Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC)C1C=CC=CC=1.[CH3:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=CC=CC=2)[C:14]=1CCC.Cl.[O:27]=[C:28]1[NH:37][C:36]2[N:35]=[CH:34][C:33](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:32][C:31]=2[CH2:30][CH2:29]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH2:12]([N:11]([CH3:10])[C:40](=[O:41])/[CH:39]=[CH:38]/[C:33]1[CH:34]=[N:35][C:36]2[NH:37][C:28](=[O:27])[CH2:29][CH2:30][C:31]=2[CH:32]=1)[C:13]1[CH:14]=[CH:15][CH:20]=[CH:21][CH:22]=1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CNCc1ccccc1
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 93 %

Procedure:
According to the procedure of Example 1 (a), except substituting benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.462 g, 93%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.37-8.33 (m, 1H), 8.08-8.06 (m, 1H), 7.54-7.49 (m, 1H), 7.37-7.21 (m, 6H), 4.82-4.61 (m, 2H), 3.10-2.85 (m, 5H), 2.56-2.49 (m, 2H); MS (APCI) m/e 322 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cc(Br)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 3,5-dibromobenzaldehyde (5.37 g, 20.37 mmol), ethylene glycol (3.40 mL, 61.10 mmol) and p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) in anhydrous toluene (30 mL) was heated at reflux under Dean-Stark conditions for 5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). The ethyl acetate layer was washed with a saturated NaHCO3 solution (25 mL). The organic layer was removed and washed with water (1×25 mL) and dried with anhydrous MgSO4, filtered and evaporated in vacuo to give a colorless viscous liquid (6.27 g). GC-MS (Cl/methane) analysis of the liquid shows the desired product's mass: m/z 306 (79Br,79BrM+), m/z 308 (79Br,81BrM+), and m/z 310 (81Br,81BrM+); Calcd for C9H8Br2O2: 307.96. 1H NMR (400 MHz, CDl3): δ 3.97-4.10 (M, 4H, 2×—CH2—O—), 5.74 (s, 1H, O—CH-0), 7.53 (d, J=1.80 Hz, 2H), 7.63 (appt, J=1.80 Hz, 1H). 1H NMR spectrum of the liquid was consistent with the suggested structure of the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.C(N(CC)CC)C.[NH:24]1[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[NH:27][CH2:26][CH2:25]1>CN(C1C=CC=CN=1)C.CC(CCO)C>[ClH:16].[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:24]2[C@@H:33]3[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)[NH:27][CH2:26][CH2:25]2)[N:3]=1
Reactant: C1CC[C@H]2NCCN[C@H]2C1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 215.6 %

Procedure:
A mixture of 7.85 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 13.3 g of triethylamine, 0.4 g of dimethylaminopyridine, 11.5 g of cis-decahydroquinoxaline and 80 ml of i-amyl alcohol was stirred at reflux for 72 hours. After cooling to room temperature, the solvent was evaporated off and the residue was purified by flash chromatography, eluting with petroleum ether:ethyl acetate:methanol:28% ammonium hydroxide 8:6:2:0.2. The obtained residue obtained was transformed into the hydrochloride salt and crystallized from i-propanol/methanol 1:1 to give 14.7 g (73%) of the desired compound; m.p. 290-295° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)#[CH:2].[CH2:10]([O:12][C:13]([C:15]1[S:19][C:18](Br)=[C:17]([CH3:21])[CH:16]=1)=[O:14])[CH3:11].C(OC(C1SC(C#C[C@H]2COC(C)(C)O2)=CC=1)=O)C>>[CH2:10]([O:12][C:13]([C:15]1[S:19][C:18]([C:2]#[C:1][C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]2)=[C:17]([CH3:21])[CH:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(Br)s1
Reactant: C#C[C@H]1COC(C)(C)O1
Agent: CCOC(=O)c1ccc(C#C[C@H]2COC(C)(C)O2)s1
Product: CCOC(=O)c1cc(C)c(C#C[C@H]2COC(C)(C)O2)s1
Yield: 67 %

Procedure:
Starting with 4(S)-EthynyI-2,2-dimethyl-[1,3]dioxolane and 2-Bromo-3-methyl-thiophene-5-carboxylic acid ethyl ester, prepared according to M. Nemec, Collection Czechoslov. Chem. Commun., compound (31) was prepared in 67% yield according to the general procedure described for compound (1).
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[C:12]([OH:15])(=[S:14])[CH3:13].Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>O>[C:12]([S:14][CH2:17][CH2:18][N:19]1[C:20](=[O:29])[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:24])(=[O:15])[CH3:13]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
0.855 kg (7.9M) Potassium-tert-butoxide is added in portions at -5° under nitrogen atmosphere to 4 1 dimethylformamide. A solution of 0.6 kg (7.9M) thioacetic acid in 2 1 dimethylformamide is added in a steady stream at such a rate that the temperature can be maintained between -5° and 0° . The reaction mixture is then stirred for 1 hour at -5° . 2.0 kg (7.9M) N-(2-bromoethyl)phthalimide in 4 1 dimethylformamide is added to the reaction mixture at such a rate that the temperature does not exceed 5° and the reaction mixture is stirred for 2 hours. 40 1 of water cooled at 5°-10° are added which raises the reaction temperature to 20° . The reaction mixture is stirred overnight at room temperature and filtered. The crude product is washed with water and dried. M.P. 112°-114°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:5])[S-:4].C([NH+](CC)CC)C.Br[CH:14]([CH3:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CC#N>[CH3:1][N:2]1[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:23])[S:5][C:3]1=[S:4]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CNC(=S)[S-]
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: Cc1sc(=S)n(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a 100 mL flask was added freshly prepared triethylammonium methydithiocarbamate (2.0 g, 9.5 mmol), anhydrous MeCN (50 mL), and 2-bromopropiophenone (2.04 g, 9.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was treated with conc H2SO4 (5 mL) with stirring at room temperature. After 20 min, the reaction mixture was diluted with water (75 mL) and then mixed with DCM (75 mL). The layers were separated and the aqueous layer extracted once more with DCM (75 mL). The combined organic layers were washed with water (3×50 mL) and then brine (50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the title product (1.95 g, 92%) as an off-white solid, which was used without further purification. 1H-NMR (CDCl3): δ 7.50 (2H, m), 7.27 (2H,m), 3.45 (3H, s), 2.06 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH3:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:12][CH2:11]1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(CC(C)C)=O>[CH3:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20.7 g of potassium carbonate and 5 ml of methanol were added to a solution of 28.9 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131) in 600 ml of methylisobutylketone. The solution was reacted for 30 minutes, while it was refluxed. Next, 27.7 ml of ethyl bromoacetate was added dropwise into the solution over about 20 minutes by means of a dropping funnel. Thereafter, the solution was stirred for 4 hours. After reaction, the solution was allowed to cool to room temperature. After the potassium carbonate has been filtered out from the filtrate, the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 35.2 g of N-(trans-4-methylcyclohexyl)-4-(ethoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][C:15]([CH3:25])([CH2:21][CH2:22][CH2:23]Br)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1.[Cl-].[Na+]>CN(C)C=O>[CH3:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:25])[CH2:21][CH2:22][CH2:23][C:2]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCC(C(=O)OCC)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
5 g of diethyl malonate was dissolved in 30 ml of N,N-dimethylformamide and 1.550 g of sodium hydride (60% oily) was added thereto under ice-cooling. Next, 7.04 g of ethyl 2,2-dimethyl-5-bromopentanoate was added to the reaction mixture and the resulting mixture was stirred at 80° C. for 2 hours. After ice-cooling the reaction mixture again, 1.550 g of sodium hydride (60% oily) was added thereto. After stirring for 25 minutes, 7.4 g of 2-chloro-5-nitropyridine was added and the resulting mixture was stirred at 80° C. for 1.5 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and repeatedly extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 9.71 g of the title compound as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[Br:13].O.C(O)(=O)C.Cl>C(O)C.[Zn]>[Br:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: Brc1cc(Br)c(-c2sc(Br)cc2Br)s1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Brc1ccsc1-c1sccc1Br
Temperature: 25 °C
Yield: 90.6 %

Procedure:
3,3′,5,5′-Tetrabromo-2,2′-bithiophene 10 (12.5 g, 25.9 mmol) was added in portions within 0.5 h to a refluxing dispersion of Zn powder (6.5 g, 0.1 mol) in 130 mL of ethanol containing 13 mL of water, 31 mL of glacial acetic acid, and 2.6 mL of 3 M HCl. After heating under reflux for two additional hours and then cooling to room temperature, the mixture was filtered and washed three times with ethanol, and the filtrate was collected. The solvent was then removed by evaporation, and 60 mL of H2O was added. The mixture was then extracted with diethyl ether, and the combined extracts were washed with water, dried over anhydrous MgSO4, and filtered. The solvent was removed by evaporation, and the crude product was recrystallized from hexane to give colorless crystals (7.6 g, yield 90%). 1H NMR (CDCl3): 7.41 (d, J=5.3 Hz, 2H), 7.09 (d, J=5.3 Hz, 2H) ppm; 13C NMR (CDCl3): δ 112.84, 127.73, 129.07, 131.01 ppm.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH2:13][P:14](=[O:17])([OH:16])[OH:15])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=2.C(N(CC)[CH:22]([CH3:24])[CH3:23])(C)C.Cl[CH2:28][O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:30]([O:29][CH2:28][O:17][P:14]([CH2:13][CH2:12][N:8]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]2[C:2](=[O:1])[C:10](=[O:11])[C:9]1=2)(=[O:15])[O:16][CH2:28][O:29][C:30](=[O:37])[C:23]1[CH:22]=[CH:24][CH:36]=[CH:31][CH:32]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OCCl)c1ccccc1
Reactant: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Solvent: CN(C)C=O
Product: O=C(OCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCOC(=O)c1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
A solution of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (20.16 mmol, 5.25 g) in dry DMF (120 mL) was treated with N,N-diisopropylethylamine (80.64 mmol, 14 ml) for ½ hour at ambient temperature. Benzoic acid chloromethyl ester (60.49 mmol, 10.32 g, synthesis described below) was added at ambient temperature under exclusion of moisture. The reaction mixture was heated to 65° C. for 20 hours. The temperature was then raised to 72° C. and stirred at 72° C. for 16 hours after which the reaction was completed. The mixture was cooled to room temperature and partitioned between 10% sodium bicarbonate and ethyl acetate. After separation of the layers the aqueous phase was again extracted with ethyl acetate (6×) until there was no more product in the water phase (by silica gel TLC, 7% 2M ammonia in methanol and 93% chloroform). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was flash chromatographed on 400 g silica gel using a solvent mixture of 1% 2M ammonia in methanol and 99% chloroform. Gradually the percentage of ammonia in methanol was increased to 7% and 93% chloroform. The solvent was evaporated in vacuo to yield the desired product (10.5 g, 99%; glass like material). MS (ES−): m/e 527 (M−H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[S:5][C:6]=1[C:7]([O-:9])=[O:8].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:37][CH2:36]1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:36][CH3:37])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:11]2=[O:19])=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(-n2c(=O)[nH]c3ccccc32)sc1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1sc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)nc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
To a 25-mL round bottom flask was added 4-methyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)thiazole-5-carboxylate (0.10 g, 0.33 mmol), tetrahydrofuran (95 mL), 4-fluorobenzyl bromide (0.08 g, 0.43 mmol) and potassium carbonate (0.10 g, 0.73 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h and refluxed for 3 h. The second portion of 4-fluorobenzyl bromide (0.08 g, 0.43 mmol) was added and stirred at ambient temperature for 17 h. The third portion of 4-fluorobenzyl bromide (0.08 g, 0.43 mmol) and second portion of potassium carbonate (0.10 g, 0.73 mmol) were added at ambient temperature. The mixture was stirred for an additional 3 h at ambient temperature, filtered and washed with tetrahydrofuran. The filtrate was concentrated and the residue was purified by column chromatography to afford the title compound as a white solid (0.08 g, 59% yield): mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ 8.58-8.55 (m, 1H), 7.38-7.31 (m, 2H), 7.26-7.16 (m, 2H), 7.05-6.95 (m, 3H), 5.09 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 2.76 (s, 3H), 1.36 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.8, 157.1, 157.0, 151.9, 131.0, 131.0, 129.5, 129.4, 128.9, 126.3, 124.2, 122.9, 116.8, 116.1, 115.8, 115.0, 108.4, 61.0, 44.5, 17.5, 14.3; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][CH:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:19]([N:6]1[CH2:7][C@@H:8]([N:10]([CH:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]2)[S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9][C@H:5]1[C:3]([O:2][CH3:1])=[O:4])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C2CCC(C)(C)CC2)S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 528.4 %

Procedure:
To a solution of methyl (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (2.37 g, 6.7 mmol) prepared in Step A of Example A1 in DCM (10 ml) was added TEA (1.36 g, 13.4 mmol), slowly added dropwise methanesulfonylchloride (104 mg, 0.91 mmol) at 0° C., and stirred at rt for 30 min. After the reaction finished, the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex ═1/1) to give the title compound (2.08 g, 72%).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=O)=[CH:12][CH:11]=2)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH3:27][NH:28][CH3:29]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:27][N:28]([CH3:29])[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]3[C:4](=[O:21])[C:3]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]4[C:1]3=[O:26])[CH:19]=2)[CH2:14][CH2:15][CH:16]=1
Reactant: CNC
Reactant: O=C1CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C1=CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Temperature: 1 °C
Reaction time: 2 h

Procedure:
A solution of titanium tetrachloride (5.4 g) in toluene (20 ml) is added over a period of 15 minutes to a stirred solution of 7-(3-phthalimido)propoxy-1-tetralone (19.9 g) suspended in a solution of anhydrous dimethyl amine (22 g) in dry toluene (200 ml) while maintaining a reaction temperature of about 1° C. under a N2 atmosphere. When the addition is complete, the reaction mixture is allowed to warm to RT and stirred at RT for 41/2 hours. The reaction mixture is filtered, the salts washed with dry toluene and the clear filtrate evaporated, affording a light yellow oil, which is stored under N2 and used in the next step without any further treatment.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5-hydroxy-2-nitro-benzaldehyde (10 g, 59.8 mmol) and cesium carbonate (23 g, 70.6 mmol) in DMF (40 mL) was added iodomethane (8.8 mL, 141 mmol), and the mixture stirred at room temperature for 17 h. The resulting red-orange suspension was diluted with ethyl acetate and the mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a thick yellow oil which solidified on standing to afford 5-methoxy-2-nitro-benzaldehyde.
Reaction SMILES: [C:1]([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]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=2[N:9]=[CH:8]1)#[C:2][CH3:3].I[C:32]1[CH:33]=[C:34]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[CH3:38].[CH2:43](N(CC)CC)C>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.[Cu]I.C(#N)C>[CH3:38][C:37]1[CH:36]=[CH:35][C:34]([S:39]([NH:42][CH3:43])(=[O:41])=[O:40])=[CH:33][C:32]=1[C:3]#[C:2][CH2:1][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]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: CC#COCCn1cnc2c(NC(=O)OCc3ccccc3)nc3ccccc3c21
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(N)(=O)=O)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CNS(=O)(=O)c1ccc(C)c(C#CCOCCn2cnc3c(NC(=O)OCc4ccccc4)nc4ccccc4c32)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Under a nitrogen atmosphere benzyl N-{1-[2-(propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-yl}carbamate (0.37 g, 0.91 mmol), 3-iodo-4-methyl-1-benzenesulfonamide (0.3 g, 0.96 mmol), triethylamine (0.2 mL, 1.36 mmol) and anhydrous acetonitrile (20 mL) were combined. Dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.018 mol) and copper(I) iodide (7 mg, 0.036 mmol) were added and the reaction solution was heated to ˜45° C. After 3 hours analysis by reverse phase HPLC indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (98/2 to 95/5 dichloromethane/methanol) to provide 0.33 g of benzyl N-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-yl)carbamate as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([NH:22][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitrobenzoyl chloride in anhydrous THF (5 mL) was added N, N-diisopropylethylamine (0.235 mL, 1.35 mmol) followed by 1-aminonaphthalene (192.9 mg, 1.35 mmol) and the solution was stirred at 40° C. for 16 hours. The solvent was evaporated to give N-naphthyl(2-nitrophenyl)carboxamide, a compound of formula (7), which was used for the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH2:1]([N:3]1[C:4](=[O:16])[CH:5]=[CH:6][C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)=[CH:8]1)[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCn1cc(C2CCC(=O)CC2)ccc1=O
Product: CCn1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-ethyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.