Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][CH:39]1[CH2:40][O:41]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), potassium carbonate (125 mg), and epibromohydrin (124 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (62 mg, yield 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Oc2ncc(Br)cn2)cc1
Reaction time: 6 h
Yield: 78 %

Procedure:
5-Bromo-2-chloropyrimidine (3.0 g), p-methoxyphenol (2.5 g), methyl ethyl ketone (50 ml--dried over anhydrous potassium carbonate) and anhydrous potassium carbonate (2.5 g) were heated under reflux with stirring for 6 hours. The solvent was evaporated under reduced pressure, the residue treated with water and the precipitated compound collected by filtration. The product was treated with 5% sodium hydroxide aqueous solution and the mixture stirred for approximately 30 minutes. The solid was collected by filtration, washed with water and recrystallised from methanol/water to give the title compound (3.4 g), m.p. 92° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][C:21](=[O:23])[CH3:22])[N:10]=[C:4]2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2cc(Br)ccn2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2cc(Br)ccn2n1
Temperature: 50 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
To a solution of 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared using the procedure in WO2006038116) (0.150 g, 0.704 mmol), diisopropylethylamine (0.363 g, 2.81 mmol), catalytic DMAP (0.09 g, 0.07 mmol) in anhydrous THF (4 mL) was added acetic anhydride (0.216 g, 2.11 mmol). The reaction mixture was stirred at 50° C. for 22 h under N2 (g). After cooling to room temperature the mixture was concentrated, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. Filtration and concentration followed by column chromatography of the residue on silica (95:5 dichlormethane/methanol) afforded N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (0.170 g, 95% yield) as a brown oil. MS (EI) for C8H7BrN4O: 256 (MH+).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(C)=C.[OH:12]O>>[OH:12][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccc(OC)cc1
Reactant: OO
Product: COc1ccc(O)cc1

Procedure:
reacting para-isopropenylanisole with hydrogen peroxide in the presence of a mineral acid and a solvent to yield para- hydroxyanisole.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][C@H:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 116.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (10 mL) was added 1-Boc-piperazine (1.2 g, 2.17 mmol). The mixture was stirred at 110° C. overnight. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to afford (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.806 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 3.68 (m, 2H), 3.60-3.40 (m, 7H), 2.84 (m, 2H), 2.30 (m, 1H), 1.67 (m, 1H), 1.49 (m, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+319.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=O.[BH4-].[Na+]>COCCOC.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCC(c2ccccc2)CC1
Temperature: 60 °C

Procedure:
4-Phenylpiperidine (12.4 mmol), paraformaldehyde (24.8 mmol) and tetraisopropoxy-titanium (12.4 mmol) are suspended in 1,2-dimethoxyethane (20 ml) and warmed to 60° C. for 30 minutes and stirred at rt for one additional hour. Sodium borohydride (12.4 mmol) is added in portions and the mixture is stirred at rt for 2 hours and at 60° C. for additional 3 hours. After cooling the solvent is evaporated and the residue is dissolved in a mixture of aqueous ammonia (60 ml) and ethyl acetate and filtered carefully. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:28])[CH3:29])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:6][CH2:7]1)(=[O:40])[CH3:39]
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)N[C@H]3CC[C@H](N)CC3)CN(C)[C@@H]1C2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@@H]3c4cccc5c4c(cn5C(C)C)C[C@H]3N(C)C2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 620 mg of (8β)-N-(trans-4-aminocyclohexyl)-1-isopropyl-6-methylergoline-8-carboxamide in 100 ml of dry tetrahydrofuran were added 222 μl of triethylamine. The solution was cooled by means of an external ice bath and 118 μl of acetyl chloride were added in dropwise fashion. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was concentrated in vacuo and ethyl acetate, water, and 2N sodium hydroxide were added. The layers were separated and the aqueous layer extracted an additional three times with ethyl acetate and six times with methylene chloride. The combined organic layers were washed twice with water, once with a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to provide 690 mg of a pale yellow solid. This material was crystallized from tetrahydrofuran/ethanol/hexanes to provide 259 mg of title product as a tan powder, m.p. >280° C. Analytical high pressure liquid chromatography indicated the material was 97.9% pure. NMR, MS
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6](=[O:30])[CH:7]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 1.19 g (2.6 mmol) trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester in 20 ml of anhydrous THF was cooled to −78° and treated dropwise with a 1M solution of lithium bis-(trimethylsilyl)-amide in THF (6.2 ml, 2.5 eq). The mixture was allowed to reach RT within ca. 1 h and cooled again to −78°. A solution of 0.18 ml (2.9 mmol, 1.1 eq) of iodomethane in 2.5 ml of THF was added and the mixture allowed reach RT within ca. 1 h. After addition of ice, the mixture was extracted with EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 600 mg (49%) of trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid tert-butyl ester as a colorless solid, MS: 483 (M+NH4+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=2)[OH:20])[CH3:16])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C(O)C>[NH2:41][C:42]1[C:43]([C:50]([N:52]=[C:53]([NH2:56])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=3)[OH:20])[CH3:16])=[CH:10][CH:11]=2)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution composed of compound 28 (0.10 g, 0.25 mmol), Hunig's base (0.21 mL, 1.23 mmol) and ethanol (5 mL) was heated at 70° C. for 30 min before 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (0.11 g, 0.27 mmol) was added. The resulting solution was continuously stirred at that temperature for an additional 3 h before it was cooled to room temperature. The solvent was removed by evaporation. The resulting residue was subjected to column chromatography eluting with a mixture of methanol (0-28%), concentrated ammonium hydroxide (0-2.8%) and dichloromethane (100-69.2%) to afford 30 (87 mg, 56%) as a yellow solid: m.p. 120-121° C. (decomposed); [α]D25 −6.65° (c 0.20, methanol); 1H NMR (500 MHz, DMSO-d6) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.72 (m, 6H), 2.55 (m, 4H), 2.64-2.92 (m, 3H), 3.16 (m, 2H), 4.56 (m, 1H), 6.76 (m, 1H), 6.82 (m, 1H), 6.92 (m, 1H), 7.10 (m, 4H), 8.07 (s, 1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H), 9.59 (s 1H); m/z (ESI) 626 [C30H40ClN9O4+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([C:14](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[CH:10][CH:9]=2)[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>C(O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:20]1[C:38]([C:37](=[O:42])[NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)=[C:39]([CH3:40])[NH:41][C:12]([C:11]2[CH:28]=[CH:29][C:8]([N:4]3[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]3)=[CH:9][CH:10]=2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C/C(N)=C/C(=O)Nc1ccccn1
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)c1ccc(-n2nc(C)nc2C)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccc(-n3nc(C)nc3C)cc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Yield: 6.4 %

Procedure:
A mixture of the product from step (a) (566 mg, 1.38 mol) and N-(2-pyridyl)-3-aminocrotonamide (245 mg, 1.38 mmol) in ethanol (10 ml) was heated at reflux under nitrogen for 8 hours. The solvent was removed and the residue purified by flash chromatography (eluting with 2% diethylamine in ethyl acetate) to afford the title compound (50 mg, 6%) as a white solid, m.p. 130° C.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:33])[C@H:24]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:33])=[O:22])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC2CCCCC2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-cyclohexylalanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[C:10](=[CH:15][N:16]([CH3:18])[CH3:17])[CH2:11]1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(=CN(C)C)C1

Procedure:
To a round bottomed flask was loaded 8.56 grams of 4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture was refluxed at 90° C. for two hours. Then it was poured into 75 ml water and extracted with 2×250 ml dichloromethane. The combined organic layers was washed with 50 ml brine and dried over magnesium sulfate. Filter off the drying agent and concentrate gave 28 grams of 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid ethyl ester. This material (12.8 grams) was then loaded into a round bottomed flask along with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 100 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vaccum dried to yielded 1.5 grams of product. MS: 278.1 (M+H). H-NMR(CDCL3): δ 8.60(s, 1H), 4.98(s, 2H), 4.78(s, 2H, CH2), 4.22(q, 2H, J=4.8 Hz), 3.75 (t, 2H, CH2, J=4 Hz), 3.51 (t, 2H, J=4 Hz), 1.32 (m, 3H, CH3, J=4.8 Hz).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([Cl:14])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1.[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]([CH:26]=[CH2:27])[C:17]=1[CH:18]=[O:19].[NH4+].[Cl-]>C(OC(C)C)(C)C.C1C=CC=CC=1>[Cl:14][C:8]1[C:7]([CH:18]([C:17]2[C:20]([CH:26]=[CH2:27])=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:16]=2[F:15])[OH:19])=[CH:12][C:11]([Cl:13])=[CH:10][N:9]=1
Reactant: Clc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccc(OC)c(F)c1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: c1ccccc1
Product: C=Cc1ccc(OC)c(F)c1C(O)c1cc(Cl)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of nBuLi (1.6 M in hexane, 29.0 mL, 46.4 mmol) in diisopropyl ether (80 mL) was added 3-bromo-2,5-dichloropyridine (10.5 g, 46.4 mmol) in diisopropylether (60 mL) slowly at −78° C. The resulting suspension was treated with 2-fluoro-3-methoxy-6-vinylbenzaldehyde (7.6 g, 42.2 mmol) in diisopropylether (60 mL) and benzene (3 mL), and allowed to stir at −78° C. for 30 min followed by warming to room temperature as the bath did. The mixture was treated with saturated NH4Cl solution and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A dry 100 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.9339 g, 5.49 mmol) and thionyl chloride (6 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (80 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(N)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
At 0° C., the product from Step 3 (40 mg, 0.074 mmol) in DCM (0.4 mL) was added to acetyl chloride (6.34 μl, 0.089 mmol) and triethylamine (15.53 μL, 0.111 mmol) and the reaction was aged for 1 h. The mixture was then purified directly by column chromatography on silica gel (30-100%, ethyl acetate: 10:1 methanol in hexanes) to afford tert-butyl 4-{[2-({3-(acetylamino)-5-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (28 mg, 65% yield). Example 109(1). MS ESI: [M+H]+ m/z 581.3. 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J=6.0 Hz, 1H); 7.90 (s, 1H); 7.76 (s, 1H); 7.65 (br s, 1H); 7.53 (s, 1H); 7.11 (s, 1H); 6.14 (d, J=6.0 Hz, 1H); 5.25 (m, 1H); 3.67 (m, 2H); 3.12 (br s, 2H); 2.64 (m, 2H); 2.43 (m, 2H); 2.13 (s, 3H); 1.92 (m, 4H); 1.66 (m, 2H); 1.43 (s, 9H). rhSYK activity=++
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[O:19]([C:17]([NH:2][N:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CC=CCC1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylami-ne (2.024 g) in methylene chloride (60 ml) was added a solution of phenyl chloroformate (1.566 g) in methylene chloride (40 ml) and the mixture was stirred for 4 hours at 5° C. Evaporation of the solvent gave a residue, which was extracted with ethyl acetate (150 ml). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give N-(phenoxy- carbonylamino)-1,2,3,6-tetrahydropyridine (2.01 g), which was recrystallized from diisopropyl ether to give the desired compound (0.732 g) as colorless needles. mp: 124°-125.5° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])C.[OH-].[Na+].CCCCCC>C(O)C>[C:19]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([OH:26])=[O:3])=[CH:18][CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)O

Procedure:
Analogously to the process described in Example 2, 13 g of α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid ethyl ester, on alkaline saponification with 27 ml of 2 N sodium hydroxide solution in 130 ml of ethanol, give α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid of melting point 59°-60° C (from cold hexane).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=NO)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: c1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
Benzamide oxime (2.00 g, 14.7 mmol) and a 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) were combined in 2-methyltetrahydrofuran (20 mL) and water (2 mL). The solution was warmed to 50° C. and 50% aqueous solution of sodium hydroxide (1.52 g, 19.1 mmol) and 2-furoyl chloride (2.00 g, 15.3 mmol) were added dropwise simultaneously over 10 min. The pot temperature rose to 74° C. The mixture was stirred at 60° C. for 48 hours and the solids dissolved. The mixture was cooled to room temperature and poured into water (25 mL). The 2-methyltetrahydrofuran was removed at reduced pressure and solids formed in the aqueous solution. The solids were collected by vacuum filtration. 3-phenyl-5-(2-furanyl)-1,2,4-oxadiazole (2.33 g, 9.5 mmol) was obtained as a white solid. (64% yield).