Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCOCCO)OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCOCCOc1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 99.8 %

Procedure:
[2-(2-Hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester (2.39 g, 10 mmol), 4-chlorophenol (1.29 g, 10 mmol), and triphenylphosphine (2.89 g, 11 mmol) were dissolved in tetrahydrofuran (50 ml), followed by the dropwise addition of diethylazodicarboxylate (1.73 ml, 11 mmol). After the addition, the reaction solution was stirred at room temperature for 10-12 hours. The solvent was then removed in vacuo. The remaining residue was stirred in 30% EtOAc in hexane (200 mL) for 10 minutes and a white solid was formed. This solid was then filtered and washed with 30% EtOAc in hexane (3×20 mL). The filtrates were combined and the solvents were removed in vacuo. The remaining residue was purified by flash column chromatography (SiO2, 2:1 hexane:EtOAc) to give {2-[2-(4-chloro-phenoxy)-ethoxy]-ethyl}-carbamic acid benzyl ester as clear solid (3.49 g, 99.8% yield). 1H-NMR (CDCl3, ppm) 7.35 (m, 5H), 7.20 (d, 2H), 6.82 (d, 2H), 5.22 (b, 1H), 5.10 (s, 2H), 4.07 (t, 2H), 3.80 (t, 2H), 3.62 (t, 2H), 3.41 (q, 2H). ESMS 350.1 (M+l), 372.1 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([O:25]C)=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][SH:32].O>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH:21]3[S:32][CH2:31][CH2:30][NH:29][C:23](=[O:25])[CH2:22]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: COC(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)SCCN1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (2E)-3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)-2-propenoate (Example 137, Step 1) (1.22 g, 3.20 mmol) and cysteamine (4.0 g) in DMF (15 mL) was heated in an oil bath at 80° C. under an atmosphere of nitrogen with stirring for 18 hours. The product mixture was treated with water and the mixture was acidified to pH 2. The resultant precipitate was filtered, dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31](C)[C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.FC1C=CC(OC)=C(C(C)(C)CC(O)(C(F)(F)F)CNC2C=C(C)C=C3C=2C=NN3C2C=C(C=CC=2)C(O)=[O:73])C=1.N[C@@H](C(O)=O)CO>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:39])[F:40])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([NH:31][C@@H:32]([C:34]([OH:36])=[O:35])[CH2:33][OH:73])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(=O)O)c1)C(F)(F)F
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Agent: N[C@H](CO)C(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(=O)O)c1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 4 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-serine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4](C)[CH:3]=1.BrC1C=CC(I)=[C:14]([O:19]CC)[CH:13]=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([O:19][CH2:14][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1I
Reactant: C=Cc1ccc(Br)cc1C
Agent: C=C[Si](C)(C)C
Product: C=Cc1ccc(Br)cc1OCC
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 62C (2 g, 6.1 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h and worked up in a manner similar as in 30A to yield 62D (1.4 g, 88%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, J=7.03 Hz, 3 H) 4.02 (q, J=6.74 Hz, 2 H) 5.27 (d, J=10.99 Hz, 1 H) 5.74 (d, 1 H) 6.92-7.01 (m, 2 H) 7.04 (d, 1 H) 7.31 (d, J=7.91 Hz, 1 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O1CCCCC1[O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=O)[O:40][CH2:39]2.Cl>C(COC)OC.C1COCC1>[OH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[C:41](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:40][CH2:39]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1OCc2cc(CCCOC3CCCCO3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a stirred solution of oxindole (401 mg, 3.0 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 1.0M LiHMDS/THF solution (6.3 ml, 6.3 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[3-(tetrahydro-pyran-2-yloxy)-propyl]-3H-isobenzofuran-1-one (500 mg, 1.81 mmol) was added. After stirred at room temperature for 2.5 hours, the mixture was poured into a mixture of THF (30 ml) and 2M HCl aqueous solution (30 ml) and heated at 65° C. for 1 hour. The mixture was cooled to room temperature, and then poured into an ice water (300 ml). The resulting solid was separated, rinsed with water, and dried to give 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (460 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][NH:22][CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][N:22]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:25][CH:26]=1
Reactant: Brc1ccccn1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccccn4)CCN3C2)cc1

Procedure:
The title compound was synthesized according to Preparation 11 using 2-bromopyridine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H -pyrido[1,2-a]pyrazine (Preparation 8). mp (—HCl) 261-263° C. HRMS calcd for C20H24FN3O: 341.1903; found, 341.1928.
Reaction SMILES: [F:1][C:2]([F:57])([F:56])[C:3]1[CH:4]=[C:5]([B-:13]([C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Na+].Cl[C:60]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(Cl)Cl>[F:51][C:48]([F:49])([F:50])[C:46]1[CH:47]=[C:42]([B-:13]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:26])([F:27])[F:25])[CH:15]=2)([C:28]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=2)[C:5]2[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:56])[F:57])[CH:4]=2)[CH:43]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:45]=1.[C:61]1([C:60]([CH2+:2])([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FC(F)(F)c1cc([B-](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: ClCCl
Product: [CH2+]C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To 0.4948 g (0.56 mmole) of sodium tetrakis(3,5-bis-trifluoromethylphenyl)borate, prepared according to the method described in Brookhart et al., Organometallics 11, pp. 3920-3922,1992, dissolved in 4.057 ml of methylene chloride was added 0.154 g (0.553 mmole) of chlorotriphenylmethane (Reagent grade, Aldrich) at room temperature, to form a 0.14 M solution of triphenylmethylcarbenium tetrakis(3,5-bis-trifluoromethyl phenyl) borate in methylene chloride. The resulting mixture was transferred in a dry box through a 0.5 mm syringe filter into a dry vial with rubber septum cap.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:28]([F:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH:54]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH3:51])[CH2:38][CH2:37]4)=[C:28]([F:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)CC=O
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)CC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E69.2 (105 mg, 0.17 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.07 ml, 0.50 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.032 ml, 0.25 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.25 mmol) was added and the mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (102 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[N:1]/[C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(/N=C/c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a stirred solution of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (5.2 g, 37.6 mmol) in EtOH (100 mL) were added 4-chlorobenzaldehyde (5.04 g, 35.8 mmol) and AcOH (0.410 mL, 7.17 mmol). The resulting mixture was heated up and stirred at 85° C. for 1 hr. The reaction was concentrated under reduced pressure and the resulting crude mixture was triturated in Et2O to afford the title product (7.6 g, 29.2 mmol) as beige solid. tR: 0.92 min (LC-MS 2).
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](=[O:22])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:3]1.C[O-].[Na+].[BH4-].[K+].Cl>CO>[ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]([OH:22])[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH2:3]1
Reactant: CN1CCN(CCC(=O)C2=Cc3ccccc3OC2)CC1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CN1CCN(CCC(O)C2=Cc3ccccc3OC2)CC1
Reaction time: 8 h

Procedure:
The hydrochloride (0.1 mole) obtained in Example 1 is dissolved in methanol (400 ml). Sodium methoxide (0.22 mole) in methanol solution is added thereto. The material is cooled to 0°-5° C. and potassium borohydride (0.4 mole) is added thereto. The material is stirred overnight. It is then evaporated in vacuo without heating, taken up into ether/H2O. The ethereal phase is washed with water, dried and evaporated, to give a pale yellow oil which is converted to the hydrochloride by addition of ethereal hydrochloric acid. M.p.=220° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[N:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccc(Br)nc1
Solvent: CCOCC
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)nc1

Procedure:
The title compound was prepared as a white solid from 2-bromo-5-methoxy-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:17]([NH:53][CH2:54][C:55]2[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=2[CH3:61])=[O:19])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCOCC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred solution of 3,6-dichloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylic acid (85 mg, 0.28 mmol) in DMF (2 ml) was added DIPEA (73 μl, 0.42 mmol) and HATU (127 mg, 0.33 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 52 mg, 0.31 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water and the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4) and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 5% MeOH in DCM and evaporated to give a glassy solid which was triturated with diethyl ether and filtered to afford the title compound as a white powder (50 mg, 41%). LC-MS 95%, m/z=439.0/440.8, 1H NMR (500 MHz, Chloroform-d) δ 11.33 (br. s, 1H), 8.20 (br. s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 4.51 (s, 2H), 4.02 (dd, J=11.4, 3.8 Hz, 2H), 3.92-3.72 (m, 1H), 3.39 (t, J=11.3 Hz, 2H), 2.78 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 1.89 (tt, J=12.0, 6.2 Hz, 2H), 1.83-1.52 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH2:25][CH2:26][F:27])[N:20]=[N:19]2)=[C:4]([F:28])[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:18]3[C:22](=[O:23])[N:21]([CH2:24][CH2:25][CH2:26][F:27])[N:20]=[N:19]3)[CH:6]=2)=[CH:14][CH:13]=1
Reactant: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Oc2cc(-n3nnn(CCCF)c3=O)c(F)cc2Cl)cc1

Procedure:
1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one is etherified with 4-fluoronitrobenzene in the presence of potassium carbonate in N,N-dimethylformamide to form 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound A). Compound A is then reduced with iron powder in acetic acid and water to produce 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound B). Acetone is added to a stirring mixture of Compound B in hydrochloric acid. The mixture is cooled to about 5° C., and a solution of an equimolar amount of sodium nitrite in water and a molar excess of methyl acrylate are added in succession. The resultant mixture is stirred for 15-20 minutes, after which copper (I) chloride is slowly added. The mixture is stirred at room temperature for approximately 30 minutes and then poured into ice water. The resulting mixture is then treated with an organic solvent (e.g., ethyl acetate) to extract the product, methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5H-5-oxo-tetrazol-1-yl]phenoxy]phenyl]propionate, which may then be purified, as by column chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:6]=1[C:7]#[N:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C(C=C1CCP(C)C1(C)C)#N>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:3]2[C:4]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:6]([C:7]#[N:8])=[C:2]2[CH3:1])=[CH:16][CH:15]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Cc1[nH]c(C(F)(F)F)cc1C#N
Agent: CP1CCC(=CC#N)C1(C)C
Solvent: Cc1ccccc1
Product: Cc1c(C#N)cc(C(F)(F)F)n1CCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A 266 mg portion of 2-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile was dissolved in 10 ml of toluene, and 0.382 ml of 2-(4-fluorophenyl)ethanol and 352 mg of cyanomethylenetrimethylphospholan were added, followed by stirring at 100° C. for 1.5 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-1:4) to obtain 451 mg of 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:18](/B(O)O)=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][O:16][N:14]([CH3:15])[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:13]
Reactant: CON(C)C(=O)c1ccc2nccc(Br)c2c1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc2nccc(/C=C/c3ccccc3)c2c1
Temperature: 35 °C

Procedure:
A mixture of 4-bromo-N-methoxy-N-methylquinoline-6-carboxamide (155 mg, 0.525 mmol), (E)-styrylboronic acid (155 mg, 1.05 mmol), Pd(OAc)2 (11.8 mg, 0.053 mmol), SPhos (43 mg, 0.105 mmol) and K3PO4.H2O (334 mg, 1.58 mmol) in anhydrous THF (5 mL) was heated at 35° C. overnight. The reaction was diluted with DCM and water. The organics were washed with water and concentrated. The resulting residue was purified by silica column chromatography (40-55% EtOAc/hexanes) to yield (E)-N-methoxy-N-methyl-4-styrylquinoline-6-carboxamide. (ES, m/z) 319.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CN(C)C=O>[O:31]1[CH2:30][CH:29]1[CH2:27][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: COc1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(OC)c1OC
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC

Procedure:
Reaction of 3′,4′,5′-trimethoxy-7-hydroxy-flavone, 25 (8.2 g, 25 mol), 50% sodium hydride (3 g, 125 mmol) and epichlorohydrin (7.8 mL, 100 mmol) in dry dimethyl formamide (145 mL) using identical procedure as described for 28 furnished 31. Yield 8 g (83%); mp 187-188° C.; MS (FAB) 385 (M++1); IR (KBr) 1651; 1H NMR (200 MHz, CDCl3) δ 8.14 (d, J=9.3 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.70 (s, 1H), 4.39 (dd, J=11.0 Hz, 2.8 Hz, 1H), 3.98 (dd, J=11.0 Hz, 5.7 Hz, 1H), 3.43-3.39 (m, 1H), 3.96 (s, 6H), 3.93 (s, 3H), 2.97 (t, J=4.5 Hz, 4.2 Hz, 1H), 2.82 (dd, J=4.7 Hz, 2.2 Hz, 1H).
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:15]([O:19][C:20](=[O:41])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][C:39]=2[CH3:40])[CH2:28][CH2:27]1)[CH3:25])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O1CCCC1>[C:15]([O:19][C:20](=[O:41])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]([C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][C:39]=2[CH3:40])[CH2:28][CH2:27]1)[CH3:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)CC(=O)O
Reactant: Cc1ccncc1CNC1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccncc1CN(C(=O)CC(C)(C)C)C1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a solution of tert-butylacetic acid (63 μL, 0.50 mmol) and DMF (3 drops) in methylene chloride (4 ml) was added oxalyl chloride (115 μL, 1.32 mmol) and the resulting orange solution was stirred at 25° C. for 3 hours. The solvent was removed in vacuo to give an orange residue. (3-{4-[(4-Methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.125 g, 0.33 mmol) and triethylamine (115 μL, 0.83 mmol) dissolved in tetrahydrofuran (5 ml) were added to the flask containing the orange residue and the resulting mixture was stirred at 50° C. for 12 hours. Standard basic workup gave the crude product as an orange oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2, v/v/v) afforded (3-{4-[(3,3-dimethyl-butyryl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.095 g, 60%) as a tan oil.