Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:4]2[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=2)CC1.S(Cl)(Cl)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[NH:47][C:33]3[N:34]=[CH:35][N:36]=[C:37]([C:38]4[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([NH2:45])[C:39]=4[CH3:46])[C:32]=3[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[C:48]1([CH3:54])C=CC=C[CH:49]=1>N1C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:30]2[NH:47][C:33]3[N:34]=[CH:35][N:36]=[C:37]([C:38]4[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([N:45]([CH:54]5[CH2:48][CH2:49]5)[C:8](=[O:9])[C:7]5[CH:11]=[CH:12][CH:4]=[CH:5][CH:6]=5)[C:39]=4[CH3:46])[C:32]=3[CH:31]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccc(C2CC2)cc1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1c(-c2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc(F)cc1N(C(=O)c1ccccc1)C1CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-cyclopropyl benzoic acid (0.58 g, 3.57 mmol) in toluene (2 ml), thionyl chloride (1.29 ml, 17.87 mmol) was added. The mixture was stirred at 80° C. for 2 hours and afterwards evaporated under reduced pressure. The residue was dissolved together with Intermediate 20 (1.0 g, 2.36 mmol) in pyridine (5 ml) and the mixture was stirred at room temperature for 2 hours. Pyridine was evaporated under reduced pressure and the residue was dissolved in DCM and washed with saturated sodium hydrogen carbonate solution and brine (2×). The residue was purified by flash chromatography on silica (cyclohexane to EtOAc) to afford the compound Intermediate 21 as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1)#[CH:2].Br[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([Br:16])[N:15]=1>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.[Cu]I.C1COCC1>[Br:16][C:14]1[N:15]=[C:10]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=2)[C:11]([NH2:17])=[N:12][CH:13]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cn1cc(C#Cc2nc(Br)cnc2N)cn1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
To a round bottom flask was added 4-ethynyl-1-methyl-1H-pyrazole (8.5 g, 80 mmol, Preparation #Q.1), 3,5-dibromopyrazin-2-amine (16.8 g, 66.4 mmol), THF (166 mL), PdCl2(PPh3)2 (2.33 g, 3.32 mmol), copper(I) iodide (0.633 g, 3.32 mmol) and TEA (27.8 mL, 199 mmol). The mixture was heated to about 70° C. for about 1 h. The mixture was cooled to rt. The solids were filtered away and rinsed with THF (50 mL). The filtrate was partitioned with water (300 mL) and the mixture was extracted with EtOAc (400 mL). The organic layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOH (100 mL) and the solid material was collected by filtration. The mother liquor was purified by flash chromatography (300 g silica gel column, heptane/EtOAc 10:1 to 0:1) to give 5-bromo-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyrazin-2-amine (15.2 g, 82%): LC/MS (Table 2, Method c) Rt=1.40 min; MS m/z 278 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][C:39]1([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C:39]3([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NC1(CO)CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3(CO)CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 1-amino-cyclopentylmethanol according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.14 (s, 4 H), 1.58-1.61 (m, 10 H), 3.26-3.31 (m, 6 H), 6.27 (d, J=5.5 Hz, 1 H), 6.53 (s, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.35 (d, J=7.7 Hz, 1 H), 7.44 (s, 1 H), 7.52-7.59 (m, 3 H), 7.78 (s, 1 H), 7.95-7.97 (m, 1H), 8.16 (d, J=5.5 Hz, 1 H), 10.41 (s, 1 H).
Reaction SMILES: [S:1]([C:19]1[CH2:20][CH:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:24])[CH:22]2[CH2:34][CH:35]=1)[C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:7])[CH:5]2[CH2:17][CH:18]=1.[S]>>[S:1]([C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1)[C:19]1[CH:20]=[C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:24])[C:22]2=[CH:34][CH:35]=1
Reactant: O=C1C2CC=C(SC3=CCC4C(=O)N(c5ccccc5)C(=O)C4C3)CC2C(=O)N1c1ccccc1
Agent: [S]
Product: O=C1c2ccc(Sc3ccc4c(c3)C(=O)N(c3ccccc3)C4=O)cc2C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 200 mg (0.41 mmol) of 4,4'-thiobis(N-phenyl-1,2,3,6-tetrahydrophthalimide) and 53 mg (1.7 mmol) of elemental sulfur was heated to 240°-260° C. (sand bath) for 20 minutes and cooled to room temperature. The resulting brown residue was purified by preparative TLC on silica gel (eluent: 1% methanol in dichloromethane) to give 61 mg (31% yield) of 4,4'-thiobis(N-phenylphthalimide) as a yellow solid. Trituration with dichloromethane afforded a white solid: mp 275°-280° C.; (lit 293°-295° C.--see U. S. Pat. No. 3,989,712); lR (KBr) 3065, 1710,1375 cm-1 ; 1H NMR (slurry in DMSO-d6) 7.52 (m,5H), 7.97 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1([CH2:42]CO)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH2:42][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCC1CCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCC4CCCCC4)c(Cl)c3)c2cc1OC
Yield: 76.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-cyclohexyl-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 67%).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.CN(C)C1C=CC=CC=1.C[Si](C)(C)Cl.Cl[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].Cl>ClCCl.C(N(CC)CC)C>[CH:36]([S:37]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:11][CH:12]=1)(=[O:39])=[O:38])=[CH2:35]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
276 mg of triethylamine was added to a dichloromethane suspension (4 ml) containing 100 mg of 6-[4-(3-aminopropoxy)phenyl]pyridazin-3(2H)-one hydrobromide and 37 mg of dimethylaniline, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 86 mg of trimethylchlorosilane was added thereto, and the mixture was stirred at room temperature for 2 hours. Again, under ice cooling, a dichloromethane solution (1 ml) containing 65 mg of chloroethylsulfonyl chloride was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. 5 ml of 1M hydrochloric acid was added to the mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (30:1)) to obtain 73 mg of 6-[4-(3-vinylsulfonylaminopropoxy)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH3:16])=[CH:15][C:3]=12.[OH-].[K+].[CH2:19](I)[CH3:20].Cl>O.C(O)C>[CH2:19]([N:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:1])[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]1=2)[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21

Procedure:
A mixture of 1.4 parts of ethyl 4-hydroxy-2-methylthieno-[2,3-b]pyridine-5-carboxylate, 12 parts by volume of 10 % aqueous potassium hydroxide, 48 parts by volume of ethanol, 60 parts by volume of water and 1.8 parts by volume of ethyl iodide is refluxed for about 3 hours. After cooling, the reaction mixture is added to 60 parts by volume of water containing 3 parts by volume of concentrated hydrochloric acid and the resulting crystals are collected by filtration to give 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid as colorless crystals. Recrystallization from chloroform-ethanol yields colorless prisms melting at 229°-230°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:30][C:28]([F:29])([F:31])[C:25]1[N:23]2[N:24]=[C:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=4)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]3)[CH:20]=[CH:21][C:22]2=[N:27][N:26]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CCOC(=O)c1cccc(C2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
Ethyl 3-(piperidin-4-yl)benzoate (1.195 g, 5.12 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol) and DIPEA (1.174 mL, 6.74 mmol) in DMA (10 mL). The resulting solution was stirred at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash silica chromatography, eluting with 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to give a beige solid, which was triturated with ether to give ethyl 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]benzoate (0.805 g, 42.7%) as a solid.
Reaction SMILES: [OH:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C@@H:5]2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[ClH:22].[CH3:23]O>>[ClH:22].[CH3:23][O:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C@@H:5]2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CO
Reactant: CN1CCN2c3ccccc3[C@H](O)c3ccccc3[C@H]2C1
Agent: Cl
Product: CO[C@@H]1c2ccccc2[C@H]2CN(C)CCN2c2ccccc21
Reaction time: 1 h

Procedure:
1 g cis-10-hydroxy-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine is suspended in 25 ml methanol, after which 2 ml of a saturated solution of HCl in methanol is added and the mixture is boiled for about 1 hour with exclusion of moisture. The solution is evaporated to dryness under vacuum and the residue is crystallized from methanol. Yield 300 mg. Melting point of the HCl salt: 247°-251° C.; melting point free base 182°-184° C.
Reaction SMILES: S(=O)(=O)(O)O.P(=O)(O)(O)[OH:7].[CH:11](=[O:16])[CH:12]=[CH:13][CH2:14][CH3:15]>O>[CH:11](=[O:16])[CH2:12][CH:13]=[CH:14][CH3:15].[CH2:11]([OH:16])[CH:12]=[CH:13][CH:14]([OH:7])[CH3:15]
Reactant: CCC=CC=O
Reactant: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)C=CCO
Product: CC=CCC=O

Procedure:
It has been disclosed in Bull. Soc. Chim. France 11 (1944), 218-223, that a mixture of aldehydes is obtained when an unsaturated diol is reacted with dilute sulfuric acid or equimolar amounts of phosphoric acid and water. Thus, a mixture of pent-2-enal and pent-3-enal is obtained from pent-2-ene-1,4-diol, a mixture of hex-2-enal and hex-3-enal is obtained from hex-2-ene-1,4-diol, and a mixture of 2,3-dimethylbut-2-enal and 2,3-dimethylbut-3-enal is obtained from 2,3-dimethylbut-2-ene-1,4-diol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
4-Chloro-8-(trifluoromethyl)quinoline (500 mg, 2.16 mmol), 4-hydroxybenzaldehyde (264 mg, 2.16 mmol), and cesium carbonate (845 mg, 2.59 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a white solid (680 mg, yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.N1C=CC=CC=1.[F:22][C:23]([F:33])([F:32])[CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29](Cl)=[O:30].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:29](=[O:30])[CH2:28][CH2:27][S:26][CH2:25][CH2:24][C:23]([F:33])([F:32])[F:22])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CCSCCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (prepared as described in the U.S. Publication No. 2012/0110702 to Yap et al.) (10.0 g, 44.9 mmol) in CH2Cl2 (100 mL), at a temperature of about 0° C. and under N2, was added pyridine (5.45 mL, 67.4 mmol), 4-dimethylaminopyridine (DMAP) (2.74 g, 22.45 mmol), and 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (9.91 g, 44.9 mmol), sequentially. The reaction was warmed to room temperature and stirred for one hour. The reaction mixture was poured into water (100 mL), and the resulting mixture was stirred for five minutes. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×50 mL), and the combined organic extracts were dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified via normal phase flash chromatography (0% to 100% EtOAc/CH2Cl2) to provide the desired product as a pale yellow solid (17.21 g, 89%): IR (thin film) 1659 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=2.6 Hz, 1H), 8.63 (dd, J=4.7, 1.3 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.96 (s, 1H), 7.47 (dd, J=8.3, 4.8 Hz, 1H), 3.72 (q, J=7.1 Hz, 2H), 2.84 (t, J=7.2 Hz, 2H), 2.66 (m, 2H), 237 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 409 ([M+2H]+).
Reaction SMILES: [C-:1]#[N:2].[Na+].O1CCCC1.[O:9]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:24][C:25]([Cl:35])=[CH:26][CH:27]1[CH:29]([C:30](Cl)=[O:31])[C:28]1([CH3:34])[CH3:33]>O1CCCC1.O.O>[Cl:24][C:25]([Cl:35])=[CH:26][CH:27]1[CH:29]([C:30]([O:20][CH:19]([C:1]#[N:2])[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:17]=2)=[O:31])[C:28]1([CH3:34])[CH3:33]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h

Procedure:
Sodium cyanide (0.765 g, 15.6 mmole), along with 20 ml of 2:1 tetrahydrofuran:water by volume, was charged to a reaction flask, and the resultant solution was stirred while the temperature was raised to 40°. 3-Phenoxybenzaldehyde (2.06 g, 10 mmole) was added in 5 ml of the tetrahydrofuran/water mixture (25 ml total). 3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (2.84 g, 12.5 mmole) was then added to the flask dropwise over a 10 minute period. The temperature of the reaction mixture was maintained between 40° and 40° during the acyl chloride addition. The reaction mixture was then stirred at 40° for an additional 2 hours, after which it was extracted three times with 15 ml portions of n-heptane. The combined organic phases were washed once with water (15 ml), once with a 2 N aqueous sodium hydroxide solution (15 ml), three more times with water (15 ml) portions), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. A quantitative yield of α-cyano-3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate remained as the residue.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH3:35][N:23]1[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=[C:22]1[N:17]1[CH2:18][CH2:19][O:20][C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1)c1ccccn1
Yield: 38.7 %

Procedure:
A solution of N-Methyl-N-(4-((2S)-morpholin-2-yl)phenyl)pyridin-2-amine (0.12 g, 0.46 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (0.08 g, 0.37 mmol), and triethylamine (0.23 g, 2.3 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to give 3-Methyl-2-((2S)-2-(4-(methyl(pyridin-2-yl)amino)phenyl)morpholin-4-yl)-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (65 mg, 13%) as a yellow oil.
Reaction SMILES: OC[CH2:3][C:4](C)([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:5].S(Cl)([Cl:22])=O.Cl[CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][C:4]([CH3:5])([S:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:22])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:3]
Reactant: CC(C)(CCO)Sc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Reactant: ClCCCl
Product: CC(C)(CCCl)Sc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-hydroxy-2-methylbutan-2-ylthio)-3-nitrobenzoic acid (3.08 g, 10.8 mmol) in DCE (50 mL) was added thionyl chloride (2.365 mL, 32.4 mmol). The reaction was heated to 70° C. and stirred at that temperature for 1 hour. The solvent was removed under reduced pressure and the resulting oil was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27](Cl)=[O:28])[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([NH:12][C:10]1[N:11]=[C:7]2[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1)=[O:28]
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2nc3c(-c4ccccc4)ccc(OC)n3n2)c1

Procedure:
According to example 6, the title compound was synthesized from 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and 3-methoxy-phenyl carboxylic acid chloride. (MS m/e (%): 374.4 (M+H+, 100).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)/[CH:23]=[CH:24]/[CH3:25]>CO>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:32])=[CH:34][CH:35]=1)/[CH:23]=[CH:24]/[CH3:25]
Reactant: C/C=C/COc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(F)(F)F)cc1
Solvent: CO
Product: C/C=C/COc1ccc(C(=O)NC(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87.8 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphorinium chloride (DMT-MM, 332 mg, 1.20 mmol) was added to a methanol (6 mL) solution of tert-butyl 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoate (305 mg, 1.00 mmol) and 4-[(2E)-buten-2-yloxy]benzoic acid (192 mg, 1.00 mmol) prepared in Example 32 (32a). The mixture was stirred at room temperature for 4 hours and 50 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 19:1 and 4:1, V/V) to give 421 mg of tert-butyl 2-({4-[(2E)-but-2-en-1-yloxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propanoate (colorless oil). This oily compound (492 mg, 1.03 mmol) was dissolved in methylene chloride (20 mL), and trifluoroacetic acid (4 mL) was added thereto at room temperature. The resulting mixture was stirred at the same temperature for 4.5 hours. The solvent was evaporated, and the residue was suspended in diisopropyl ether. The insoluble substance was collected by filtration, washed with diisopropyl ether, and dried to give 284 mg of the title compound (white powder, yield: 57%).