Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OCC
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with 4-carboxymethyl-2-ethoxy-benzoic acid ethyl ester (Aldrich, 50.4 mg, 0.20 mmol), in the presence of HATU (91.0 mg, 0.24 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) at rt for 2 hrs to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid ethyl ester (52.6 mg, 37.6%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH:1]1([C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:19][CH:20]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C2CC2)cc1
Reaction time: 7 h
Yield: 75.4 %

Procedure:
3.2 g (30.6 millimoles) of cyclopropanecarboxylic acid chloride, dissolved in 20 ml of absolute tetrahydrofuran, are added dropwise, at room temperature, to a stirred solution of 5.0 g (25.9 millimoles) of 3-(p-aminobenzoyl)-propionic acid in 100 ml of absolute tetrahydrofuran; a precipitate forms. The reaction mixture is then kept for 7 hours under reflux. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 5.1 g (75% of theory) of 3-(p-cyclopropylcarbonylaminobenzoyl)-propionic acid are obtained as yellow crystals, of melting point 229°-230° C. (after recrystallization from ethanol/water).
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:27][CH2:26][C:25]([CH3:29])([OH:28])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>O>[CH3:29][C:25]1([OH:28])[CH2:26][CH2:27][CH:22]([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:23][CH2:24]1
Reactant: CC1(O)CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(O)CCC(n2nnc3cnc4[nH]ccc4c32)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-1-methyl-cyclohexanol (the resulting solution of previous step) was added a solution of sodium hydroxide (178 mg, 4.45 mmol) in water (2 mL), then the reaction mixture was stirred at 50° C. for 2 hours and neutralized with dilute hydrochloride acid until pH=7. The reaction mixture was purified by a reverse-phase preparatory HPLC (Column: Waters Xbridge C18 150*30 mm*5 um, 25% to 55%: acetonitrile+0.05% NH4OH in water, 10 min, 25 mL/min) to give 20 mg (12%) of 1-Methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=0.725 min, m+H=272.1. 1H NMR (400 MHz, CDCl3) δ: 10.00 (s, 1H), 9.10-9.09 (m, 1H), 7.45-7.44 (m, 1H), 6.82-6.80 (m, 1H), 4.97-4.93 (m, 1H), 2.39-2.34 (m, 4H), 2.06-2.00 (m, 2H), 1.82-1.74 (m, 2H), 1.44 (s, 3H); and 22 mg (14%) of 1-Methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=1.023 min, m+H=272.1. 1H NMR (400 MHz, CDCl3) δ: 10.65-10.63 (m, 1H), 9.11 (s, 1H), 7.44-7.44 (m, 1H), 7.17-7.16 (m, 1H), 5.04-4.97 (m, 1H), 2.80-2.70 (m, 2H), 2.05-1.93 (m, 4H), 1.77-1.69 (m, 2H), 1.40 (s, 3H)
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([S:14][CH3:15])[CH:8]=2)=[O:4].[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Br)([CH3:20])([CH3:19])[CH3:18]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].[OH-].[Na+].O>[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([S:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[C:3](=[O:4])[CH:2]([CH3:16])[CH3:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CSc1ccc2cc(C(=O)C(C)C)[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc2cc(C(=O)C(C)C)n(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.7 %

Procedure:
To a solution of 2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one (600 mg, 2.57 mmol) and Bu4NBr (4.12 g, 12.85 mmol) in 9 N NaOH (10 mL, cooled) was added tert-butyl(2-bromoethyl)carbamate (2.87 g, 12.85 mmol). The reaction mixture was stirred at rt for 72 h. The mixture was diluted with water (20 mL) at 0° C. and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel eluting with (petroleum ether/EtOAc 10:1) to afford tert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate (200 mg, 20.66% yield) as a colorless oil. LC-MS MS (ESI) m/z 321.1 [M-56+H]+, 277.1 [M-100+H]+. 1H NMR (CDCl3 400 MHz): δ 7.57 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.80 (brs, 1H), 4.62 (t, J=6.4 Hz, 2H), 3.58-3.42 (m, 3H), 2.58 (s, 3H), 1.38 (s, 9H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([CH:12]([CH2:17][CH:18]=[CH2:19])[C:13](OC)=[O:14])[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH:1]1[C:11]2[CH:10]([CH:12]([CH2:17][CH:18]=[CH2:19])[CH2:13][OH:14])[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C(=O)OC)C1c2ccccc2COc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CO)C1c2ccccc2COc2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
Dissolved methyl 2-[6, 11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-enoate (9.00 g, 0.0292 mol) in 100 mL of dry THF, and cooled to 0° C. under a nitrogen atmosphere. Added 1.0M lithium aluminum hydride in THF (29.2 mL, 0.0292 mol) via addition funnel. Stirred at room temperature for 45 mins. Added 1 mL of water, 1 mL of 1N NaOH, then 3 mL of water. Stirred at room temperature for 30 mins. then filtered through celite. Washed celite cake with ethyl acetate. Washed filtrate with saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane then 25% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 6.78 g (83% yield) of 2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.247 g, 1 mmol) in dichloromethane (10 mL) and pyridine (0.5 mL) was added a solution of 4-biphenylcarbonyl chloride (0.217 g, 1 mmol) in dichloromethane (5 mL). After stirring overnight the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL). Separate the layers and wash the organic layer with water (2×10 mL), saturated sodium bicarbonate (2×20 mL), hydrochloric acid (0.2 N, 1×20 mL). Dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified by RPHPLC (30% ethyl acetate/hexane) to give 0.4 g (94%) of pure product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1([N:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[N:16][CH:15]=[N:14]1.[I:32]I>O1CCCC1.C(OCC)(=O)C>[C:26]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:13]2[C:17]([I:32])=[N:16][CH:15]=[N:14]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(C(=Nn2cncn2)c2ccccc2)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Ic1ncnn1N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.3 g (12.8 mmol) of diisopropyl amine in 30 mL is cooled to -78° C. n-Butyllithium (4.3 mL of a 1.6M solution in hexanes, 6.9 mmol) is added dropwise. Over 1/2 h, the solution is warmed to 0° C. and recooled to -78° C. A solution of 2.0 g (6.3 mmol) of N-(1H-1,2,4-triazol-1-yl)-benzophenone imine in 5 mL of tetrahydrofuran is added. The solution is stirred 10 min before 1.7 g (6.7 mmol) of iodine are added. The reaction mixture is warmed to room temperature, diluted with ethyl acetate and washed with saturated aqueous NaHSO3, water and brine. Drying (MgSO4) and removal of solvent gives the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19].Cl>ClCCl>[N:1]([C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:6][CH2:7]1)=[C:18]=[S:19]
Reactant: N[C@H]1CC[C@H](CCCCC2CCCCC2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Product: S=C=N[C@H]1CC[C@H](CCCCC2CCCCC2)CC1
Reaction time: 8 h

Procedure:
A solution of 12.2 g of trans-4-(4-aminocyclohexyl)-butylcyclohexane in 135 ml of dichloromethane is added dropwise at 0° under nitrogen to a solution of 15.2 g of 1,1'-thiocarbonyldiimidazole in 90 ml of dichloromethane in the course of 1.5 hours. After standing overnight, about 140 ml of 3% hydrochloric acid are added at 0°-4° until pH 2 is obtained. The organic phase separated off is washed with water until pH 6, is dried over sodium sulfate and evaporated. Purification of the crude product (15.6 g) by column chromatography leaves 13.1 g of trans-4-(4-isothiocyanatocyclohexyl)-butylcyclohexane. Melting point (m.p.) +23°; clear point (c.p.) +72.9°.
Reaction SMILES: [NH2:1][C@:2]([CH3:12])([CH2:5][CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:13](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:14].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][C@@:2]1([CH2:5][CH2:6][C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:13](=[O:14])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@](N)(CO)CCc1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@]1(CCc2ccco2)COC(=O)N1
Yield: 57.6 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(furan-2-yl)butan-1-ol ½ D-(−)tartrate (51.2 mg, 0.16 mmol) obtained above in dichloromethane (1.6 ml) were added successively di-t-butyl dicarbonate (0.17 g, 0.78 mmol), triethylamine (0.22 ml, 1.58 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) with stirring, and the resulting mixture was stirred at room temperature for 20 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford (4R)-4-methyl-4-[2-(furan-2-yl)ethyl]-1,3-oxazolidin-2-one (18.0 mg, yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8].IC.[C:42]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[N:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:29])=[O:30])[CH3:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)NC(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the product obtained from Step B (59.3 mg, 0.1 mmol) and iodomethane (excess) in DMF was added solid K2CO3 (excess). The mixture was stirred at room temperature under N2 for 4 h. LC-MS indicated the completion of reaction. Most of the solvent was evaporated, and mixture was diluted with ethyl acetate, washed with water, brine and dried. After reverse phase HPLC (acetonitrile/water) purification, the desired tert-butyl 7-(3,4-dichlorophenyl)-6-((4-methoxyphenylsulfonyl)(methyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidine-4(7H)-carboxylate was obtained as white solid. LC-MS found: (M+1)+=607.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:27]3[CH2:28][CH2:29][CH2:30][CH:23]2[C:24](=[CH:32]O)[C:25](=O)[CH2:26]3)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[CH:27]3[CH2:28][CH2:29][CH2:30][CH:23]2[C:24]2[CH:32]=[N:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:25]=2[CH2:26]3)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)c1ccc(NN)cc1
Product: CC(C)c1ccc(-n2ncc3c2CC2CCCC3N2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
Prepared as described in Example 5 using 4-isopropylphenylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:17]([CH2:26][CH3:27])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH2:26][CH3:27])[N:18]([CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:39]([NH:38][CH:35]([CH3:37])[CH3:36])=[O:40])=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)N=C=O
Reactant: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(CCCNC(=O)NC(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 22.4 %

Procedure:
7-(3-Aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and isopropyl isocyanate (128 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0° C. and the reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×20 mL). The combined organic fractions were sequentially dried (MgSO4), filtered and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA over 2000 mL). The desired product was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 10% methanol in dichloromethane over 1500 mL). A final purification by recrystallization from acetonitrile provided 142 mg of N-{3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}-N′-isopropylurea as a white solid, mp 213-216° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([OH:13])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)OCc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)OCc1ccccc1C(=O)O
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (6.80 g, 19.1 mmol) obtained from Example 17-(1) and anisole (5 g) was dissolved in trifluoroacetic acid (10 ml) at room temperature. The mixture was stirred for 15 minutes, then diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was washed with hexane to afford the crude title compound (3.87 g, 86%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[CH:24][C:16]=1[F:15]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1F
Yield: 72.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2-fluoro-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.075 g; 0.318 mmol), 2-fluoro-4-(3-fluorobenzyl)benzoic acid (0.087 g; 349 mmol), HATU (0.121 g: 0.318 mmol) and N,N-diisopropylethylamine (0.139 mL; 0.795 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 0 to 10% of ethyl acetate in dichloromethane) followed by recrystallization from a mixture of dichloromethane/heptane, furnished 0.098 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Zn+2].C([O-])(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25]#[N:26])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C#N)c2s1
Temperature: 100 °C
Yield: 100 %

Procedure:
1-(5-(benzyloxy)-7-bromobenzo[d]thiazol-2-yl)-3-ethylurea (5.00 g, 12.29 mmol), zinc cyanide (1.58 g, 13.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene (20 mg, 0.033 mmol), zinc acetate (90 mg, 0.50 mmol) and zinc dust (33.3 mg, 0.50 mmol) were stirred in a reaction tube in degassed DMF (60 ml) and water (600 ul). Tris(dibenzylideneacetone)dipalladium(0) (113.2 mg, 0.133 mmol) was added and the reaction purged with N2, sealed and heated to 100° C. for 18 h with stirring. LCMS indicated clean conversion to the desired material. The solvents were removed under reduced pressure, the resulting residue triturated with water, the solid collected by filtration and dried in a vacuum oven to afford the desired material as a pale white solid 4.4 g (100%). This material was used directly in the next step with no further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17]C(=O)C)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:21])[CH3:6])[CH3:2].N1CCOCC1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:21])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC(C)=O)cc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(O)cc21
Temperature: 25 °C

Procedure:
To a solution of the crude 2-(6-acetoxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester in THF (80 mL) was added morpholine (5.5 mL, 63 mmol) and the mixture was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (100 mL). The mixture was washed with brine (30 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatograph on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (3.2 g, 57% over two steps). 1H NMR (CDCl3, 400 MHz): δ 6.88 (d, J=8.8 Hz, 1H), 6.47 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 5.24 (q, J=6.8 Hz, 1H), 4.54 (d, J=14.8 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H). The phenol OH was not observed in CDCl3.