Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:10][NH:11][CH2:12][CH:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:40](=O)[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:10][N:11]([CH2:12][CH:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:40][CH3:41])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CNC[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C)COCc1ccccc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(CC(COCc1ccccc1)NC(=O)OC(C)(C)C)C[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
The product from Example 17C (0.15 g) in dichloroethane (5 mL) was treated with acetaldehyde (20 μL, 0.36 mmol). After stirring at ambient temperature for 10 minutes, the mixture was treated with sodium triacetoxyborohydride (0.10 g, 0.47 mmol) and acetic acid (20 μL, 0.35 mmol). After stirring at ambient temperature overnight, the mixture was diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes:ethyl acetate, 1:1) to provide the title compound (75 mg, 44%). 1H NMR (CDCl3) δ 7.36-7.24 (m, 10H), 4.93 (br s, 2H), 4.54-4.41 (m, 4H), 3.77-3.63 (m, 2H), 3.61 (dd, J=3.4, 9.2 Hz, 2H), 3.5-3.38 (m, 2H), 2.66-2.42 (m, 6H), 1.44 (s, 9H), 1.43 (s, 9H), 0.98 (t, J=7.1 Hz, 1.5H), 0.96 (t, J=7.1 Hz, 1.5H); MS (APCI+) m/z 572 (M+H)+.
Reaction SMILES: Br.Br.[CH3:3][C:4]([NH2:9])([CH3:8])[CH2:5][CH2:6][NH2:7].C[O-].[Na+].[Br:13][C:14]#[N:15]>CO.O>[BrH:13].[CH3:3][C:4]1([CH3:8])[CH2:5][CH2:6][NH:7][C:14]([NH2:15])=[N:9]1
Reactant: N#CBr
Reactant: CC(C)(N)CCN
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CCNC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.8 %

Procedure:
1.95 g of 3-methylbutane-1,3-diamine dihydrobromide are suspended in 20 mL of MeOH, 1.2 g of sodium methanolate are added. The mixture is stirred at RT for 2 h. The mixture is filtered and then dry evaporated. The reaction crude is solubilized in 20 mL of water, cooled with an ice bath. 0.78 g of BrCN are added and stirred at RT for 12 h. The mixture is dry evaporated, 3 g (quantitative yield) of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide are obtained as a translucent oil which will be used as such for the following:
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH2:16])(=[S:15])[CH3:14]>CCO>[CH3:14][C:13]1[S:15][C:2]2[CH:3]([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:5][CH2:6][C:7]=2[N:16]=1
Reactant: CC(N)=S
Reactant: COC(=O)C1CCCC(=O)C1Br
Solvent: CCO
Product: COC(=O)C1CCCc2nc(C)sc21

Procedure:
A soln. of methyl 2-bromo-3-oxocyclohexanecarboxylate (150 mg, 0.64 mmol) and thioacetamide (53 mg, 0.70 mmol) in EtOH (3 mL) was stirred at 85° C. overnight. Subsequently, the mixture was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (0-40% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2=[C:6]3[C:12]([CH:13]=[C:2]12)=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]3.[CH3:14][C:15]1C=C2C(C=C[CH:27]=1)=C1C(SC=C1)=C2.S1C=CC2=C3C(C=C12)=CC=CC=C3>>[CH:15]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[CH:7][CH:8]=1)[C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]=2)([CH3:27])[CH3:14]
Reactant: Cc1cccc2c3ccsc3cc-2c1
Reactant: c1ccc2cc3sccc3c-2cc1
Product: CC(C)c1ccc2cc3ccsc3c-2cc1

Procedure:
The position numbering system of the following azuleno[2,1-b]thiophene derivatives is ##STR11## Azuleno[2,1-b]thiophene 7-Methylazuleno[2,1-b]thiophene
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:20]([CH3:29])[N:19]=[N:18][C:17]=2[Cl:30])=[C:11]([F:31])[CH:10]=1.[ClH:32]>[Cu](Cl)Cl.C(#N)C>[Cl:30][C:17]1[N:18]=[N:19][C:20]([CH3:29])=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:16]=1[C:12]1[C:11]([F:31])=[CH:10][C:9]([Cl:32])=[CH:14][C:13]=1[F:15]
Reactant: Cc1nnc(Cl)c(-c2c(F)cc(N)cc2F)c1-c1ccc(Cl)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1nnc(Cl)c(-c2c(F)cc(Cl)cc2F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 323 mg of copper (II) chloride (CuCl2), 309 mg of tert-butyl nitrite and 13 ml of acetonitrile was added 732 mg of 4-(4-amino-2,6-difluorophenyl)-3-chloro-5-(4-chlorophenyl)-6-methylpyridazine portion-wise under ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was poured into a mixture of ice and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with sodium bicarbonate water and saturated brine, and dried over anhydrous magnesium sulfate then concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=7:1), to obtain 0.62 g of 3-chloro-4-(4-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xi) of the present invention).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:12]Br)[C:7]([CH2:10]Br)=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH2:12][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)c(CN2CCCCC2)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
In a 500 ml. round-bottomed reaction flask equipped with magnetic stirrer, reflux condenser and nitrogen-inlet tube, there were placed 10 g. (0.032 mole) of crude 4-nitro-α,α'-dibromo-o-xylene [M. Kerfanto, Bulletin de la Societe Chimique de France, Vol. 12, p. 3537 (1965)] and 44.8 g. (0.526 mole) of piperidine (52 ml.) all dissolved in 100 ml. of benzene. The resulting mixture was then heated at the reflux point for a period of 18 hours and finally cooled to room temperature (~25° C.). The spent reaction mixture was then diluted with 500 ml. of benzene and thereafter washed with four-100 ml. portions of water, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a 59% yield of crude 1,1'-[4-nitro-1,2-phenylenebis(methylene)]bispiperidine as a residue in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Sc1nc2cc(Cl)ccc2o1
Solvent: Cc1ccccc1
Product: CN1CCCN(c2nc3cc(Cl)ccc3o2)CC1

Procedure:
5-Chloro-2-mercaptobenzoxazole (1 g) was dissolved in toluene (50 ml), N-methylhomopiperazine (3.3 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-2-(4-methyl-1-homopiperazinyl)benzoxazole (882 mg).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.[I:24]I>CCOCC.C1COCC1>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([I:24])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1cccnc1Cl
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1nccc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at −78° C., under nitrogen atmosphere, was added 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol) dropwise. The resulting reaction mixture was stirred at −78° C. for 10 min, and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to room temperature overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and concentrated to yield intermediate compound D1 (8.21 g, 44%) as a pale cream solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-:13]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=[C:8]([CH3:12])[N+:7]=1[O-:13]
Reactant: Cc1cccc(Br)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To cooled nitric acid (concentrated, 168 ml) was added sulfuric acid (concentrated, 300 ml) under cooling followed by 2-bromo-6-methyl-pyridine 1-oxide (35 g, 0.186 mol). The mixture was stirred at 70° C. for 4 hours, cooled to room temperature and poored slowly on crushed ice. A stream of nitrogen was bubbled through the mixture overnight. The mixture was basified to pH 8 under cooling with NaOH (10N, ca. 1 L), diluted with water (3 L) and extracted with DCM (5×). The combined organic phases were dried (sodium sulfate) and evaporated to dryness to yield 27.6 g of a yellow crystaline solid (0.118 mol, 57%).
Reaction SMILES: F[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]=[C:10]([O:11]CCN(C)C)[C:4]=2[CH:3]=1.Cl>>[O:11]=[C:10]1[C:4]2[CH:3]=[CH:2][CH:22]=[CH:21][C:5]=2[O:6][C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9]1
Reactant: CN(C)CCOC1=Cc2ccccc2Oc2ccc(F)cc21
Agent: Cl
Product: O=C1Cc2ccccc2Oc2ccccc21

Procedure:
Reflux of 25 ml of 2-fluoro-11-[β-(dimethylamino) ethoxy]dibenz[b,f]oxepin stock solution produced no apparent decomposition after 45 minutes. Addition of 2.5 ml of concentrated hydrochloric acid and further reflux for 10 mins gave complete decomposition to 10,11-dihydro-10-oxodibenz [b,f]oxepin.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[N:33]([CH3:34])[C:32](=[O:35])[C:31]([F:37])([F:36])[CH2:30][N:29]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:43]=3)=[CH:18][C:17]=2[F:44])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:38]1([N:29]2[CH2:30][C:31]([F:37])([F:36])[C:32](=[O:35])[N:33]([CH3:34])[C:27]3[CH:26]=[N:25][C:24]([NH:23][C:19]4[C:20]([F:22])=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:45])=[C:17]([F:44])[CH:18]=4)=[N:43][C:28]2=3)[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCNCC4)cc3F)ncc21
Yield: 96.7 %

Procedure:
A solution of 0.0781 g (0.123 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-239) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0637 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-piperidin-4-yl-benzamide (I-240) as a white solid.
Reaction SMILES: [C:1]([CH:4]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[CH2:17]([Zn]CC)C.ICI.O>C(Cl)Cl.C1(C)C=CC=CC=1>[O:3]=[C:1]([CH3:2])[CH:4]([C:9]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:17][CH2:10]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC[Zn]CC
Reactant: C=C(c1ccccc1)C(C(C)=O)C(=O)OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: ICI
Product: COC(=O)C(C(C)=O)C1(c2ccccc2)CC1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a solution of 1 g (4.6 mmol) of methyl 2-acetyl-3-phenylbut-3-enoate in 16 mL of DCM are successively added dropwise 20.8 mL (22.9 mmol) of a 1.1M solution of diethylzinc in toluene and 3.7 mL (45.8 mmol) of diiodomethane. The reaction medium is refluxed for 18 hours. After cooling to room temperature, the reaction mixture is treated with 100 mL of water and then extracted with DCM (3×100 mL). The organic phases are combined, washed successively with water (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 cyclohexane/EtOAc mixture. 280 mg of methyl 3-oxo-2(1-phenylcyclopropyl)butanoate are obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=[O:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9])=[O:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(Oc1cccc(C=O)c1)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
The obtained Compound 97b (1.0 eq.) was dissolved in 1,4-dioxane, and 1 N NaOH (1.4 eq.) was added thereto. The reaction mixture was stirred at room temperature, and after a volatile material was evaporated, the residual was distributed between methylene chloride and water. An aqueous layer was acidified by using a 12 N HCl and extracted by using methylene chloride. An organic layer was evaporated to obtain Compound 97d.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][C@H:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1I.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1>[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][C@H:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(Cn3ccnn3)C2)cc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(Cn5ccnn5)C4)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C
Yield: 31.7 %

Procedure:
1-({3-[4-(Trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl}methyl)-1H-1,2,3-triazole (0.62 g, 1.58 mmol), N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.5 g, 1.32 mmol) and tri-2-furylphosphine (0.08 g, 0.34 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris(dibenzylideneacetone)palladium (0) (0.16 g, 0.18 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.20 g desired product.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:9]1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[F:36][C:21]([F:20])([F:37])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([N:8]2[CH2:9][CH:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH2:11]2)=[O:31])[N:23]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(C2CNC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2CN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 47 %

Procedure:
This compound was synthesized from 6-(azetidin-3-yl)nicotinonitrile TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (70 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 9.06 (m, 1H), 8.30-8.29 (m, 2H), 8.21-8.19 (d, J=7.8 Hz, 1H), 7.96-7.94 (d, J=7.8 Hz, 1H), 7.74-7.70 (t, J=7.7 Hz, 1H), 7.63-7.61 (d, J=8.1 Hz, 1H), 4.76-4.72 (m, 1H), 4.52-4.46 (m, 2H), 4.25-4.18 (m, 2H). MS (ESI) m/z: Calculated for C19H12F3N5O2: 399.09. found: 400.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([F:11])[C:9]#[N:10])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.[Cl:38][CH:39]([Cl:55])[C:40]([NH:42][C@H:43]([CH2:53][F:54])[C@H:44]([OH:52])[C:45]1[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=1)=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:38][CH:39]([Cl:55])[C:40]([NH:42][C@H:43]([CH2:53][F:54])[C@@H:44]([C:45]1[CH:46]=[CH:47][C:48]([C:2]2[CH:7]=[N:6][C:5]([CH:8]([C:9]#[N:10])[F:11])=[CH:4][CH:3]=2)=[CH:49][CH:50]=1)[OH:52])=[O:41]
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Reactant: N#CC(F)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CC(F)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A stirred mixture of the product of step 1, Example 22 (127 mg, 0.591 mmol), bis(pinacolato)diboron (163 mg, 0.640 mmol), and potassium acetate (193 mg, 1.97 mmol) in dry dimethylformamide (4.9 mL) is sparged with nitrogen for 5 min before [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40.2 mg, 0.0492 mmol) is added. The mixture is sparged with nitrogen for another 5 min, heated to 80° C. under nitrogen and maintained at this temperature. After 4.5 hours, the mixture is cooled to ambient temperature, solid 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (previously described in WO13057619 Preparation 1 page 16, 200 mg, 0.492 mmol) and cesium carbonate (0.562 g, 1.72 mmol) were added under a stream of nitrogen, and the mixture is sparged with nitrogen for 5 min and heated to 80° C. After 2 hours, the mixture is cooled to ambient temperature, diluted with water (25 mL), and extracted with ethylacetate (2×25 mL). The combined organic phase is washed with water (3×20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 25-45% ethyl acetate/hexanes) gave the title compound (77 mg): 1H NMR (300 MHz, DMSO-d6) δ 4.28 (m, 1.5H), 4.45 (m, 0.5H), 4.58 (m, 0.5H), 4.72 (m, 0.5H), 4.93 (m, 1H), 6.02 (d, 1H), 6.53 (s, 1H), 6.93 (d, 1H), 7.51 (d, 2H), 7.77 (m, 3H), 8.28 (dd, 1H), 8.62 (bd, 1H), 9.04 (m, 1H). MS (ESI+) m/z 414 [M+H].
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH2:28][CH3:29])[CH:26]=[O:27])=[CH:6][CH:5]=1>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH2:28][CH3:29])[CH2:26][OH:27])=[CH:6][CH:5]=1
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Sodium borohydride (13.5 mg, 0.357 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (151 mg, 0.357 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (143 mg, 0.337 mmol, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Mg]Br.O.CO.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:21]
Reactant: Cc1ccccc1[Mg]Br
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1(O)C(=O)Nc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 mL round-bottomed flask, a solution of 7-chloroindoline-2,3-dione (1 g, 5.51 mmol) in THF (10 mL) was cooled in an ice/water bath. A solution of o-tolylmagnesium bromide (2M, 5.51 mL, 11.01 mmol) was added, and the reaction mixture was removed from the cooling bath and warmed to room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give Intermediate A-20A. MS(ES): m/z=272 [M−H−]; HPLC: RT=2.478 min (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([CH:28]=O)[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C.ClCCl>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:17][CH2:18][N:19]([CH2:28][C:25]3[CH:24]=[C:23]([CH3:22])[O:27][N:26]=3)[CH2:20][CH2:21]2)[N:3]=1
Reactant: Cc1cc(C=O)no1
Reactant: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CN2CCN(c3cc4nc(-c5ccco5)nn4c(N)n3)CC2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
Into 15 mL of dichloromethane, 1.50 g (5.26 mmol) of Compound F and 934 mg (8.42 mmol) of 5-methylisoxazole-3-carboxaldehyde were dissolved, and the solution was cooled to 0° C. in an ice bath. Then, 1.5 mL of acetic acid and 1.78 g (8.42 mmol; 1.6 eq.) of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature overnight. After completion of the reaction, water was added to the reaction mixture, and a 1.0 mol/L aqueous sodium hydroxide solution was further added thereto to adjust the solution to be basic. Then, the mixture was extracted by adding chloroform, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (2% methanol-chloroform) and then recrystallized from ethanol to obtain 222 mg of Compound 21 as white powder (yield: 11%).