Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[CH3:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1B(O)O>COCCOC.C(OCC)(=O)C>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]4[C@H:6]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]34)[CH:10]=2)=[C:27]([CH3:26])[CH:32]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A (80 mg, 0.18 mmol) in 25 mL of DME (10 mL) was added 2-methyl-4-methoxyphenyl boronic acid (45 mg, 0.27 mmol) and TEA (0.26 mL, 1.8 mmol). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(dppf)2 (15 mg, 0.1 mmol) and the mixture was stirred at 85° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with sat'd aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford (35 mg, 45% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 7.13 (d, 1H, J=8.1 Hz), 6.97 (s, 1H), 6.75 (m, 3H), 3.83 (s, 3H), 3.79 (m, 1H), 3.65 (m, 2H), 3.52 (m, 3H), 3.21 (m, 2H), 3.01 (m, 2H), 2.24 (s, 3H), 1.97 (m, 2H), 1.60 (m, 2H), 1.21 (s, 9H). LRMS (ES+): 467 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].N1C=C[CH:25]=[CH:24][CH:23]=1.ClC1C=CC=CC=1Cl.S(Cl)(Cl)=O>CO>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([O:21][CH:24]([CH3:25])[CH3:23])=[O:20]
Reactant: c1ccncc1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
While a solution of 100 parts of 1-amino-4-bromoanthraquinone-2-carboxylic acid, 1.6 parts of pyridine and 500 parts of orthodichlorobenzene was stirred at room temperature, 87 parts of thionyl chloride was added thereto dropwise over about 30 minutes. After the completion of the addition, the solution was heated at 100° C. for 2 hours. Afterward, excess thionyl chloride was distilled off under reduced pressure, and 88 parts of isopropyl alcohol was added dropwise to the solution at about 80° C. Reaction was performed at the same temperature as above for 2 hours, and the solution was then cooled to room temperature. Afterward, the solution was introduced into 1,000 parts of methanol, followed by stirring for 30 minutes. The resulting precipitate was collected by filtration, washed with methanol and dried, thereby obtaining 90 parts of isopropyl 1-amino-4-bromoanthraquinone-2-carboxylate. To the thus obtained product were added 34 parts of potassium acetate, 3 parts of copper sulfate, 6 parts of benzyl alcohol, 59 parts of m-toludine and 206 parts of dipropylene glycol, and the solution was then heated up to 135° C. in a nitrogen atmosphere and reaction was carried out for 2.5 hours. Afterward, the solution was cooled to 50° C. and was then introduced into 2,000 parts of methanol, followed by enough stirring for 30 minutes. The resulting precipitate was then collected by filtration, introduced into 2,000 parts of methanol again, stirred, filtered, and dried, so that 89 parts of isopropyl 1-amino-4-m-toluidinoanthraquinone-2-carboxylate (melting point 133°-134° C.) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)CC1

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Intermediate J, 50 mg, 0.160 mmol) and 1-acetylpiperazine (41.0 mg, 0.320 mmol) (tR 3.17 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.85 (d, 1H); 8.33 (d, 1H); 7.94 (d, 1H); 7.84 (d, 1H); 7.74 (d, 1H); 7.46 (m, 1H); 7.44 (s, 1H); 7.14 (d, 1H); 4.40 (s, 2H); 3.48 (s, 6H); 3.42 (m, 2H); 2.00 (s, 3H)).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1([CH3:15])[C:3]2[CH:4]=[C:5]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC1(C)c2ccccc2-c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 119.6 %

Procedure:
9,9-Dimethyl-9H-fluorene (40 g, 1 eq, 0.146 mol) and phthalic anhydride (36.5 g, 1.1 eq, 0.161 mol) were placed in a reaction vessel, and dichloromethane (1.5 l) was added thereto. Then, aluminum chloride (29.2 g, 1.5 eq, 0.219 mol) was gradually added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, distilled water was gradually added at 0° C., and the resultant solution was extracted with an excess of dichloromethane and several times washed with distilled water. After solvent removal, the resultant solid was placed in a hexane (2 l)-containing vessel, washed, filtered, and dried to give 2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (59.8 g, yield=82%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][N:19]=[CH:20][C:13]=23)[S:9][CH:8]=1)([CH2:5][CH3:6])[C:3]#[N:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:18]1[C:14]2=[N:15][CH:16]=[CH:17][C:12]([C:10]3[S:9][CH:8]=[C:7]([C:2]([CH3:1])([CH2:5][CH3:6])[CH2:3][NH2:4])[CH:11]=3)=[C:13]2[CH:20]=[N:19]1
Reactant: CCC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)(CN)c1csc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
A cooled solution of 2-methyl-2-[5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3-thienyl]butanenitrile (234 mg, 0.8287 mmol) in THF (10.00 mL) was treated with LiAlH4 in THF (1.658 mL of 2 M, 3.315 mmol) dropwise over a period of 3 minutes. The reaction was allowed to stir at RT overnight and then quenched with water whilst cooling. The mixture was extracted with EtOAc (2×) and the organics dried (MgSO4), filtered, concentrated and purified by column chromatography (70:9:1 DCM/MeOH/NH4OH) to give the product as a white solid (19.0 mg, 8% Yield). 1H NMR (DMSO, 400 MHz) δ 0.71 (3H, t), 1.25 (3H, s), 1.50-1.64 (1H, m), 1.70-1.84 (1H, m), 2.67 (1H, d), 2.79 (1H, d), 7.46-7.48 (2H, m), 7.89 (1H, s), 8.48 (1H, s), 8.50 (1H, d); MS (ES+) 287.09
Reaction SMILES: O.C(O)(=O)C.[CH:6]([S:9][C:10]1[CH:15]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-])=O)([CH3:8])[CH3:7].C(SC1C=C(C2C(C(F)(F)F)=NNC=2)C=CC=1C(OC)=O)CC>C1(C)C=CC=CC=1.[Fe]>[Cl:27][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:21]([Cl:22])[C:16]=1[C:14]1[CH:13]=[CH:12][C:11]([NH2:28])=[C:10]([S:9][CH:6]([CH3:8])[CH3:7])[CH:15]=1
Reactant: CC(C)Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(=O)OC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1N
Temperature: 25 °C
Yield: 36 %

Procedure:
3.5 g (63.6 mmol) of iron powder, 10 m of water and 1 m of acetic acid were stirred in 20 ml toluene at 60° C. for 30 minutes, and 3.0 g (7.3 mmol) of [5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrophenyl] isopropyl sulfide (the compound prepared in Example 8 (2)) in 10 ml toluene was added dropwise. The reaction was carried out with reflux and heating for another 3 hours, and then the reaction mixture was cooled to room temperature. The insolubles were filtered off, and the filtrate was separated with water and toluene. The toluene layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.0 g of 4-(2,6-dichloro-4-trifluoromethylphenyl)-2-isopropylthioaniline (yield 36.0%) as a pale yellow dough (nD20 1.5782).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65](O)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1>CN(C=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1
Reactant: C1COCCN1
Reactant: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HATU (0.38 g, 0.99 mmol), diisopropylethylamine (0.41 mL, 2.48 mmol) and morpholine (0.08 mL, 0.99 mmol) were added at 0° C. to a solution of 300b) (0.35, 0.83 mmol) in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 6 h and then quenched with ice-cold water. The mixture was extracted with dichloromethane (2×50 mL), the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The remnant was purified by flash column chromatography [silica, dichloromethane with 1.5% methanol]. White solid. Yield: 0.32 g (80% of theory)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: C#CCCN1Cc2ccccc2C1=O
Reactant: Ic1ccccn1
Product: O=C1c2ccccc2CN1CCC#Cc1ccccn1
Yield: 37 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (94 mg, 0.46 mmol) and 2-(but-3-ynyl)isoindolin-1-one (85 mg, 0.46 mmol). Reaction conditions: 14 hours at room temperature. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1 to 0:1) to yield 45 mg (0.17 mmol, 37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindolin-1-one as a white solid (M.P.=94-98° C.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([OH:13])=[O:12].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:11]([O:13][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
At 10° C., cesium carbonate (5.81 g) was added to a DMF (30 mL) solution of 3-fluoro-5-nitrobenzoic acid (2.20 g), followed by stirring for 30 minutes. Then, benzyl bromide (2.07 g) was dropwise added with taking 30 minutes, and then followed by further stirring for 10 minutes. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. This was subjected to liquid-liquid separation with ether and water added thereto, and the organic layer was dried and then evaporated to obtain benzyl 3-fluoro-5-nitrobenzoate (3.11 g). EI: 275.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1>>[C:11]12([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=3[OH:1])[CH:6]=[O:7])[CH2:16][CH:15]3[CH2:4][CH:5]([CH2:8][CH:13]([CH2:14]3)[CH2:12]1)[CH2:6]2
Reactant: O=Cc1ccc(O)cc1
Reactant: Oc1ccc(Br)cc1
Product: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Yield: 56 %

Procedure:
When 4-hydroxybenzaldehyde was substituted for 4-bromophenol in Example 31, Step A, the similar procedure afforded 3-(1-admantanyl)-4-hydroxybenzaldehyde in 56% yield, as a pale white solid. 1H-NMR (CDCl3) 9.84 (s, 1H); 7.78 (d, 1H, J=2.07 Hz); 7.61 (dd, 1H, J=8.13, 2.01 Hz); 6.77 (d, 1H, J=8.16 Hz); 5.88 (bs, 1H); 2.12 (s, 6H); 2.09 (s, 3H); 1.78 (s, 6H). This was methylated by similar procedure as described in Example 31, Step B, to give the title compound in 64% yield, as light yellow solid. 1H-NMR (CDCl3) 9.86 (s, 1H); 7.76 (d, 1H, J=2.07 Hz); 7.7 (dd, 1H, J=8.4, 2.1 Hz); 6.95 (d, 1H, J=8.4 Hz); 3.91 (s, 3H); 2.09 (s, 9H); 1.76 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH:3]1[NH:15]C(=O)OCC1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH2:5][CH2:4][CH:3]1[NH2:15]
Reactant: CN1CCN(C2CCC(NC(=O)OCc3ccccc3)C(C)(C)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C2CCC(N)C(C)(C)C2)CC1
Reaction time: 2 h
Yield: 95 %

Procedure:
Benzyl 2,2-dimethyl-4-(4-methylpiperazin-1-yl)cyclohexylcarbamate (0.5 g, 1.393 mmol, 1 eq) was dissolved in MeOH (6 ml); Pd(OH)2 (150 mg) was added, and hydrogenation was carried out for 2 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and the filtrate was concentrated under reduced pressure. The desired product was thus obtained and was used in the next stage without being purified further. Yield: 95% (300 mg, 1.33 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:37]2[S:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[S:38][C:39]5[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=5[N:41]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4nc5ccccc5s4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-piperazin-1-yl-benzothiazole.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].[Cl-].[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH3+:36])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=[O:26]>>[CH3:1][C:2]1[S:3][C:4]([CH3:21])=[C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:6]=1[C:7]([NH:36][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=2)[CH2:35][CH2:34]1)=[O:8]
Reactant: COC(=O)c1ccc(C2([NH3+])CC2)cc1
Reactant: Cc1sc(C)c(C(=O)O)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Product: COC(=O)c1ccc(C2(NC(=O)c3c(C)sc(C)c3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxylic acid from Example 11, Step 4 (275 mg, 0.87 mmol) was reacted with 1-[4-(methoxycarbonyl)phenyl]cyclopropanaminium chloride from Example 16, Step 2 (167 mg, 0.86 mmol) under conditions similar to Example 11, Step 5. The crude product was purified by Combi Flash chromatography system (2-5% EtOAc/CHCl3 in 20 min.) to afford the desired product as a white solid.
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.ClC1C=C(C=O)C=NC=1.N1CCCC1.[Cl:26][C:27]1[CH:35]=[C:34]2[C:30](/[C:31](=[CH:37]/[C:38]3[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=3)/[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1>CO>[Cl:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31](=[CH:37][C:38]3[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=3)[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cncc(Cl)c1
Agent: O=C1Cc2ccc(Cl)cc2N1
Agent: O=Cc1cncc(Cl)c1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cncc(Cl)c1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (0.93 g, 5.6 mmol) and 5-chloro-pyridine-3-carbaldehyde (0.8 g, 5.6 mmol) in methanol (10 mL) was added pyrrolidine (0.6 g, 5.6 mmol) dropwise. The mixture was then heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-pyridine-3-ylmethylene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 1.0 g, 63%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3c[nH]c4ccccc34)n2)cc1
Yield: 81 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (44 mg, 81% yield.) MS/ES+: m/z=474.
Reaction SMILES: CO.[NH:3]1[CH:7]=[C:6]([CH:8]=O)[N:5]=[CH:4]1.[CH2:10]([NH2:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>Cl.[Pd].C(OCC)(=O)C>[CH2:10]([NH:20][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCN
Reactant: O=Cc1c[nH]cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCNCc1c[nH]cn1
Reaction time: 8 h

Procedure:
A 500 mL flask under a nitrogen atmosphere was charged with anhydrous methanol (150 mL), imidazole-4-carboxaldehyde (45.82 grams, 476 mmol) and decylamine (74.99 grams, 476 mmol) with stirring. Several drops of concentrated hydrochloric acid were added to the mixture and the mixture was allowed to reflux overnight under nitrogen. The mixture was taken up into ethyl acetate, washed with water and brine, dried with sodium sulfate, and evaporated to dryness. The crude product was dissolved in a 4:1 ratio of anhydrous THF and anhydrous MeOH and transferred to a hydrogenation reaction flask. To this solution was added 5 wt. % Pd/C (5 wt. %) and the resulting mixture was hydrogenated overnight at 30 psi H2. After hydrogenation was complete, the solution was filtered through Celite under vacuum to remove the Pd/C and the filtrate was evaporated to dryness. 1H NMR (CDCl3) δ 7.5-7.6 (1H), 6.8-6.9 (1H), 3.6-3.8 (2H), 2.6 (t, 2H), 1.5 (t, 2H), 1.2-1.4 (m, 14H), 0.8-0.9 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:8][C:7]2[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[O:5]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][CH:4]1[CH2:8][CH:7]2[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][CH:6]2[O:5]1)[CH3:2]
Reactant: CCOC1CC2=C(CCCC2=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC1CC2C(=O)CCCC2O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the ketone 10 (140 mg, 0.77 mmol) in EtOAc (9 mL) was added 5% Pd/C (128 mg, 60 μmol) and the mixture was stirred under H2 (1 atm) for 1.5 h at room temperature. The mixture was then filtered on Celite and the pad washed with EtOAc. Evaporation of the solvent furnished the corresponding crude ketone 11 as an essentially pure mixture of diastereoisomers (130 mg, dr=9:1). The ketone was directly submitted to the next step without purification. TLC Major isomer: Rf=0.35 (hexanes:EtOAc=2:1).
Reaction SMILES: [O:1]1C=CCCC1OOC.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].[CH3:18][CH2:19][O:20][CH2:21][CH3:22].B.OO.[OH-].[Na+]>O1CCCC1>[OH:1][CH:14]1[CH2:15][O:10][CH:11]([CH2:16][OH:17])[CH2:12][CH2:13]1.[CH3:18][CH2:19][O:20][CH2:21][CH3:22]
Reactant: OCC1CCC=CO1
Reactant: COOC1CCC=CO1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCC(O)CO1

Procedure:
A dihydro-2H-pyran-2-ylmethoxy ether of Formula 1 is an especially useful intermediate to the ethers of formula 1 in which R is, e.g. hydroxy, oxo, methylene, alkyl or alkoxy by use of conventional synthesis techniques. For example, (3,4-dihydro-2H-pyran-2-yl)methanol ether is treated with, e.g. borane in tetrahydrofuran followed by hydrogen peroxide and sodium hydroxide, to give the corresponding (3,4,5,6-tetrahydro-5-hydroxy-2H-pyran-2-yl)methanol ether. This hydroxy ether is treated with, e.g. oxalyl chloride in dimethyl sulfoxide, to obtain the corresponding (3,4,5,6-tetrahydro-2H-5-oxo-pyran-2-yl)methanol ether. This oxo ether is treated with, e.g. methyl triphenyl phosphonium bromide, to obtain the corresponding (3,4,5,6-tetrahydro-2H-5-methylene-pyran-2-yl)methanol ether. This ether is treated with, e.g. hydrogen in the presence of platinum oxide and ethyl acetate, to give the corresponding (3,4,5,6-tetrahydro-2H-5-methoxypyran-2-yl)methanol ether.