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (10 mL) and stirred overnight. The phases were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organics were dried over potassium carbonate, filtered, and concentrated to afford 0.35 g of N-methoxy-N-[4-(2-propy-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:38]([O:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:13]([NH:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[C:2]([OH:1])[CH:3]=1)=[O:14])[C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2cnc3ccccc3c2OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) (6.7 mg, 0.02 mmol) and Cs2CO3 (13 mg, 0.04 mmol) in DMF (0.2 mL) was added BnBr (10 uL, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide (275). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.79 (t, J=2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (m, 6H), 7.11 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.4, 2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H). HPLC ret. time 3.93 min, 10-99% CH3CN, 5 min run; ESI-MS 427.1 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14]I.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:14])[C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CI
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Cl)c2c(n1)N(C)C(=O)CO2

Procedure:
Using the method of Sazonov, et al., Khimiya Geterotsiklicheskikh Soedinenii, 9, 1285-1288 (1972), 4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4-b ][1,4]oxazin-7-one was prepared. To a mixture of 8.0 g (0.0402 mole) of 4-chloro-6,7-dihydro-2-methyl-8H-pyrimido [5,4-b]1,4]oxazin-7-one and 17.9 ml of methyl iodide was added 8.75 g of 25% sodium methoxide in 250 ml of methanol, and the solution was heated at its reflux temperature for three hours. The solvent was removed by evaporation under vacuum, and the solid was separated by filtration, washed with water, and dried. The yellow solid was 4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4-b][1,4]oxazin-7-one, m.p. 142°-143° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.CCN(CC)CC>CO.N.[Pd]>[NH2:19][C:3]1[CH:2]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)C1CCc2ccc([N+](=O)[O-])c(Cl)c2C1
Agent: [Pd]
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(CCC)C1CCc2ccc(N)cc2C1
Reaction time: 5 h
Yield: 48.2 %

Procedure:
A mixture of 3b (1.65 g), Pd/C (0.8 g) and Et3N (6 ml) in MeOH (70 ml) was hydrogenated at 36 psi in a Parr apparatus for 5 hours. The mixture was filtered through celite and the solvent was evaporated to yield 2.5 g of the raw product, which was suspended in diluted ammonia and extracted three times with Et2O. The combined organic extracts were dried (MgSO4), filtered and evaporated to yield 0.63 g (48%) of pure 7-amino-2-(N,N-di-n-propylamino)tetralin (4b).