Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][CH2:35][C:36]([OH:38])=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].[CH3:39][O:40][C:41](=[O:56])[CH2:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH2:55])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:56])[CH2:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][C:36](=[O:38])[CH2:35][CH2:34][C:26]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)Cc1cccc(-c2ccccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC HCl (61 mg, 0.32 mmol) and Et3N (44 μL, 0.32 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) and DMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (49) (50 mg, 0.21 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (50) (46 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H); 3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m, 3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz); 8.31 (br.d, 1H, J=7.8 Hz).
Reaction SMILES: [NH2:1][C@:2]([CH3:48])([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42](Br)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C@:2]([CH3:48])([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28]
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4Br)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 150 °C
Yield: 18.4 %

Procedure:
A suspension of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-14-(5-bromo-1H-1,2,4-triazol-1-yl)-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 11, 37.2 mg, 0.044 mmol), cesium carbonate (255 mg, 0.78 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (129 mg, 0.63 mmol), palladium (II) acetate (14.4 mg, 0.06 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (24 mg, 0.05 mmol) in dioxane (1.2 mL) was blanketed with nitrogen and heated in a microwave at 150° C. for 45 minutes. The mixture was cooled to room temperature, filtered and purified by reverse phase HPLC using a 19×150 mm Sunfire Preparative C18 OBD column eluting with acetonitrile/water+0.1% TFA. Product fractions were evaporated and freeze-dried from a mixture of ethanol and benzene to give the title compound (5.9 mg) as a white solid (trifluoroacetic acid salt).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[N:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:28][C:29]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:15][CH:14]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:13]4)=[N:8][C:6]=3[N:7]=2)[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)nc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)nc2n1
Yield: 70.7 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thiazolo[4,5-d]pyrimidine (50 mg, 0.12 mmol), 2-methyl-1H-benzoimidazole (18 mg, 0.13 mmol), Pd2(dba)3 (5.5 mg, 0.006 mmol), XPhos (5.7 mg, 0.02 mmol) and cesium carbonate (78 mg, 0.24 mmol) in 1,4-dioxane (1.5 mL) was purged with argon gas for 15 min. The resulting reaction mixture was irradiated with microwaves at 145° C. for 30 min. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 4:96). The solvents were reduced in vacuo to afford 256 as a brown solid (43 mg, 70%). LCMS (Method G): RT 5.52 min, [M+H]+ 507. 1H NMR (400 MHz, CDCl3): δ 8.22-8.21 (1 H, m), 7.71-7.70 (1 H, m), 7.30-7.27 (2 H, m), 4.18 (2 H, s), 4.03 (4 H, t, J=4.80 Hz), 3.89 (4 H, t, J=4.80 Hz), 3.76-3.72 (6 H, m), 3.27 (2 H, m), 3.15 (1 H, m), 3.00 (3 H, s), 2.37 (4 H, br s)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:24]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[C:21]=2[C:22]#[N:23])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cccc(F)c2C#N)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.6 g; 2.6 mmol) was added to a suspension of sodium hydride (125 mg; 3.1 mmol) in 5 mL of anhydrous dimethylformamide at 0° C. Mixture was then heated to 40° C. for 2 hours. Anion was cooled to room temperature and added to a 0° C. mixture of 2,6-difluorobenzonitrile in 5 mL of dimethylformamide. After 16 hours at room temperature, reaction was quenched over 20 g of ice, mixture was extracted 4×50 mL with ethyl acetate. Combined organics was washed with 6×40 mLs water, brine and dried over MgSO4. Crude oil was obtained after filtration and concentration. Material was purified by flash chromatography using 2-3.5% methanol/dichloromethane gradient to obtain 660 mg of title compound. (73% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: Cc1ccc(CCC[C@H]2C(=O)N(OC3CCCCO3)[C@H]2C)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(CCC[C@@H](C(=O)O)[C@H](C)NOC2CCCCO2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-methylphenyl)-1-propyl)-4-methylazetidin-2-one (160 mg, 0.51 mmol) in dioxane (1.5 mL) is added 1 M aqueous sodium hydroxide (0.75 mL). The solution is stirred at 23° C. for 20 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-methylphenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (114 mg, 67% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O(Cl)[Cl:23].[P+5]>>[Cl:23][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)c2cnc3ccccc3c2O)cc1
Reactant: ClOCl
Agent: [P+5]
Product: Cc1ccc(S(=O)(=O)c2cnc3ccccc3c2Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 3-(4-methyl-benzenesulfonyl)-quinolin-4-ol (0.24 g, 0.8 mmol) and phosphorus(V) oxychloride (15 ml) was refluxed for 5 hours. Phosphorus(V) oxychloride was distilled off, and the residue was poured onto ice. The slurry was stirred for 2 hours at 0-5° C., neutralized with sodium carbonate and extracted with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give 0.23 g of the title compound in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[CH:13](OC)(OC)[O:14][CH3:15].CC(OC(C)=O)=O>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:6](=[O:11])[C:7]([F:10])([F:8])[F:9])=[CH:13][O:14][CH3:15])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=COC)C(=O)C(F)(F)F
Yield: 26 %

Procedure:
A solution 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (23.1 g, 0.13 mol), trimethyl orthoformate (2 eq, 0.251 mol, 27.5 ml), and Ac2O (3 eq, 0.38 mol, 35.6 ml) was heated under an atmosphere of nitrogen at 120° C. for 5 hours. The solution was concentrated to afford an oil which was distilled to obtain 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester as the mixture of isomers (7.37 g, 26% yield after distillation). The mixture was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:20])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([Cl:20])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(=O)O
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)Cl
Reaction time: 0.75 h

Procedure:
A suspension of (2-methoxy-4-nitro-phenoxy)acetic acid [FEBS Lett. (1983), 153(2), 431], (3.12 g 15.9 mmol) in dichloromethane (100 ml) was cooled down to 0° C. in an ice bath before oxalyl chloride (5.26 g, 41.7 mmol) was added. The reaction mixture was stirred for 45 minutes, giving a clear solution. The solvents were removed in vacuo to give (2-methoxy-4-nitro-phenoxy)-acetyl chloride as a pale yellow solid. (3.41 g, 100%);
Reaction SMILES: N#N.Br[C:4]1[N:5]=[C:6]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[N:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=12.[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[CH:14]1([C:6]2[N:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]3=[C:4]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:21]5[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=5)=[N:25]4)=[CH:30][CH:29]=3)[N:5]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1nccn2c(C3CCC3)nc(Br)c12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccncc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccncc5)nc4c3)c12
Temperature: 80 °C
Reaction time: 40 h

Procedure:
N2 was bubbled into a stirred mixture of 1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine (48 mg, 0.18 mmol), 2-pyridin-4-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline (90 mg, 0.27 mmol), Pd(PPh3)4 (12.5 mg, 0.0108 mmol), and Na2CO3 (48 mg, 0.45 mmol) in DMF/H2O (5/1, 6 mL) for 5 min. This mixture was then stirred at 80° C. under N2 for 40 h. The solvents were removed; the residue was dissolved in MeOH and submitted to the mass-directed purification system and provided the desired product; 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.10 (m, 1 H), 2.17-2.24 (m, 1 H), 2.50-2.57 (m, 2 H), 2.62-2.70 (m, 2 H), 3.84-3.89 (m, 1 H), 5.45 (s, br, 2 H), 7.10 (d, J=4.4 Hz, 1 H), 7.17 (d, J=5.2 Hz, 1 H), 7.96 (d, J=8.8 Hz, 1 H), 8.00-8.01 (m, 2 H), 8.10 (d, J=6.0 Hz, 2 H), 8.35 (d, J=8.4 Hz, 1 H), 8.45 (s, 1 H), 8.80 (d, J=4.8 Hz, 2 H); MS (ES+): m/z 393 [MH+]; HPLC: tR=1.94 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][CH3:38])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCCNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-N-propylamine in DMF. ES-MS m/e (%): 442 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1CCCC1=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:22])[CH2:19][CH2:18]3)[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: Nc1cccc2c1C(=O)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1CCc2cccc(Nc3cnc4ccccc4c3)c21
Temperature: 200 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
0.43 g of 3-bromoquinoline, 0.29 g of 7-aminoindan-1-one, 0.08 g of copper (I) iodide, 0.41 g of potassium carbonate, and 4 ml of N-methylpyrrolidone were mixed, and then the mixture was stirred for 2 hours at 200° C. The resultant mixture was purified by silica gel column chromatography to obtain 0.15 g of 7-(quinolin-3-ylamino)-indan-1-one (Compound Number 50).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:7]=1[O:8][CH3:9].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:3]=[N:4][C:5]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:7]=2[O:8][CH3:9])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(F)(F)F)nnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)nnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a stirred solution of 3-bromo-4-methoxy-6-trifluoromethyl-pyridazine (D6) (0.79 g, 3.07 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.74 g, 3.69 mmol) and cesium carbonate (2.0 g, 6.14 mmol) in toluene (15 ml) in a sealed tube under nitrogen, were added (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.29 g, 0.46 mmol) and palladium(II) acetate (0.034 g, 0.15 mmol). The reactiom mixture was stirred at 110° C. for 18 h. After cooling to room temperature, the reaction mixture was filtered though Celite and the filtrate was evaporated. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D7 (0.73 g, 63%) as a yellow solid. C16H23F3N4O3 requires 376; Found 377 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][C:8]=2[CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:19]([CH3:20])[CH3:21])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane (Intermediate 102, 210.0 mg, 0.70 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>N1C=CC=CC=1>[O:21]=[C:13]1[N:12]2[CH2:22][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]=[C:11]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (10.8 mg, 0.037 mmol) in 0.7 mL pyridine at rt was added 3-(trifluoromethyl)benzoyl chloride (0.0066 mL, 0.044 mmol) and the reaction stirred at rt. After 5 min, the reaction was briefly warmed to dissolve solids and then allowed to cool to rt. At 45 min an additional amount (pipet tip) of 3-(trifluoromethyl)benzoyl chloride was added, the reaction briefly warmed, and then allowed to stir at rt overnight. At 24 hours the reaction was quenched with MeOH and evaporated. The crude mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The resulting solid was triturated with hot EtOAc, hexane added, the solid filtered and rinsed with 30% EtOAc/hexane to give the title compound as an off-white solid (10.3 mg, 60%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.25 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.02 (dd, J=8.1, 1.3 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.65-7.75 (m, 3H), 7.43-7.50 (m, 1H), 7.29-7.35 (m, 2H), 7.10-7.17 (m, 1H), 7.00-7.05 (m, 1H), 4.39-4.47 (m, 1H), 3.81-3.90 (m, 1H), 3.61-3.72 (m, 2H), 3.07-3.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C([O-])(=O)C.[Na+].Cl(O)(=O)(=O)=O.CN(C)[CH:19]=[C:20]([CH3:33])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=O>C(O)(=O)C>[CH3:33][C:20]1[CH:19]=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[C:21]=1[C:23]1[CH:24]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: Cc1cnc2ccnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 1.84 g. of 3-aminopyrazole, 50 ml. of glacial acetic acid, 1.80 g. of sodium acetate and 7.90 g. of 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone perchlorate is refluxed for 6 hours and then evaporated. The residue is reacted as described in Example 1, giving the desired product, m.p. 168°-169° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: Nc1ccc(F)cc1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 175 °C
Yield: 49 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (145 mg, 0.61 mmol) and 500 μL of 4-fluoroaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature, and the resultant solid was washed with 1:1 hexane:ethyl acetate. The solid was purified by flash chromatography eluting with ethyl acetate to provide 85 mg (49%) of 8-ethyl-2-(4-fluorophenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 215-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9](O)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)C(O)NC(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)NC(=O)c1ccc(Cl)cc1

Procedure:
12.1 g (0.05 mol) of 1-(p-chlorobenzamido)-3,3-dimethyl-1-hydroxy-butan-2-one were dissolved in 80 ml. of carbon tetrachloride. 10.4 g (0.05 mol) of phosphorus pentachloride were added at 50° C. and the mixture was then heated for 2 hours under reflux. It was then filtered hot and the filtrate was concentrated in a waterpump vacuum. The crude 1-chloro-1-(p-chlorobenzamido)-3,3-dimethyl-butan-2-one thus obtained could be directly reacted further. The melting point was 132°-135° C. ##STR45##
Reaction SMILES: N#N.II.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH3:13].[O:14]1[CH2:16][CH2:15]1>C1COCC1>[CH2:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:16][CH2:15][OH:14])[CH3:13]
Reactant: CCc1ccccc1Br
Reactant: C1CO1
Agent: II
Agent: N#N
Solvent: C1CCOC1
Product: CCc1ccccc1CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Into a 250-mL round-bottom flask protected by N2 was placed tetrahydrofuran (100 mL), Mg (1.0 g, 41.67 mmol, 2.14 equiv) and I2 (0.010 g). Then a solution of 1-bromo-2-ethylbenzene (3.6 g, 19.45 mmol, 1.00 equiv) in THF (15 mL) was added dropwise. The resulting mixture was heated to reflux for 1 h. Then it was cooled to 0° C. and oxirane (50 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 1.83 g (63%) of 2-(2-ethylphenyl)ethan-1-ol as a colorless oil.