Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])[N:7]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([OH:34])=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39]1([CH3:46])[O:43][CH:42]([CH2:44][NH2:45])[CH2:41][O:40]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl.O.C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])[N:7]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:45][CH2:44][CH:42]2[CH2:41][O:40][C:39]([CH3:46])([CH3:38])[O:43]2)=[O:34])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OCC(CN)O1
Reactant: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)O)c3)c(F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)NCC4COC(C)(C)O4)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid (300.0 mg, 0.60 mmol), 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (93.8 mg, 0.71 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (136.6 mg, 0.71 mmol), 4-dimethylaminopyridine (87.3 mg, 0.71 mmol) and 1-hydroxybenzotriazole (96.6 mg, 0.71 mmol) in THF and DCM was stirred at room temperature overnight. Ethyl acetate and water were added, and the organic phase was washed with brine, dried over MgSO4. and evaporated at reduced pressure. HPLC purification (10-90% aqueous acetonitrile) afforded pure title compound (270 mg, 73%). 1H-NMR (DMSO-d6) δ 8.93 (s, 1H), 8.88 (s, 1H), 8.72 (t, J=6.07.66 (m, 2H), 8.30 (d, J=5.7 Hz), 8.13 (t, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.69 (m, 2H), 7.19 (d, J=14.7 Hz, 1H), 6.96 (d, J=10.2 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J=5.7 Hz, 1H), 6.41 (s, 1H), 3.95 (t, J=6.3 Hz, 1H), 3.68 (t, J=6.0 Hz, 1H) 3.28-3.45 (m, 2H), 1.314 (s, 3H), 1.27 (s, 9H), 1.22 (s, 3H); MS LC-MS [M+H]+=617.3, RT=2.54 min.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=[C:3]1SC.[C:20]1([CH2:26][C@H:27]([NH2:30])[CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[NH2:30][C@@H:27]([CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][NH:29][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c([N+](=O)[O-])c(=O)n1C
Solvent: CN(C)C=O
Product: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-2-methylsulfanyl-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (0.31 mmol) in dimethylformamide (DMF) was added 3-phenyl-propane-1,2 (S)-diamine (0.92 mmol) and stirred overnight at room temperature. The DMF was removed under vacuum, and the product purified on silica as a mixture of isomers. M+1=381.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].CCCCC.[C:10]([N:14]=[N:15][C:16](Cl)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].O>C(O)(C)C>[C:10]([N:14]=[N:15][C:16]([N:3]=[C:2]=[O:1])([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: N#C[O-]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: [K+]
Solvent: CCCCC
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N=NC(C)(C)N=C=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 40.5 grams (0.5 moles) of potassium cyanate in 250 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added the above pentane solution of 2-t-butylazo-2-chloropropane over 15 minutes, holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 2 hours at room temperature, 500 ml of water added and the reaction stirred until the salts dissolved. The pentane layer was separated, washed with 250 ml water, 250 ml 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 59.6 grams (70% overall crude yield) of a yellow liquid. The product had a strong broad band at 2225 cm-1 in its infrared spectrum.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([CH3:20])(O)[CH3:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(Cl)(Cl)Cl.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[C:30]([O:40][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)OCC(C)CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-butanol (4.68 g, 15.3 mmol) and triethylamine (2.23 g, 22.3 mmol) in chloroform (20 ml) was added decanoyl chloride (3.5 g, 18.4 mmol, 1.2 eq) dropwise at 0° C. The reaction was stirred at ambient temperature for 4 hours. The solvent was removed. The residue was purified by flash chromatography over a silica gel column (SiO2, 65 g, eluted with DCM, 1 l, 1% CH3OH in DCM, 1 l). The product thus purified weighed 5.7 g (80%) as an oil. This oily product was converted to the fumarate salt in ethanol with fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g, m.p.=133°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 98.6 %

Procedure:
4-Fluoro-3-nitrophenyl isocyanate (15 g, 82.40 mmol) was dissolved in 200 mL of methylene chloride under a nitrogen atmosphere. A solution of 3-trifluoromethyl aniline (13.27 g, 82.40 mmol) dissolved in 50 mL of methylene chloride was added drop-wise. The reaction was left to stir for 12 hours. During this time, a yellow precipitate formed. This solid was collected by filtration and dried under vacuum to give 27.9 g of pure product (98% yield). 1H NMR (400 MHz CDCl3) δ: 7.25 (dd, 1H), 7.39–7.46 (m, 2H), 7.55 (d, 1H), 7.63–7.67 (m, 1H), 7.94 (s, 1H), 8.36 (dd, 1H), 9.14 (s, 1H), 9.21 (s, 1H). MS: m/z 366 (M+Na+).
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Li]CCCC.C[O:19][CH:20](OC)[C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](C(OC)=O)=[CH:26][C:25]=2[CH:33]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[C:3](=[O:4])[O:5][C:6]([C:27]2[O:28][C:24]3[CH:23]=[CH:22][C:21]([CH:20]=[O:19])=[CH:33][C:25]=3[CH:26]=2)=[C:8]([CH3:9])[C:7]=1[OH:10]
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: COC(=O)c1cc2cc(C(OC)OC)ccc2o1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(-c2cc3cc(C=O)ccc3o2)oc(=O)c(C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-methyl-3-oxopentanoate (7.5 g) in THF (50 ml) was slowly added to a suspension of NaH (2.1 g) in THF (200 ml), and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (32 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 5-(dimethoxymethyl)benzofuran-2-carboxylate (10 g) in THF (50 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution (30 ml) was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (100 ml) and THF (100 ml), a 4 N lithium hydroxide aqueous solution (25 ml) was added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (50 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 3,5-dimethyl-6-(5-formylbenzofuran-2-yl)-4-hydroxy-2H-pyran-2-one
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[C:18]1([N:24]2[CH:28]=[CH:27][CH:26]=[C:25]2[CH:29]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[CH3:7]/[C:6](=[CH:29]/[C:25]1[N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:28]=[CH:27][CH:26]=1)/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cccn1-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C\c1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyl 2-phosphonopropionate (0.714 mol, 153 ml) was dissolved in THF (75 ml) and added slowly to NaH (1.0 mol, 24.3 g) in THF (60 ml) at 0° C. The mixture was slowly warmed to room temperature and stirring was continued for 1 h after gas evolution had ceased. The temperature was lowered to −10° C. and a solution of the above described 1-Phenylpyrrole-2-carbaldehyde (0.665 mol, 113.0 g) in 200 ml of THF was added dropwise. The flask and contents were warmed to room temperature over a 30 minute period resulting in a thick precipitate which decoupled the magnetic stirrer. A saturated solution of NH4Cl (100 ml) was added cautiously dissolving the precipitate to give a two phase solution. After evaporating the THF, the crude product was extracted with ether (2×200 ml). The extract was washed with brine solution, dried over MgSO4, and solvents were removed on a rotoevaporator. Yield: 178 g of product as a white solid (98%). The title compound was analysed by 1H-NMR and 13C-NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH:10]([NH:15][CH:16]([C:23]([O:25][CH3:26])=[O:24])[CH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=1)[CH2:38]Br>C(#N)C.C(OCC)(=O)C.O.CCCCCC>[CH2:1]([O:8][C:9](=[O:27])[CH:10]([NH:15][CH:16]([C:23]([O:25][CH3:26])=[O:24])[CH2:17][C:18]1[N:19]([CH2:38][C:37]2[CH:36]=[C:35]([Cl:34])[CH:42]=[C:41]([Cl:43])[CH:40]=2)[N:20]=[CH:21][CH:22]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1cc[nH]n1)NC(CC(C)C)C(=O)OCc1ccccc1
Reactant: Clc1cc(Cl)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C(Cc1ccnn1Cc1cc(Cl)cc(Cl)c1)NC(CC(C)C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The pyrazole 53-6 (300 mg, 0.803 mmol) was dissolved in acetonitrile (8 mL). K2CO3 (212 mg, 1.61 mmol) and 3,5-dichlorobenzyl bromide (231 mg, 0.964 mmol) were added, and the resulting mixture was warmed to 50° C. and stirred overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. Combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Purification by column chromatography (ISCO chromatography system, SiO2, elution with 10 to 20% ethyl acetate in hexane) provided two sets of fractions. A pale yellow oil (152 mg, Rf=0.5, 40% ethyl acetate in hexane) provided a 1H NMR consistent with the previously isolated 53-7a. Another yellow oil (38 mg, mixture of spots by TLC) provided a 1H NMR consistent with a mixture of compounds. Further purification of this material by column chromatography (ISCO chromatography system, SiO2, elution with 10 to 20% ethyl acetate in hexane) provided a colorless oil (23 mg, Rf=0.58, 40% ethyl acetate in hexane) consistent with 2-{2-[2-(3,5 dichloro-benzyl)-2H-pyrazol-3-yl]-1-methoxycarbonyl-ethylamino}-4-methyl-pentanoic acid benzyl ester 53-7b. The proposed structure was supported by 2D NMR methods (NOESY, HMBC and HMQC).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[OH:28].N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH:18]([F:17])[F:29])=[C:21]([OH:28])[CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(OC(F)F)c(O)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-(difluoromethoxy)-3-hydroxybenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product was scraped and collected. (100 mg)
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCC.[C:33]([N:46]=[C:47]=[S:48])(=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:65]=[CH:66][C:67]([NH:68][C:47]([NH:46][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[S:48])=[CH:69][CH:70]=1
Reactant: CCCCCCCCCCCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available dodecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and dodecanoyl isothiocyanate was prepared using the resultant dodecanoyl chloride as a starting compound according to the description of the literature. Dodecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (58 mg, yield 60%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:10]2)[N:3]=1.[CH3:24][O-:25].[Na+].CO>COCCOC>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:9]([C:4]2[N:3]=[C:2]([O:25][CH3:24])[C:7]([F:8])=[CH:6][N:5]=2)[CH2:10]1
Reactant: Fc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(N2CCC(NCc3ccc(Cl)cc3Cl)C2)ncc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Dissolve (S)-[1-(4-chloro-5-fluoropyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (318 mg, 0.84 mmol) in dry 1,2-dimethoxyethane (20 mL) and add dropwise sodium methoxide in methanol (25% w/v, 1.9 mL, 8.46 mmol). Stir at 70° C. overnight. Add aqueous 2 N hydrochloric acid to a pH of about 6-7 and extract with 30:70 isopropanol:chloroform. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulphate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give the title compound (130 mg, 41%). Dissolve the title compound in methanol and add 1 M hydrogen chloride in diethyl ether (350 μL, 0.35 mmol), triturate, and concentrate to give the hydrochloride salt of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.96 (1H, s), 7.65-7.76 (2H, m), 7.51 (1H, dd, J=8.2, 1.6 Hz), 4.45-4.56 (2H, m), 4.17 (2H, d, J=6.4 Hz), 3.99-4.10 (2H, m), 3.85-3.95 (4H, m), 2.61 (1H, d, J=6.4 Hz), 2.39 (1H, d, J=6.1 Hz); MS (ES): m/z=371 [M+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pt].C(OCC)(=O)C.ClCCl>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Reaction time: 8 h

Procedure:
A hydrogenation flask was charged with platinum on carbon (5%, 2 g) followed by a solution of tert-butyl 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propylcarbamate in ethyl acetate (200 mL) and dichloromethane (75 mL). The reaction mixture was shaken under H2 at 46 PSI (3.2×105 Pa) overnight and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to give 9.3 g of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.N1C=CC=CC=1>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCC1CO1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OCC2CO2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A mixture of methyl 4-hydroxyphenylacetate (4.98 g, 0.030 mol), epichlorohydrin (23.5 ml, 0.30 mol) and pyridine (121 μl, 1.5 mmol) was stirred at 85° C. for 2 hours. The reaction mixture was cooled, and excess epichlorohydrin was distilled off (rotavapor). The residue was taken up in ethyl acetate, washed with brine and dried (Na2SO4). The solution was filtered and concentrated. The dark residue was chromatographed (silica, hexane/ethyl acetate 7:3) to give 2.25 g (34%) of a colourless oil. 1H (300 MHz) and 13C NMR (75 MHz) spectra were in accordance with the structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[NH4+].[Cl-].[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1>CCOCC>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:13][CH2:12][CH2:11][CH2:15][CH2:15][CH2:11][CH2:12][CH2:13][CH2:7][CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: Clc1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccccc1Cl
Yield: 47.4 %

Procedure:
To 0.05 g (0.065 mmoles) of [NitriphosCl]PF6 and 2.00 g (13.61 mmoles) of o-dichlorobenzene in 20 mL of ether at 0° C. was added 19.65 g (13.70 mmoles) of 0.697 mmoles/g of n-dodecylMgBr in THF. The mixture was refluxed overnight, poured into NH4Cl solution, extracted with ether, dried over MgSO4, and the solvent was removed by rotary evaporation. The residue was distilled (101° to 105° C./0.14 mm) to give 1.806 g (6.44 mmoles, 47.4%) of 1-chloro-2-dodecylbenzene. 1H NMR (200 MHz, CDCl3): δ7.4-7.0 (m, 4H), 2.70 (t, J=8 Hz, 2H), 1.6 (m, 2H), 1.3 (br s, 18H), 0.9 (m, 3H). High resolution mass spectrum: calculated for C18H29Cl: 280.1957; Found: 280.1954. Elemental analysis: Calculated for C18H29Cl: C, 76.97; H, 10.41; Found: C, 77.11; H, 10.47. IR(neat): 2935s, 2860s, 1478m, 1470m, 1460sh, 1445m cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=O)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.[CH:26]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][O:27]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(#N)C>[CH:26]12[CH2:32][CH:29]([N:30]([CH2:18][C:16]3[CH:15]=[N:14][C:13]4[N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=5)[C:9](=[O:23])[N:10]5[N:22]=[CH:21][N:20]=[C:11]5[C:12]=4[CH:17]=3)[CH2:31]1)[CH2:28][O:27]2
Reactant: C1OC2CNC1C2
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CC5CC4CO5)cnc32)cc1
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
6-(4-Methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbaldehyde (49 mg, 0.15 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane (49 mg, 0.36 mmol), ACN (1 mL), TEA (0.051 mL, 0.37 mmol) and acetic acid (0.040 mL, 0.69 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 18 h at room temperature. The mixture was diluted with methanol, filtered, and purified by preparative HPLC to afford the title compound (35 mg, 45%) as the trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.25 (d, J=11.42 Hz, 1H), 2.43 (br s, 1H), 3.44-3.63 (m, 2H), 3.76 (s, 3H), 3.91 (d, J=10.42 Hz, 1H), 4.37-4.53 (m, 3H), 4.56-4.65 (m, 1H), 4.73 (s, 1H), 5.74 (s, 2H), 6.76-6.91 (m, 2H), 7.60 (d, J=8.78 Hz, 2H), 8.38 (s, 1H), 8.83 (s, 1H), 9.08 (s, 1H). [M+H]=419.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].I[CH2:11][CH3:12]>CCCCCC.C1COCC1>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:9])[CH3:12]
Reactant: OCCCCCO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
NaH (4.2 g, 0.11 mol) was washed with hexane and then suspended in dry THF (400 mL). Pentane-1,5-diol (10.4 g, 0.1 mol) in THF (50 mL) was added and stirred for 1 h at room temperature. Iodoethane (17.2 g, 0.11 mol) in THF (50 mL) was added and the mixture was refluxed for 48 h. After evaporation of the solvent, the residue was dissolved in EtOAc (300 mL). The organic phase was washed with water (2×50 mL), brine (50 mL), and dried (Na2SO4). The residue was purified by column chromatography on alumina with 10% 2-propanol in hexane, and then Kugelrohr distillation to give the title product (2) (9.4 g, 71%); bp 45° C.-46° C./0.005 torr; IR(neat): 3400 (broad) and 1115 cm-1 ; 1H NMR: 1.22 (t, 3H, J=6.8 Hz), 1.42 (m, 2H), 1.56 (m, 4H), 3.43 (t, 4H, J=5.8 Hz), 3.48 (q, 2H, J=6.8 Hz), and 3.58 ppm (b s, IH).