Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C(C(C)=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Cl)cc(Cl)c2cccnc12
Reactant: CCOC(=O)CN=C=O
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Oc1c(Cl)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
5,7-Dichloro-8-hydroxyquinoline (21.4 g), ethyl isocyanatoacetate (21.3 g) and triethylamine (1.0 ml) were mixed together in 400 ml of methyl ethyl ketone and stirred at room temperature for about 42 hours resulting in the precipitation of a white crystalline solid. This solid was removed from the reaction mixture by filtration and was determined to be the desired ethyl N-(((5,7-dichloro-8-quinolinyl)oxy)carbonyl)glycinate, m.p. 119.5° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10]>C1COCC1>[CH3:10][C:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:4][O:11]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)c1ccncc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2ccncc2)CO1

Procedure:
Sodium hydride (5.0 g of a 50% dispersion in oil) was added portionwise to a stirred suspension of trimethylsulphoxonium iodide (22.0 g) in THF (150 cm3) and the mixture was heated under reflux for 3 hours. After cooling to 40°, 4-acetyl-pyridine (10.0 g) was added and the mixture was again heated under reflux for 1 hour. The cooled mixture was evaporated in vacuo, partitioned between ether (100 cm3) and water (50 cm3) and the aqueous phase was further extracted with ether (2×50 cm3). The combined dried extracts were evaporated to afford 2-methyl-2-[4-pyridyl]oxirane as a crude oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](OCC)=[O:15])=[C:9]1[C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].Cl>COCCOCCOC>[CH2:1]([N:8]1[C:9]2[C:19](=[O:21])[NH:25][NH:26][C:14](=[O:15])[C:10]=2[CH:11]=[C:12]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(Cc2ccccc2)c1C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc2c(=O)[nH][nH]c(=O)c2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 175.3 g (0.56 mol) of diethyl 1-benzyl-5-methylpyrrole-2,3-dicarboxylate and 540 ml (11.1 mol) of hydrazine hydrate in 880 ml of diglyme is heated to 110° C. After 2 h, a further 270 ml (5.5 mol) of hydrazine hydrate are added dropwise in the course of 90 min. The mixture is subsequently stirred at 110° C. for a further 16 h. After cooling and addition of 2 1 of ice-water, the mixture is adjusted to pH 5 with conc. hydrochloric acid. The precipitate is filtered with suction and washed with 5 1 of water. After drying over potassium hydroxide in a high vacuum and precipitating from diisopropyl ether/ethyl acetate, 127.3 g (89%) of the title compound are isolated. M.p.: 322°-324° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[N:8]1([C:6]2[N:7]=[C:2]([C:33]3[CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[CH:30]=[CH:31][CH:32]=3)[CH:3]=[C:4]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(-c2cc(Nc3ccc(OC(F)(F)F)cc3)nc(N3CCOCC3)n2)c1
Temperature: 30 °C
Yield: 49.7 %

Procedure:
To a mixture of compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.3 g, 0.8 mmol) and 3-acetyl benzene boronic acid (0.13 g, 0.79 mmol) in DMF (10 mL) was added palladium tetrakis triphenyl phosphine (0.027 g, 0.023 mmol) and 2M Na2CO3 soln (0.67 g, 6.32 mmol) at room temperature. The reaction mixture was then heated for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C., diluted with water, extracted with ethyl acetate (3×10 mL). Combined organic layers were concentrated and the residue was purified by column chromatography using 15% ethylacetate in pet-ether to afford the desired compound (0.18 g, 49%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2(C(OCC)=O)[CH2:11][C@@H:10]([C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][C:8]2=[O:28])=[CH:4][CH:3]=1.Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:8](=[O:28])[O:9][C@H:10]([C@@H:12]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1(Cc2ccc(Br)cc2)C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of the product from Example 92A (22.4 g) in ethanol (120 mL) was treated with LiOH monohydrate (8.0 g, 190.7 mmol) solution in water (30 mL) and the mixture was stirred at 25° C. for 16 hours. The mixture was cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (400 mL) was then heated at reflux for 18 hours, cooled and concentrated to give the title compound (18.4 g), which was used without further purification.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:54])[NH:29][C@H:30]([CH2:35][O:36][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:31]([CH3:34])[CH2:32][CH3:33])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:54])[NH:29][C@H:30]([CH2:35][OH:36])[C@@H:31]([CH3:34])[CH2:32][CH3:33])[N:27]=2)[CH2:20]1
Reactant: CC[C@H](C)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 110.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.89 g, 2.45 mmol) (obtained as described in Reference Example 38(2)) in anhydrous tetrahydrofuran (95 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (5.87 ml, 5.87 mmol) in an ice bath. The mixture was stirred in the ice bath overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (9:1) as the eluant to afford 3-hydroxy-1-{4-[(1S,2S)-1-(hydroxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (811 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16](O)=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:27])=O.CCN(C1C=CC=CC=1)CC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16]([Cl:27])=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(O)nc3s2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(Cl)nc3s2)cc1

Procedure:
6.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was added to a mixture of 25 ml of phosphorus oxychloride and 4 ml of diethylaniline, and the resulting mixture was heated at a temperature of 70° to 80° C. for 2 hours. After cooling, the precipitate formed was filtered, washed successively with water, isopropanol and diethyl ether to obtain 4.3 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as crystals having a melting point of 245° to 248° C.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][N:10]=1.[F:22][C:23]([F:41])([F:40])[O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>O>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][C:28]3[CH:38]=[CH:39][C:25]([O:24][C:23]([F:22])([F:40])[F:41])=[CH:26][CH:27]=3)[CH2:33][CH2:34]2)=[N:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(OCCC2CCNCC2)cc1
Reactant: Brc1ccc(OC2CCCCO2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(OCCC2CCN(c3ccc(OC4CCCCO4)cn3)CC2)cc1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
Toluene (15 ml) was added to a mixture of 2-bromo-5-(tetrahydropyran-2-yloxy)pyridine (2.58 g, 10 mmol), 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine (3.18 g, 11 mmol) and sodium tert-butoxide (1.35 g, 14 mmol), and then the atmosphere was replaced with nitrogen. Bis(dibenzylideneacetone)palladium (Pd2(dba)3 complex) (0.23 g, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine (xantphos) (0.36 g, 0.63 mmol) were added to the mixture, and the reaction mixture was heated at 100° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The result was purified by silica gel column chromatography (ethyl acetate:hexane=10:90→25:75) to afford the title compound as a pale brown powder (4.45 g, 95%).
Reaction SMILES: [NH:1]1C=CN=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=1.[OH-:26].[Na+]>C(O)C>[NH2:18][C:15]1[N:14]=[C:13]([NH2:19])[C:12]([O:11][C:10]2[C:9]([CH:21]([CH3:23])[CH3:22])=[CH:8][C:7]([O:24][CH3:25])=[C:6]([CH:20]=2)[C:2]([NH2:1])=[O:26])=[CH:17][N:16]=1
Reactant: [OH-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ncc[nH]1
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Temperature: 110 °C

Procedure:
To 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (49 mg, 0.16 mmol, from Example 15) suspended in ethanol (1 mL) was added sodium hydroxide (64 mg, 1.60 mmol, dissolved in 1 mL water). The reaction was heated at 110° C. for 5 hours, cooled, and washed with dichloromethane (25 mL). The dichloromethane layer was concentrated and purified by preparatory TLC plates (92/8/0.5 dichloromethane/methanol/ammonium hydroxide) to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide as white solid (9 mg, 17%, MS (M+H)=318), which was converted to the hydrochloride salt.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Product: O=C(Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1)c1ccncc1
Yield: 17 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and isonicotinoyl chloride give the title compound in 17% yield as a yellow solid, mp 252.1° C. 1H NMR (DMSO-d6) δ 2.94 (br s, 2H), 3.87 (br s, 2H), 6.82 (s, 1H), 6.90-7.62 (m, 12H), 7.83 (d, 2H), 8.79 (d, 2H), 10.47 (s, 1H); MS (ES) 403 (M+H), 401 (M−H). HPLC shows 93% purity.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH:30]1(O)[CH2:35]CC[CH:32]([OH:36])[CH2:31]1>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH:27]3[CH2:35][CH2:30][CH2:31][CH:32]([OH:36])[CH2:28]3)=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: OC1CCCC(O)C1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OC1CCCC(O)C1)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 1,3-cyclohexanediol (0.44 g, 3.8 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.0 mL) was stirred at 130° C. for 1.5 days. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 13%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[C:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:26]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:25]#[N:26])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-cyanomethylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=461.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: c1cc2cc(-c3cncc(N4CC5CC6CC4CN(C6)C5)c3)ccc2[nH]1

Procedure:
The title compound was prepared from the product of Example 65A and 1H-indol-5-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 344.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: [ClH:1].Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(O[CH2:21][CH2:22][N:23]3[CH2:28]CN(C)C[CH2:24]3)=CN2N=CN=1.Cl.[F:46][C:47]1[CH:48]=[C:49]([NH:73][C:74](=[O:86])[CH2:75][C:76]([NH:78][C:79]2C=CC(F)=[CH:81][CH:80]=2)=O)[CH:50]=[CH:51][C:52]=1[O:53][C:54]1[C:59]2=[C:60]([CH3:72])[C:61]([O:63][CH2:64]CN3CCOCC3)=[CH:62][N:58]2[N:57]=[CH:56][N:55]=1>>[ClH:1].[ClH:1].[CH3:24][N:23]([CH3:28])[CH2:22][CH2:21][CH2:64][O:63][C:61]1[C:60]([CH3:72])=[C:59]2[N:58]([CH:62]=1)[N:57]=[CH:56][N:55]=[C:54]2[O:53][C:52]1[CH:51]=[CH:50][C:49]([NH:73][C:74](=[O:86])[C:75]2[CH:81]=[CH:80][CH:79]=[N:78][CH:76]=2)=[CH:48][C:47]=1[F:46]
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 11 %

Procedure:
4-(6-(3-(Dimethylamino)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (54 mg, 0.15 mmol, Compound B of Example 32) as converted to the title compound (8.7 mg, 11 %) in a manner similar to the preparation of Compound D of Example 36. 1H NMR (CD3OD) δ 9.47 (s, 1H), 9.20-9.19 (m, 1H), 9.08-9.07 (m, 1H), 8.30-8.27 (m, 1H), 7.97-7.93 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.64-7.61 (m, 1H), 7.43-7.39 (m, 1H), 4.26-4.11 (m, 2H), 3.43-3.39 (m, 2H), 2.98 (s, 6H), 2.46 (s, 3H), 2.34-2.30 (m, 2H); HRMS(ESI), 463.1894 (M−H)− calc, 463.1905 (M−H)− found.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH:12][CH2:13][C:14]([CH3:18])([CH2:16]O)[CH3:15].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:13][C:14]([CH3:18])([CH3:16])[CH2:15][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(C)(CO)CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCC(C)(C)CO2)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde (60.0 g, 279 mmol) was dissolved in toluene (600 mL), and after addition of neopentyl glycol (32.0 g, 306 mmol) and Amberlyst-15 (3.6 g) the reaction mixture was heated under reflux for 2 hours on a water separator. After cooling, the reaction mixture was filtered, washed twice with water, and then concentrated under reduced pressure. The oil residue was combined with heptane, and the product which precipitated was filtered off and washed with heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([Cl:16])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2E)-3-(4-chlorophenyl)prop-2-enoic acid (2.0 g, 11 mmol) in 50 mL methylene chloride was added oxalyl chloride (1.05 mL, 12.1 mmol) and N,N-dimethylformamide (0.05 mL, 0.6 mmol). The resulting mixture was stirred at r.t. for 6 h. The solvent was removed under vacuum. The resulting solid was diluted with hexanes and the solvent removed under vacuum to provide an off-white solid which was used without further purification.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1>C(Cl)(Cl)Cl>[NH2:30][C:15]1[C:14]2[N:31]=[C:11]([CH2:10][CH2:9][O:8][CH3:7])[N:12]([CH2:32][CH2:33][CH3:34])[C:13]=2[C:22]2[CH:21]=[CH:20][C:19]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:26][CH2:25]3)=[CH:18][C:17]=2[N:16]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)NC(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
Isopropyl isocyanate (0.256 mL, 2.61 mmol) was added dropwise to a stirred mixture of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (1.00 g, 2.61 mmol) in chloroform at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 4-12% CMA in chloroform) followed by recrystallization from acetonitrile to afford 0.530 g of 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide as white crystals, mp 176-179° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:22]([Cl:23])=[CH:21][N:20]([CH3:24])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.[F:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:23][C:22]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[C:31]([OH:33])=[O:32])[N:7]([CH2:6][C:5]4[CH:34]=[CH:35][C:2]([N:40]5[CH2:41][CH2:42][CH:37]([F:36])[CH2:38][CH2:39]5)=[CH:3][CH:4]=4)[C:11]=3[CH:12]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: FC1CCNCC1
Reactant: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)CC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions described in Example 152 using 4-fluoropiperidine. MS (ESI): mass calcd. for C31H35ClFN5O3, 580.11; m/z found, 581.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.68 (t, J=4.5, 2H), 7.31 (d, J=2.1, 1H), 7.26 (dd, J=9.0, 2.3, 1H), 7.14-7.02 (m, 4H), 5.70 (s, 2H), 5.03 (s, 2H), 4.79-4.68 (m, 1H), 3.81 (s, 3H), 3.66-3.53 (m, 1H), 3.51-3.36 (m, 2H), 3.28-3.17 (m, 2H), 2.88 (s, 1H), 2.40-2.13 (m, 2H), 2.12-1.84 (m, 6H), 1.84-1.63 (m, 2H), 1.61-1.46 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CCO>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:16]([OH:17])[CH2:18][NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC1CCCCC1
Yield: 65.3 %

Procedure:
((S)-(S)-1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (10 g, 38 mmol, 1 equiv) [Chirex 1819W94 Lot#9924382] was dissolved in EtOH (100 ml) and cyclohexylamine (13 ml, 114 mmol, 3 equiv) was added. The resulting mixture was heated, under an atmosphere of nitrogen, for 12 h at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The resulting white solid was washed with H2O and then with Et2O before drying in vacuo to give ((1S,2R)-1-benzyl-3-cyclohexylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (H1) (9.0 g, 66%). [M+H]+=363.2
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:21]1([CH2:20][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (2.0 g, 7.77 mM), benzyl bromide (0.94 ml, 7.93 mM), and potassium carbonate (2.15 g, 15.5 mM) in 39 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate and 1N HCl. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers were extracted with 1N HCl twice, once with water and once with brine. After drying (NaSO4), evaporation in vacuo afforded 2.61 g (97%) of 9-[(phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.6-7.4 (m, 6H), 7.0 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 316, 348.