Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:19])([C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][P:5](=[O:12])([O:9]CC)[O:6]CC.C[Si](Br)(C)C.CO.C1OC1C>C(Cl)Cl.C(OCC)C>[OH:1][C:2]([CH3:19])([C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][P:5](=[O:6])([OH:12])[OH:9]
Reactant: CCOP(=O)(CCC(C)(O)c1ncnn1C)OCC
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cn1ncnc1C(C)(O)CCP(=O)(O)O
Reaction time: 16 h

Procedure:
To a solution of diethyl 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propylphosphonate (1.2 g, 4.12 mmol) in CH2Cl2 (24 ml) was added TMSBr (2.72 ml, 20.6 mmol, 5 eq) at room temperature under nitrogen. The reaction mixture was stirred for 16 hours. Then methanol (12 ml) was added to the mixture. After stirring for 2 hours, addition of propylene oxide (2.4 ml) and dilution with diethylether gave colourless precipitates which were collected on a glass filter under nitrogen, washed with diethylether, and dried in vacuo to give pure 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propyl-phosphonic acid, compound no 5.001 (0,63 g, 65% yield). ##STR49##
Reaction SMILES: Cl[S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3].C(#N)C.C[Si](C)(C)[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]>N1C=CC=CC=1>[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[NH:21][S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
A solution consisting of 102.4 mg (0.415 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine, 2.0 ml of acetonitrile, and 33.6 μl (0.415 mmole) of pyridine was stirred 5 minutes. N-trimethylsilyl-2,6-dichloroaniline, 86.9 μl (0.456 mmole) was added. The solution was stirred at room temperature for 16 hours and the reaction monitored by thin layer chromatography and by reverse phase HPLC. The 2-chlorosulfonyl compound gradually disappeared and a new peak appeared. The reaction was about 10-30 percent complete after 16 hours. An additional 33.6 μl of pyridine was added and the solution heated at 65° C. for 4 hours and at reflux for 16 hours. The solvent was removed under nitrogen and the residue treated with 4 ml of 0.5N NaOH and stirred for 0.5 hour. The solution was extracted with CH2Cl2, acidified with concentrated HCl and filtered. The precipitate was washed with water and dissolved in CH3CN. The resulting solution was heated to reflux, filtered through silica gel and the solvent removed in vacuo to obtain 119 mg (0.321 mmole, 77.2 percent yield) of N-(2,6-dichlorophenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide as a light yellow solid. The product was further purified by washing with acetone, and recrystallizing from refluxing CH3CN to obtain 91.5 mg (0.246 mmole) of product as a white powder, m.p. 263°-265° C.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[C:7]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11]2)=[O:4].P([O-])(O)(O)=[O:28].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>ClCCl.C(O)(C)(C)C.O>[CH3:1][C:2]([CH3:25])([CH3:26])[C:3]([O:5][C:6]1[C:7]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]([OH:28])=[O:17])[CH:12]=[CH:11]2)=[O:4]
Reactant: CCCCOC(=O)c1ccc2ccc(C=O)nc2c1OC(=O)C(C)(C)C
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2ccc(C(=O)O)nc2c1OC(=O)C(C)(C)C
Yield: 64.3 %

Procedure:
A mixture of the preceding aldehyde 4 (step 3) (3.5 g, 10 mmol), sodium dihydrogen phosphate (1.7 g, 12 mmol), 2-methyl-2-butene (6.1 ml, 57 mmol) and sodium chlorite (2.6 g, 29 mmol) is stirred at 20° C. in 160 ml of a 5/1 tert-butanol/water mixture and 30 ml of dichloromethane for 12 hours. The reaction medium is concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with pure ethyl acetate so as to give 2.4 g (64%) of 8-(2,2-dimethylpropionyloxy)-7-butoxycarbonylquinoline-2-carboxylic acid 5 in the form of white crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH2:18][CH2:17]1.Cl.[NH2:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([NH:39][C:40]3[CH:45]=[C:44]([O:46][C:47]([O:49][CH3:50])=[O:48])[C:43]([CH3:51])=[CH:42][C:41]=3[F:52])=[N:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>N1C=CC=CC=1>[F:52][C:41]1[CH:42]=[C:43]([CH3:51])[C:44]([O:46][C:47]([O:49][CH3:50])=[O:48])=[CH:45][C:40]=1[NH:39][C:33]1[C:32]2[C:37](=[CH:38][C:29]([NH:28][C:24](=[O:26])[CH2:23][CH2:22][N:19]3[CH2:18][CH2:17][O:16][CH2:21][CH2:20]3)=[CH:30][CH:31]=2)[N:36]=[CH:35][N:34]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reactant: O=C(O)CCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Oc1cc(Nc2ncnc3cc(NC(=O)CCN4CCOCC4)ccc23)c(F)cc1C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
1,3-Dicyclohexylcarbodiimide (343 mg, 1.6 mmol) was added to a suspension of 3-morpholinopropionic acid (325 mg, 1.6 mmol) in pyridine (12 ml) and the mixture stirred for 10 minutes. 7-Amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (370 mg, 0.97 mmol), (prepared as described for the starting material in Example 29), was added and the mixture stirred for 32 hours. 3-Morpholinopropionic acid (57 mg, 0.29 mmol) followed by 1,3-dicyclohexylcarbodiimide (100 mg, 0.48 mmol) was added and the mixture stirred for a further 18 hours. The solvent was removed by evaporation, the residue partitioned between water and ethyl acetate and the aqueous layer adjusted to pH8 with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(3-morpholinopropionamido)quinazoline (226 mg, 48%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[C:4]([S:12][CH3:13])[CH:3]=1.[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[O:11][N:10]=[C:8]([C:6]2[N:7]=[C:2]([NH2:1])[CH:3]=[C:4]([S:12][CH3:13])[CH:5]=2)[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1cc(N)nc(C(=N)NO)c1
Product: CSc1cc(N)nc(-c2noc(C)n2)c1

Procedure:
A solution of 0.094 g 6-Amino-N-hydroxy-4-methylsulfanyl-pyridine-2-carboxamidine in 1.5 ml acetic acid anhydride was heated to reflux for 6 h. The solvent was evaporated and the solidifying residue was taken up in 1.5 ml 1N hydrochloric acid and heated to reflux for 1 h. The reaction mixture was partitioned between 2 ml 1N aqueous sodium hydroxide and ethyl acetate. The phases were separated and the organic phase was washed with water and brine dried over magnesium sulfate and evaporated. The residue triturated in ethyl acetate (1 ml) and the resulting solid was collected by filtration to yield 0.057 g of the title compound as light yellow solid MS (ISP) M+H+=223.3
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13](OCC)=O)[CH:9]([CH3:18])[CH2:8]1)=[O:5].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][N:37]=[C:36]([NH2:39])[CH:35]=2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:39][C:36]2[CH:35]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[NH:38][N:37]=2)[CH:9]([CH3:18])[CH2:8]1)=[O:5]
Reactant: CCOC(=O)C1CCC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1C
Reactant: Nc1cc(-c2ccc(F)cc2)[nH]n1
Product: CC1CC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CCC1CNc1cc(-c2ccc(F)cc2)[nH]n1

Procedure:
The title compound is prepared analogously to Example 1 by replacing trans-4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexane carboxylic acid methyl ester (Ex. 1 Step 2) with ethyl 4-(2-chloro-5-(trifluoromethyl)benzamido)-2-methyl cyclohexane carboxylate (Ex. 1.35 step 2) and by replacing 2-amino-3-picoline (Ex. 1 step 4) with 5-(4-fluorophenyl)-1H-pyrazol-3-amine. [MH]+509.40.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:21]([O-])=O)[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])[NH2:21])=[C:6]([CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCCOc2cc([N+](=O)[O-])c(C)cc2Cl)c(CCC(F)(F)F)c1O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Cl)c(CCC(F)(F)F)c1O

Procedure:
1.0 g of Raney nickel is added to a solution of 3.7 g of 3-[3-(4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy)-propoxy]-4-chloro-6-methyl-nitrobenzene in 40 ml of tetrahydrofuran and the starting substance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure and the residue is crystallised from ether/petroleum ether. 3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-aniline of melting point 111°-113° is thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH2:24])=[O:25])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)c1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1

Procedure:
0.47 mmol of the compound obtained in Example 14 and 1 g of polyphosphoric acid are heated at 85° C. for 90 minutes. The combined mixture is then hydrolyzed with a water/ice mixture and the pH of this solution brought to 11-12 using concentrated sodium hydroxide solution. After extraction with a chloroform/methanol (80/15) mixture, drying and evaporation, the expected product is purified by chromatography on a silica column, using a THF/hexane/methanol/aqueous ammonia (80/18/2/0.2) mixture as solvent.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH2:20][C:21]2[O:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]2[O:25][C:24]([NH:26][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:23][N:22]=2)[CH2:19][CH2:18]1
Reactant: Nc1nnc(CC2CC2)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnc(CC2CC2)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 158-159° C. and MS: m/e=334.3 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]#[CH:12].Cl[CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16]>O1CCCC1>[CH2:9]([NH:8][CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:34]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16])[CH2:10][C:11]#[CH:12]
Reactant: C#CCCN
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCNCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 55 °C

Procedure:
Add triethylamine (0.85 mL; 2.0 equiv; 6.13 mmoles) followed by 1-amino-3-butyne (0.38 mL; 1.5 equiv; 4.59 mmoles) to a solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (1.05 g; 1.0 equiv; 3.06 mmoles) in tetrahydrofuran (10.2 mL), and heat to 55° C. for 16 hours, then concentrate and use the 2-(but-3-ynylamino)-1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]ethanone directly in the next step: MS (m/z): 376(M+1).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)C.C1(C)C=CC=CC=1>[S:1]([C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:25]=[CH:24][O:23][C:22]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
(4-sulfamoylphenyl)boronic acid (1.76. gm, 8.77 mmol) and Potassium carbonate (2.52 gm, 18.26 mmol) were added to a stirred suspension of ethyl 3-bromofuran-2-carboxylate (Prepared according to the procedure reported in the literature EP1489077A1, 2004, 1.6 gm, 7.30 mmol) in a mixture of 80 ml of ethanol and 20 ml of toluene (80 ml:20 ml) under nitrogen atmosphere at room temperature (25° C.) in a tube. A nitrogen gas was purged to the suspension for 15 minute at room temperature (about 25° C.). To the reaction mixture was then added Tetrakis(triphenyl phosphine)Palladium(0) (0.422 gm, 0.365 mmol) at 25° C. and tube was sealed. The reaction mixture was then stirred at 100° C. for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2×100 ml). The combined organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (11.2 gm), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.2 g, 55.60%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13][C:14](O)=O.[CH3:17][NH:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13][C:14]1[N:18]([CH3:17])[C:19]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:20]=2[N:26]=1
Reactant: O=C(O)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CNc1c(N)cccc1N
Solvent: Cc1ccccc1
Product: Cn1c(Cc2c(Cl)cc(C(F)(F)F)cc2Cl)nc2cccc(N)c21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of [2,6-dichloro-4-(trifluoromethyl)phenyl]acetic acid (273 mg, 1.00 mmol) in toluene (2.0 mL) was added N,N′-carbonyldiimidazole (162 mg, 1.00 mmol) at room temperature. After the reaction mixture was stirred at 50° C. for 15 min, N2-methylbenzene-1,2,3-triamine (137 mg, 1.00 mmol) in toluene (2 mL) was added to the mixture, and the mixture was refluxed for further 60 hr. After the reaction mixture was cooled, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with 40-60% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.455 mmol, 45%) as a colorless solid. The resulting solid was recrystallized from n-hexane/ethyl acetate to give the title compound (137 mg, 0.38 mmol).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[C:21]#[N:22])[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: CCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2C#N)CC1

Procedure:
To a solution of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidine (1.57 g, 5.4 mmol) in N,N-dimethylformamide (35 ml) was added sodium cyanide (1.0 g, 20 mmol) and 18-crown-6-ether (50 mg). The mixture was heated at reflux for 15 h and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 0.72 g (45%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 272-274° C. MS m/z (relative intensity, 70 eV) 296 (M+, 4), 268 (16), 267 (bp), 204 (3), 184 (3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([F:13])=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:12][C:10]1[C:9]([F:13])=[C:4]([C:3]([CH3:14])=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c(N)cc(Br)c1F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1c(C)c(NC2CCOCC2)cc(Br)c1F
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
To a solution of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate (2.23 g, 8.08 mmol) in 1,2-Dichloroethane (32 ml) at room temperature and under nitrogen was added oxan-4-one (1.49 ml, 16.17 mmol) followed by acetic acid (2.78 ml, 48.5 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (5.14 g, 24.25 mmol) at room temperature. After stirring for 5.5 hours there was no unreacted starting material present by LCMS. Deionized water (32 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×32 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 6:4 Heptane:EtOAc) to give 2.3 g (82%) of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate as a off-white solid. LC-MS 99%, 2.13 min (3 minute LC-MS method), m/z=245.9/247.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.78 (d, J=5.9 Hz, 1H), 4.01 (dt, J=11.9, 3.4 Hz, 2H), 3.93 (s, 3H), 3.53 (td, J=11.7, 2.1 Hz, 2H), 3.49-3.42 (m, 1H), 3.34 (s, 1H), 2.04 (s, 5H), 1.48 (qd, J=11.0, 4.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 29.9 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (27 mg, 30% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD TFA-d) δ 9.40 (br s, 1H), 8.28-8.15 (m, 2H), 8.06 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.66 (dd, J=9.1, 2.8 Hz, 1H), 7.16-7.05 (m, 3H), 4.53 (d, J=11.0 Hz, 1H), 4.01 (dd, J=13.4, 4.6 Hz, 1H), 3.41-3.23 (m, 3H), 2.86 (br s, 1H), 2.23-2.15 (m, 1H), 1.99-1.88 (m, 1H), 1.79-1.66 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.78 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[OH:20][C@H:21]1[CH2:27][CH2:26][C@@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]1=[O:23].C(OCC)C>CN(C)C=O.[Ag]=O>[CH2:10]([O:9][C:7]([C:6]1[CH:18]=[CH:19][C:3]([CH2:2][O:20][C@H:21]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]2=[O:23])=[CH:4][CH:5]=1)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCOC(=O)c1ccc(CBr)cc1
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Agent: O=[Ag]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)c1ccc(CO[C@H]2CC[C@H](CCCCCC)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
In 1.5 ml of dry dimethylformamide were dissolved 180 mg of octyl p-bromomethylbenzoate and 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone, and 300 mg of silver oxide was added to the solution and the mixture was stirred overnight at room temperature to effect reaction. After the reaction, diethyl ether was added to the reacted solution to extract the reaction product. The extract was washed with a saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate. Diethyl ether was removed by distillation under a reduced pressure. The obtained crude product was purified by the silica gel column chromatography to obtain 5 mg of (2S,5S)-2-(4'-octyloxycarbonylbenzyloxy)-5-hexyl-δ-valerolactone.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:13]([CH3:20])[CH2:14][C:15](OCC)=[O:16]>CC(O)=O>[OH:16][C:15]1[N:1]([C:3]2[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=2)[C:9]([OH:11])=[O:10])[N:2]=[C:13]([CH3:20])[CH:14]=1
Reactant: NNc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2cc(C(=O)O)ccn2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carboxylic acid (306 mg, 2 mmol, PREPARATION 1) and ethyl 3-oxobutanoate (390 mg, 3 mmol) in AcOH (5 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (72 mg, 16%) as yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.72 (3H, s), 4.86 (1H, s), 7.71 (1H, d, J=4.8 Hz), 8.55 (1H, d J=4.8 Hz), 8.81 (1H, s). [M+H] Calc'd for C10H9N3O3, 220. Found, 220.