Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4ccc(C)nc4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 61.8 %

Procedure:
A solution of Example C1 (0.15 g, 0.4 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.57 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.11 g, 0.8 mmol) in water (1 mL) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as an orange foam (0.106 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.29 (dd, J=8.1, 2.4 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.79 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.36-3.34 (m, 2H), 2.51 (s, 3H), 2.38 (s, 3H), 1.15 (s, 3H); MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1CBr.[OH-].[K+]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccccc1-c1ccc2ccccc2c1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1ccc2ccccc2c1)C(=O)O
Temperature: 130 °C

Procedure:
70 g (0.37 mmol) of diethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH were added dropwise at room temperature to 8.5 g (0.37 mmol) of sodium in 100 cm3 of H2O-free EtOH. Subsequently, 110 g (0.37 mmol) of 14 in 200 cm3 of H2O-free EtOH were added dropwise and the mixture was heated under reflux for 3 hours. 62 g (1.1 mol) of KOH dissolved in 100 cm3 of H2O were added at room temperature and the mixture was heated under reflux for a further 4 hours. The solvents were removed under reduced pressure, the residue was admixed with H2O until completely dissolved and acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated at 130° C. for 1 hour. This gave 90 g (84%) of 15 as a viscous oil.
Reaction SMILES: N(C1CC1)=C=S.N.[CH:8]1([NH:11][C:12]([NH2:14])=[S:13])[CH2:10][CH2:9]1.Br[CH2:16][C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=O>C1COCC1.CO>[CH:8]1([NH:11][C:12]2[S:13][CH:16]=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1
Reactant: NC(=S)NC1CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Agent: N
Agent: S=C=NC1CC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(NC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isothiocyanato-cyclopropane (4 g) was mixed with ammonia (37% in water, 8 mL) and methanol (32 mL) at 0° C. and then stirred for 16 hours at room temperature. The mixture was then cooled to 0° C., filtered, washed with a little water and dried. The Cyclopropyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=261.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH:30]1([OH:33])[CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][CH:30]2[CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: OC1CC1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CC5)c34)cc2o1
Temperature: 25 °C
Yield: 80 %

Procedure:
6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopropanol (2 equiv), sodium tert-butoxide (2 equiv), 1,4-dioxane (0.03 M) were combined and stirred at 25° C. The reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (0-50% ethyl acetate in hexane) column, to give the title compound (80% yield) as clear oil. MS (ESI) m/z 471.5 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography). Title compound: ESI-MS: 535.1 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][O:43][NH:44][CH3:45]>C(Cl)Cl.O>[CH3:42][O:43][N:44]([CH3:45])[C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18]
Reactant: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To the solution of 166 (170 mg, 0.69 mmol) in DCM (5 mL) was added EDC.HCl (190 mg, 1 mmol), HOBt (160 mg, 1 mmol), TEA (0.3 mL) and N-methoxymethanamine hydrochloride (100 mg, 1 mmol). The mixture was stirred at RT overnight. The mixture was poured into water, extracted with EtOAc, washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography affording 140 mg (85%) of 1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide (168) as a light yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:33][C@@H:34]([C@@H:36]4[CH2:40][C:39](=[O:41])[NH:38][CH2:37]4)[CH3:35])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH:23]6[CH2:25][CH:21]([N:22]6C(OC(C)(C)C)=O)[CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:23]12[CH2:25][CH:21]([NH:22]1)[CH2:20][N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]3[N:10]=[C:9]([O:33][C@@H:34]([C@H:36]4[CH2:37][NH:38][C:39](=[O:41])[CH2:40]4)[CH3:35])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)=[CH:18][CH:17]=1)[CH2:24]2
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4C(=O)OC(C)(C)C)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
In a round-bottomed, 100-mL, single-necked flask was placed tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (200.0 mg, 0.27 mmol) in dichloromethane (1 mL). To this was added trifluoroacetic acid (3.1 ml, 40.81 mmol). The mixture was stirred at room temperature for 3 h. Then, it was neutralized with sat. NaHCO3 and the organic layers were extracted with dichloromethane (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 124.8 mg (71%) of (4R)-4-((1R)-1-((6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.57 (s, 1H), 6.78 (d, J=9.1 Hz, 2H), 5.57 (m, 1H), 3.57 (m, 8H), 2.84 (m, 2H), 2.57 (m, 1H), 2.39 (m, 3H), 1.53 (m, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.18 (m, 4H). MS (ESI+) m/z 459.1 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(I)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 620.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), tert-butyl piperazine-1-carboxylate (218 mg, 1.17 mmol), and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by flash chromatography to give the title compound (70 mg, yield 32%). LC-MS (ESI) m/z: 556 (M+1)+.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:6][N:5]([C:8]([C@@:10]2([CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1>Cl.CCOCC.CO>[NH2:15][C@@H:12]1[CH2:13][CH2:14][C@@:10]([C:8]([N:5]2[CH2:4][CH2:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([OH:1])[CH2:7][CH2:6]2)=[O:9])([CH:23]([CH3:24])[CH3:25])[CH2:11]1
Reactant: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](N)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl {(1R,3S)-3-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-3-isopropyl-cyclopentyl}carbamate (0.30 g, 0.70 mmol) was dissolved in a 2.0 M solution of HCl in ether (10 mL). After being stirred for 3.5 h, a few drops of MeOH was added to get a clear solution. The mixture was concentrated to give an oil. The crude product was used in the next reaction without purification. MS calculated for C20H30N2O2: (M+H)331; found 331.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][N:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.[H-].[Na+].[CH3:48]N(C)C=O.CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([N:19]([CH3:48])[C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[CH:23][N:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: CN(C)C=O
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Yield: 78 %

Procedure:
To a mixture of diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer as washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzoyl)(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (39.8 mg, yield 78%).
Reaction SMILES: C([C:8]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[O:11][C:10](=[O:27])[CH:9]=1)[N:18]([C:22](=[O:24])[CH3:23])[C@@H:17]([CH3:25])[CH2:16][C@H:15]3[NH2:26])C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([N:18]1[C:19]2[C:14](=[C:13]3[CH:8]=[CH:9][C:10](=[O:27])[O:11][C:12]3=[CH:21][CH:20]=2)[C@H:15]([NH:26][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:16][C@@H:17]1[CH3:25])(=[O:24])[CH3:23]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](N)C[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc3oc(=O)ccc3c2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
[Step 5] 22 mg of the cis-benzyl-7-acetyl-10-amino-8-methyl-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-3-one and 19 mg of 4-chlorophenylboronic acid were dissolved in 10 mL of dichloromethane followed by adding 29 mg of divalent copper acetate and 34 μL of triethylamine and stirring for 18 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite and water was added followed by extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 7 mg of the target compound in the form of a yellow solid (23%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Yield: 96 %

Procedure:
To a mixture of 0.51 g of 3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.53 g of triphenylphosphine, 0.89 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 25”).
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[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][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.Cl.[F:37][C:38]1([F:42])[CH2:41][NH:40][CH2:39]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[F:37][C:38]1([F:42])[CH2:41][N:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=2)[CH2:39]1
Reactant: FC1(F)CNC1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: Cc1ccc(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting (1R*,2S*)-2-(1-(4-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid, 3,3-difluoroazetidine hydrochloride (4 eq), and 5 eq LiHMDS. MS (ESI): mass calcd. for C31H32F2N4O3, 546.24; m/z found, 547.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.82 (d, J=7.9, 1H), 6.73 (d, J=8.8, 1H), 6.61 (d, J=7.9, 1H), 6.23-6.03 (m, 4H), 5.68 (d, J=8.4, 2H), 4.57 (q, J=16.7, 2H), 4.29 (s, 2H), 3.36 (t, J=11.9, 4H), 2.80-2.70 (m, 1H), 2.10-2.00 (m, 1H), 1.61-1.46 (m, 4H), 1.21-1.13 (m, 1H), 1.12-0.86 (m, 4H), 0.75-0.55 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:21]COC(C)=O>CO>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:11]([O:13][CH3:21])=[O:12])([O-:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 100 %

Procedure:
Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100%) which is used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[N:3]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>>[N+:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:4]1[N:3]=[C:2]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]3)[N:10]=[C:9]3[C:5]=1[N:6]=[CH:7][NH:8]3)[CH2:12][CH2:13]2)([O-:22])=[O:21]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2c1nc(Cl)nc2[nH]cnc12
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4cc([N+](=O)[O-])ccc43)c3nc[nH]c3n2)CC1
Temperature: 140 °C

Procedure:
56 g of product obtained in stage 1 above are mixed with 140 g of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 55 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 19.7 g of product are recovered.
Reaction SMILES: N12CCCNC1=NCCC2.[CH3:11]/[C:12](/[N+]([O-])=O)=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][N+:28]#[C-:29])[CH3:24]>C(O)(C)C.C1COCC1>[CH2:23]([O:25][C:26]([C:27]1[NH:28][CH:29]=[C:12]([CH3:11])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:30])[CH3:24]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C(=C\c1ccccc1)[N+](=O)[O-]
Agent: C1CN=C2NCCCN2C1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
1,5,7-Triazabicyclo[4.4.0]dec-5-ene on polystyrene (4.7 g, 2.6 mmol/g, 12.2 mmol) was added to a reaction mixture of trans-β-methyl-β-nitrostyrene (997 mg, 6.11 mmol) and isocyanoacetic acid ethyl ester (691 mg, 6.11 mmol) in isopropanol (5 mL) and THF (5 mL) and the reaction mixture was stirred overnight at RT under nitrogen as protective gas. The reaction mixture was filtered out and the residue washed with isopropanol and THF. The desired product 4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.25 g, 89% of theoretical) was obtained.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>ClCCl>[F:16][CH:17]([F:20])[CH2:18][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:11])=[O:10]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In a flask under argon was placed triflic anhydride (10.22 mL, 61 mmol) and dichloromethane (10 mL) and it was cooled to −70° C. To this cooled mixture was added slowly a solution of 2,2-difluoroethanol (5.00 g, 61 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (10 mL). After the addition was complete, the mixture was warmed to 25° C. and then concentrated in vacuo. This material was distilled at 60° C. and 50 mm Hg which afforded trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (9.74 g, 75%) as a colorless oil.