Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (180 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (46 mg) and triethylamine (95 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (525 mg, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 430 (MH+).
Reaction SMILES: [N+](=C)=[N-].[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])[CH3:5].[C:31](O)(=O)C>CCOCC>[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:31])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoic acid (11.5 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields the title ester as a yellow viscous oil.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Al+3].[Cl-:10].[Cl-].[Cl-].ClCl.Cl>C(Cl)(Cl)Cl>[Cl:10][C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[S:5][CH:6]=1
Reactant: CC(=O)c1cccs1
Reactant: [Cl-]
Agent: Cl
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Cl)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
2-Acetylthiophene (21.6 ml, 0.20 mol) was dissolved in chloroform (200 ml) at −10° C. AlCl3 (54 g, 0.40 mole) was added in small portions at such a rate as to keep temperature below 5° C. A saturated solution of chlorine, Cl2, in chloroform (100 ml) was then added dropwise at −10° C. over a period of 30 minutes. After the addition was completed, the reaction mixture was immediately poured into a mixture of 1 L ice water and 500 ml of 1 N HCl and stirred for 30 minutes. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to a yellow liquid. NMR analysis showed this to be a 3:1 mixture of 4-chloro-2-acetylthiophene and 4,5-dichloro-2-acetylthiophene. Partial purification was achieved by a Kugelrohr distillation, yielding 4-chloro-2-acetylthiophene (31 g, 83% pure, 80% yield). This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=1.2 Hz), 7.41 (1H, d, J=1.2 Hz), 2.54 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([N:1]=[CH:10][N:11]([CH3:13])[CH3:12])[S:3][CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1csc(N)n1
Solvent: Cc1ccccc1
Product: Cc1csc(N=CN(C)C)n1
Yield: 100 %

Procedure:
A solution 2-amino-4-methylthiazole (Formula C-1)(11.4 g) in toluene (100 ml) at 25° was treated with dimethylformamide dimethyl acetal (15.9 mL, 200 mmol), dropwise over five minutes. The mixture was heated to reflux temperature for 22 hours. The reaction was cooled to 25° and the solvent evaporated to an orange oil (17 g). The oil was triturated with hexane to yield yellow crystals. Recrystallization from warm hexane gave N′-(4-Methyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula C-2) (16.9 g, 99.6%), m.p. 54-56°.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25](B(O)O)[CH:24]=1.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O1CCCC1>[CH3:3][C:2]([CH:17]1[CH2:22][CH2:21][N:20]([C:25]2[CH:24]=[N:23][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=1)(=[O:5])=[O:6])[CH3:1]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C1CCN(c2cnc3ccccc3c2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (30 mg, 0.089 mmol), quinolin-3-ylboronic acid (62 mg, 0.358 mmol), copper acetate (32.5 mg, 0.179 mmol), diisopropylethyl amine (0.049 ml, 0.358 mmol) and 1 ml tetrahydrofuran. The resulting reaction mixture was stirred at room temperature for one hour then 60° C. 3 hours. After aqueous work up, the crude product was purified on reverse phase column eluted with water/acetonitrile gradient solvent to give 24 mg desired product as fluffy white solid after lyophilizing.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[Cl:47][C:48]1[CH:58]=[CH:57][C:51](/[C:52](=[N:55]/[H])/[NH:53]O)=[CH:50][N:49]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[Cl:47][C:48]1[N:49]=[CH:50][C:51]([C:52]2[N:55]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[O:1])[O:21][N:53]=2)=[CH:57][CH:58]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(Cl)nc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(Cl)nc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-6-chloro-N-hydroxynicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.00 (dd, J=0.7, 2.4, 1H), 8.21 (dd, J=2.4, 8.3, 1H), 7.45 (dd, J=0.7, 8.4, 1H), 7.38-7.24 (m, 10H), 4.90 (s, 2H), 3.58 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 431.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5C=CN=CC=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2[O:49][N:48]=[C:47]([CH3:50])[N:46]=2)=CC=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[O:49][N:48]=[C:47]([CH3:50])[N:46]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2nc(C)no2)cc1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: Cc1noc(-c2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)n1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-(4-ethynyl-phenyl)-3-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]1(/[CH:33]=[CH:34]/B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([NH:6][O:5][CH2:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[CH:34]=[CH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:22])=[CH:17][CH:18]=1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Reactant: OB(O)/C=C/c1ccccc1
Product: O=C(NOCc1ccccc1C=Cc1ccccc1)c1ccccc1NCc1ccncc1

Procedure:
Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (example 360) and trans-2-phenylvinylboronic acid (Aldrich).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19])([O-])=O.P(OCC)(OCC)OCC.C1C2NC3C(=CC=CC=3)C=2C=CC=1>CCOCC>[CH2:12]1[C:11]2[C:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:18]=3[CH:17]=[CH:16][C:15]=2[C:14](=[O:19])[CH2:13]1
Reactant: O=C1CCc2c1cccc2-c1ccccc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Agent: c1ccc2c(c1)[nH]c1ccccc12
Solvent: CCOCC
Product: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Temperature: 90 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
Compound 45 (5.0 g) was divided into five portions (1.0 g each). P(OEt)3 (per 7 mL) was added to each portion. The resulting product was subjected to argon blow in a flask, heated to 90° C., kept at this temperature for 3 days, then cooled. The carbazole precipitate was diluted with ether. The precipitate was filtered and washed with ether. If the initial biphenyl was present in the filtrate (TLC monitoring, eluent: hexane-ethyl acetate, 1:1), this filtrate was evaporated, then P(OEt)3 was added (1 mL to each flask), and subjected to cyclization for 1 day. The procedure was repeated until the precipitation ceased and TLC showed the absence of the initial biphenyl. Carbazol 46 (2.7 g) was obtained.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)O1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[NH:10]1[C:11]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:6](=[O:8])[CH:5]=[CH:9]1
Reactant: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1cc[nH]c2ccncc12
Temperature: 25 °C

Procedure:
Dowtherm A (60 mL) was brought to reflux and (a) (6.3 g, 25.4 mmol) was added portionwise over 2 minutes. The mixture was heated for a further 5 minutes then allowed to cool to room temperature. The resulting solid was washed with a small amount of cold ethanol and dried in vacuo (2.6 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8][CH2:7]2)([O-])=O>C(O)C.O1CCCC1.[Pd]>[N:17]1([CH2:16][CH2:15][CH2:14][N:10]2[C:11]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCN2CCCN1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (270 mg, 0.933 mmol) in ethanol (5 ml) and tetrahydrofuran (5.00 ml) was added palladium on activated carbon, 10 wt. % (99 mg, 0.093 mmol). The resulting suspension was stirred under an atmosphere of hydrogen (balloon pressure) and monitored by TLC. After 2 h, the reaction mixture was filtered through a pad of celite, which was then washed with methanol. The filtrate was then concentrated, giving the desired 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (238 mg, 0.918 mmol, 98% yield) as a dark oil.
Reaction SMILES: Cl.Cl[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:4]1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24](=[O:32])(=[O:31])[N:23](CCC2C(C)=NOC=2C)[C:22]1=[O:42]>CN(C=O)C>[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24](=[O:32])(=[O:31])[N:23]([CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:4]2)[C:22]1=[O:42]
Reactant: CCN1CCCC(Cl)C1
Reactant: Cc1noc(C)c1CCN1C(=O)N(Cc2c(F)cccc2F)c2ccccc2S1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(N2C(=O)N(Cc3c(F)cccc3F)c3ccccc3S2(=O)=O)C1

Procedure:
The title compound (42 mg, 0.09 mmol) was prepared from (IntE3) (100 mg, 0.31 mmol), 3-chloro-1-ethylpiperidine hydrochloride (142 mg, 0.77 mmol), KI (10.2 mg, 0.06 mmol) and K2CO3 (107 mg, 0.77 mmol) in DMF (5 mL) in a CEM Discover microwave reactor (100° C., 1 h) using the methods of (120).
Reaction SMILES: [Cl-].[NH4+].[OH2:3].C([C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:9]=1[C:10]#[N:11])C(C)C>[Fe].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]([O:3][CH2:8][CH:9]([CH3:12])[CH3:10])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)COc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ammonium chloride (5.6 g) and iron powder (21 g) were added to a mixed solvent of water (80 ml) and ethanol (240 ml), and the mixture was heated to 65° C. Then, 2-isobutyl-5-nitrobenzonitrile (20 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (17 g), melting point: 88–93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[F:35][C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([NH:42][C:38]2[CH:39]=[N:40][CH:41]=[C:36]([F:35])[CH:37]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: Nc1cncc(F)c1
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cncc(F)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 246 using 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoropyridin-3-amine (Matrix Scientific), and was isolated as an orange amorphous solid (10%). m/z (ESI, +ve ion) 332.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.27 (1H, s); 8.77-8.84 (2H, m); 8.44-8.51 (2H, m); 8.21 (1H, d, J=2.5 Hz); 8.05 (1H, br. s.); 7.91 (1H, br. s.); 2.47 (3H, s).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccccc2F)cc1
Yield: 18.4 %

Procedure:
The title compound (50 mg, 18%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (260 mg, 0.773 mmol, prepared in example 1), 2-fluorobenzeneboronic acid (130 mg, 0.929 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (280 mg in 1.3 mL water), and 1,2-dimethoxyethane (5.2 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 230 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])C.C(O)(=O)C.O>Cl>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:9][N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnoc1-c1ccc(Br)cc1

Procedure:
5-(4-Bromo-phenyl)-isoxazole-4-carboxylic acid ethyl ester (0.500 g, 1.69 mmol) was dissolved in concentrated hydrochloric acid (2 mL), acetic acid (5 mL), and H2O (5 mL), and the reaction was stirred at 100° C. overnight. The mixture was partitioned between EtOAc and H2O, and the organic layer was separated, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH:13]=[CH2:14])[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:34]=[O:35])C>C1COCC1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH:13]=[CH2:14])[C:7]([CH:34]=[O:35])=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: CN(C)C=O
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCn1c(C=O)nc2c1c(=O)n(C)c(=O)n2CCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.05 g, 3.6 mmol) in THF (15 ml) at −78° C. was added LiHMDS (4 ml, 1M in hexane, 4 mmol) over 10 min and the solution stirred for 0.5 h. DMF (0.5 ml) was added and the solution stirred at −78° C. for a further 0.5 h then allowed to warm to ambient temperature with the cooling bath over 2 h. The reaction was quenched with 2N hydrochloric acid (3 ml) and partioned between ethyl acetate and brine. The organics were isolated, dried and concentrated. The crude product was chomatographed over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) to afford the title compound as a white solid (0.35 g, 30%). m/z 305[MH+]
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([NH2:27])[C:24]([CH3:28])=[N:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:27][C:25]2[C:24]([CH3:28])=[N:23][N:22]([CH3:21])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1nn(C)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cn(C)nc2C)ncc1Cl
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 17.8 %

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (250 mg, 0.8 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (187 mg, 1.68 mmol), cesium carbonate (783 mg, 2.4 mmol) and dioxane/THF (3:1 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (9 mg, 0.04 mmol) and BINAP (50 mg, 0.08 mmol) were added. The mixture was stirred in a microwave at 140° C. for 40 min. It was evaporated and the residue dissolved in MeOH was filtered thru celite and thru an Acrodisc and purified further using preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. Ether was added to the residue and a tan precipitate crashed out. It was filtered off and dried under vacuum at 40° C. for 2 days to afford the desired product (55 mg, 18%) as a tan solid. LC-MS (ES) m/z=387.1, [M+H]+=389.1. 1H NMR (400 MHz, DMSO-d6) ppm 11.93 (br. s., 1 H) 9.51 (br. s., 1 H) 8.03 (s, 1 H) 7.96 (s, 1 H) 7.82 (s, 1 H) 7.51-7.61 (m, 3 H) 7.07-7.15 (m, 1 H) 6.68 (s, 1 H) 3.70 (d, J=4.29 Hz, 6 H) 2.07 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][NH2:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:24][CH3:23])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A quantity of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 was placed in a pressure tube with a magnetic stirring bar. The tube was cooled in a dry ice-acetone bath and ca. 3 mL of monomethylamine gas was condensed in the tube. Dimethylformamide (1.0 mL) was added, and the tube was closed and allowed to warm to room temperature. With stirring, the reaction mixture was heated behind a shield in a 110° C. oil bath. After 10 minutes, all solid was in solution. The solution was heated in the oil bath for 20 hours. The tube was cooled in an ice-acetone bath, opened, and warmed to room temperature to vent the excess amine. Most of the dimethylformamide was evaporated at reduced pressure to yield crystals. The solid was triturated with 5 mL of water, filtered, washed with water and dried; wt 0.128 g. Purification was effected by recrystallization from ethyl acetate-petroleum ether to give 0.081 g of pure product; mp 243°-244° C.