Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH:6]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:16]/[C:15]1[CH:18]=[CH:19][C:12]([O:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1)([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To an acetic acid (17.0 mL) solution of 4-(pyridine-3-yloxy)-benzaldehyde (1.70 g, 8.53 mmol) described in Manufacturing Example 76-1-1 were added nitromethane (2.60 g, 42.7 mmol) and ammonium acetate (1.32 g, 17.1 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 110° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.00 g) as a crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-fluoro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 318.1 ([M−H]−).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][OH:17])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C>CO.[OH-].[Pd+2].[OH-]>[OH:17][CH2:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OCCC1(O)CCNCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
To a solution of compound 25 (1.32 g, 5.30 mmol) in methanol (10 mL) under argon was added palladium hydroxide (20%) on activated charcoal (132 mg, 10% w/w). The solution was purged three times with hydrogen and stirred under hydrogen atmosphere at 60° C. for 4 hrs. The resulting solution was then filtered on celite plug to give desired compound 26 (790 mg, 94%) which was used as such for the next step.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2nc(C)c3c(C)nc4ccc(F)cc4n23)c1
Yield: 49.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-methoxyphenylboronic acid (46 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (40 mg, 50% yield). EIMS 322.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Yield: 94.7 %

Procedure:
To methyl 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylate (463 mg, 1.52 mmol) were added methanol (10 ml), THF (10 ml) and a 1 N aqueous solution of sodium hydroxide (4.56 ml), and the resulting mixture was stirred at room temperature for 24 hours. After addition of 1 N hydrochloric acid (4.56 ml), the reaction mixture was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was successively washed with water and diisopropyl ether, and was then dried under reduced pressure to obtain 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylic acid (417 mg, 1.44 mmol, 94%).
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)C.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=O.O.[NH2:23][NH2:24]>C(O)C.O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([N:5]2[CH:4]=[N:24][N:23]=[C:15]2[C:14]([F:21])([F:20])[F:13])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC=Nc1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1nncn1-c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Prepared from ethyl-N-(4 -chlorophenyl)formimidate, ethyl trifluoroacetate and hydrazine hydrate using the method of Example 1, in 50% yield m.p. 108° (from ethanol/water). (Found: C, 44.03%; H, 2.11%; Cl, 14.00%; F, 23.2%; N, 16.82%. C9H5ClF3N3 requires C, 43.66%; H, 2.04%; Cl, 14.32%; F, 23.0%; N, 16.97%) δ(CDCl3): 8.37 (1H, s); 7.50 (4H, m). m/e, 247 and 249.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 20 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (35 mg)was reacted with 4-acetylphenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (20% yield). M.p.=200° C., LCMS: m/z=358.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.61 (3H, s), 4.36 (2H, s), 5.22 (2H, s), 7.21 (1H, d, J=2.0 Hz), 7.28 (4H, m), 7.37 (4H, m), 7.96 (2H, d, J=8.3 Hz), 8.01 (1H, d, J=1.8 Hz).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][O-:27].[Na+]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([O:27][CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.1 g) was heated with a solution of sodium methoxide (made from sodium (0.2 g) in dry methanol (10 ml)) at reflux for 3 h. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by chromatography eluting with 70% ethyl acetate in isohexane to give the title product as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][N:34]=2)[CH2:13][C:14](=[O:32])[N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH2:17][CH2:16]2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[BH-](O[C:51]([CH3:53])=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.N1CCCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][N:8]3[CH2:53][CH2:51][CH2:5][CH2:6][CH2:7]3)=[CH:35][N:34]=2)[CH2:13][C:14]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH2:17][CH2:16]2)=[O:32])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(C=O)cn2)cc2cn[nH]c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCNCC1
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(CN3CCCCC3)cn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of (±)-6-(1-(7-methyl-1H-indazol-5-yl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butan-2-yl)nicotinaldehyde (previous example, 8 mg, 0.015 mmol, 1.0 equiv.) in dichloroethane (1 mL) was treated with by 2 drops of piperidine. Excess Na(OAc)3BH was added and the reaction mixture was stirred at room temperature overnight. The mixture was directly purified by flash column chromatography (10% of 2M ammonia in methanol in methylene chloride) afforded the desired product (10.1 mg, 72% for two steps).
Reaction SMILES: C([N:5]([C:13]1[C:17]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][NH:15][C:14]=1[C:25]([O:27]C)=O)[C:6]([NH:8]C(OC)=O)=[NH:7])(OC)=O.[OH-].[Na+].C(O)(=O)C>CO>[NH2:7][C:6]1[NH:8][C:25](=[O:27])[C:14]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13]=2[N:5]=1
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2cccnc2)c[nH]c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(Cc3cccnc3)c[nH]c2c(=O)[nH]1
Yield: 88 %

Procedure:
Methyl 3-(N,N′-bis-carbomethoxyguanidinyl)-4-(3-pyridylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 26 (15.0 g, 0.04 mol), methanol (100 mL) and sodium hydroxide pellets (3.7 g, 0.9 mol) were stirred together and boiled under reflux for 18 hours. The mixture was cooled, neutralized with acetic acid (5.4 g. 0.09 mol) and the solid collected by filtration. The product was washed in turn with methanol (20 mL), water (200 mL) and methanol (30 mL) and dried at 110° C. overnight to give 8.2 g (88%) of an off-white powder, mp>300° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])#[N:2]
Reactant: NCCc1ccccc1Cl
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.9 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fraction were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanolhexane to give the title compound (0.56 g, 2.0 mmol, yield: 75%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:27][C:26](=[O:28])[CH:25]=[CH:24][NH:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([N:23]1[CH:24]=[CH:25][C:26](=[O:28])[CH2:27][CH:22]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C1C=CNC(c2ccccc2)C1
Reactant: COc1cc(I)c(CC(=O)O)cc1OC
Product: COc1cc(I)c(CC(=O)N2C=CC(=O)CC2c2ccccc2)cc1OC

Procedure:
1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one was prepared by reacting (2-iodo-4,5-dimethoxy-phenyl)-acetic acid with 2-Phenyl-2,3-dihydro-1H-pyridin-4-one following the procedure of step 3 of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:16]([O:18]CC)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(CNC(=O)OC(C)(C)C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CCOCC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of the compound (11.3 g) obtained in step 3 in methanol (190 mL) was added 2N aqueous sodium hydroxide solution (79 mL), and the mixture was stirred at 40° C. for 2 hr. The mixture was concentrated, diluted with ethyl acetate, and neutralized with 1N hydrochloric acid. The separated aqueous layer was extracted with ethyl acetate. The combined organic layer was dried, and concentrated under reduced pressure to give the title compound (9.3 g, 91%) as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[C:40]([N:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1.O>[C:43]([O:42][C:40]([N:47]1[CH2:52][CH2:51][CH:50]([O:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH2:49][CH2:48]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of triphenyl phosphine (7.7 g, 29 mmol), in tetrahydrofuran (40 mL), diethylazodicarboxylate (5.12 g, 29 mmol) was added and the solution was stirred for 20 minutes. 4-Fluorophenol (3 g, 27 mmol) was added and the mixture was stirred for another 20 minutes at 0° C. N—Boc-4-hydroxypiperidine (5.9 g, 29 mmol) was added dissolved in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 1:1) to give 4.8 g (60%) of the product as a white solid. MS (m/e): 296.3 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:35]([CH3:39])[C:36](=[O:38])[CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:12][CH2:13][CH2:14][CH2:15][C:16]([N:35]([CH3:39])[C:36](=[O:38])[CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:31])([CH3:32])[C:28]([CH3:33])([CH3:34])[O:27]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(CCCN)(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNCc1ccc(Cl)c(Cl)c1)N(C)C(C)=O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 3,4-dichlorobenzaldehyde (55 mg, 0.31 mmol) and ethyl 2-(3-aminopropyl)-2-(N-methylacetamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate hydrochloride (120 mg, 0.26 mmol) in dichloromethane (3 mL) was stirred at room temperature. After 30 min, sodium triacetoxyborohydride (138 mg, 0.65 mmol) was added in one portion and stirring was continuated overnight. Once complete, the solution was diluted with dichloromethane (10 mL), quenched with aq 5% NaHCO3 (W/V, 5 mL) and stirred vigorously for 30 min. The layers were separated and the organic phase was washed with water and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (2-20% methanol in dichloromethane) gave ethyl 2-(3-(3,4-dichlorobenzylamino)propyl)-2-(N-methylacetamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (78 mg). ESI MS found for C27H43BCl2N2O5 m/z [557.6/559.6 (M+1)].
Reaction SMILES: [O:1]=[C:2]1[N:7]2[NH:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C(C)=O

Procedure:
0.54 g of methyl 4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate are suspended in 16 ml of acetic anhydride and heated to about 100° for 3 hours. The reaction solution is evaporated in vacuo and the residue is taken up in 32 ml of water and stirred up. The mixture is extracted twice with 30 ml of dichloromethane each time and once with 15 ml of dichloromethane. After drying over sodium sulfate, it is filtered and evaporated in vacuo. The residue is chromatographed on silica gel with dichloromethane/acetone (9:1). By recrystallization from ether there is obtained methyl 5-acetyl-4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate of m.p. 132°-134°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:29])([F:28])[F:19])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-trifluoromethylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:29][CH:30]=1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccn1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 40 °C
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was heated to 70° C. for 48 hours rather than to 40° C. for 18 hours, N-[3-(4-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-chloromethylpyridine to give the title compound in 72% yield; NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 5.28 (s, 2H), 7.16 (d, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.53 (m, 1H), 7.62 (m, 2H), 7.85 (m, 2H), 7.95 (m, 1H), 8.12 (d, 1H), 8.23 (m, 1H), 8.52 (m, 1H), 8.59 (m, 2H), 9.0 (d, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Nc1ncccn1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ncc(Cl)c(Nc2ncccn2)n1
Temperature: 110 °C

Procedure:
The mixture of pyrimidin-2-amine (48 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and potassium carbonate (69 mg, 0.5 mmol) in 3 mL of 1,4-dioxane is heated at 110° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford N-(2,5-Dichloropyrimidin-4-yl)pyrimidin-2-amine; ESMS m/z 242.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O-])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN1CCOCC1.[BH4-].[Na+].[OH-].[Na+]>COCCOC.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH2:12][OH:13])=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CO)cc1N
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a solution of 1-methyl 2-aminoterephthalate (10.0 g, 51.2 mmol) and NMM (5.75 mL, 1 equiv) in DME (90 mL) at −15° C. was added dropwise IBCl (6.7 mL, 1 equiv). The mixture was stirred at this temperature for 15 min. The salt was removed by filtration and the solution was cooled down to −15° C. A solution of NaBH4 (3.06 g, 1.5 equiv) in water (30 mL) was added carefully dropwise. At the end of the addition, water (100 mL) was added and the mixture was stirred at r.t. for 15 min. Aq NaOH (2N, 50 mL) was added and the aqueous phase was extracted twice with AcOEt. The organic phase were combined and dried (Na2SO4). The solution was concentrated in vacuo to afford a white solid (8.0 g, 86%) (ES-MS: m/z 182.1 [M+H]+, rt 3.50 min)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=3)[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 63 mg (0.23 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 11 mg (0.27 mmol) of 60% sodium hydride, 65 mg (0.27 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 31 mg of a white solid: LC-MSD, m/z for C24H18F3N3O2 [M+H]+=438.1; HPLC retention time: 1.6 min.