Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[Br:11]Br.C(OC(=O)C)C>C(O)(=O)C.Br>[BrH:11].[Br:11][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[O:10]
Reactant: CC(=O)c1ccncc1F
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccncc1F
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to −78° C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0° C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at −78° C. for 1.5 h. The solution was warmed to −30° C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3×400 mL) and the organic layers were washed with brine (4×200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fluoropyridin-4-yl)ethanol (10 g, 70.3 mmol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3-fluoro-4-acetyl pyridine (6.9 g, 70%) that was used directly in the next step. To a stirred solution of 3-fluoro-4-acetylpyridine (5.3 g, 38.1 mmol) in glacial acetic acid (14 mL) and 48% hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60° C. for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82% yield (9.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:23]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1)=O.C(O)=O.[CH:32]([NH2:34])=O>>[N:10]1([C:8]([C:6]2[CH:7]=[C:2]3[C:3]([C:17]([C:19]4[N:23]5[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[N:34][CH:32]=[N:1]3)=[CH:4][CH:5]=2)=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC=O
Reactant: Nc1cc(C(=O)N2CCCCCC2)ccc1C(=O)c1cnc2ccc(F)cn12
Solvent: O=CO
Product: O=C(c1ccc2c(-c3cnc4ccc(F)cn34)ncnc2c1)N1CCCCCC1
Temperature: 170 °C

Procedure:
A solution of example 30 (50 mg) in a mixture of formic acid (160 μL, 32 equiv.) and formamide (640 μL, 122 equiv.), under argon atmosphere, was heated through microwave irradiation for 25 min at 170° C.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]CCCCCCN(C)C.[K].O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[CH3:22][N:23]([CH3:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Reactant: CN(C)CCCCCCOCCCCCCN(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCCCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 6-dimethylaminohexyloxide in N.N-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(6-dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[CH:4]=[C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: C1CNCCN1
Reactant: COc1cc2ccc(CCl)cc2c(OC)c1OC
Product: COc1cc2ccc(CN3CCN(Cc4ccc5cc(OC)c(OC)c(OC)c5c4)CC3)cc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxynaphthalene (226 mg) and piperazine (37 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][NH2:2].[C:3]1(=[O:9])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1>C1C=CC=CC=1.N1C=CC=CC=1>[C:3]([OH:8])(=[O:9])[CH2:4][CH2:5][C:6]([OH:1])=[O:7].[NH2:2][OH:1]
Reactant: O=C1CCC(=O)O1
Agent: NO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This example that demonstrates how this method could be performed. Part 1: To a solution of 2 g hydroxy amine in 100 ml dry benzene and 100 ml pyridine, 9.4 g succinic anhydride is added and the reaction mixture stirred at room temperature for 2 h and refluxed for 2 h. The solvent is evaporated under vacuum and the residue is purified by flash chromatography using silica gel.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:27])=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[F:26])[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:27][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([F:15])[C:11]=1[C:16]1[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)ccc(OCc3ccccc3)c2F)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(-c2c(F)ccc(O)c2F)n1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) in methanol (0.1 M) was added 10% Pd/C (0.1 equiv.) in ethyl acetate. The reaction was placed under an atmosphere of hydrogen and stirred for 2 hours. Upon completion, the solution was filtered over a pad of Celite, the pad was washed with methanol, the filtrate was concentrated in vacuo to give methyl 6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinate as a grey oil in 86% yield. LC/MS=284.0 (M+H), Rt=0.90 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([N+:1]([O-:4])=[O:2])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To a mixture of 370 ml of conc. sulfuric acid and 61.2 ml of 70% nitric acid, 36.6 g of 2,4,5-trifluoro-3-methylbenzoic acid was added at 55° to 70° C. by portions with stirring. After 2 hours at room temperature, the reaction mixture was poured into ice and extracted with isopropyl ether. The combined extracts were washed with brine, dried and evaporated to give 30.6 g of the desired compound as yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]2[CH2:9][CH2:10][N:11]=[C:7]2[CH:6]=[C:5]([Cl:12])[N:4]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>>[ClH:12].[CH3:2][C:3]1[N:8]2[CH2:9][CH2:10][N:11]=[C:7]2[CH:6]=[C:5]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: C1CCNC1
Reactant: CC1=NC(Cl)=CC2=NCCN12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NC(N2CCCC2)=CC2=NCCN12
Reaction time: 3 h

Procedure:
A reaction mixture was prepared from 2.0 g. of 5-methyl-7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride and 0.7 g. of pyrrolidine in a saturated aqueous sodium bicarbonate solution. The reaction mixture was allowed to remain at ambient temperature for about three hours, after which time the solvent was removed in vacuo. The resulting residue was heated in ethanol. Solids were separated by filtration and dilute aqueous hydrochloric acid was added to the ethanolic filtrate. The solvent was removed from the filtrate in vacuo to yield 5-methyl-7-pyrrolidino-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride formed in the above reaction which decomposed above 245° C. after recrystallization from an ethanol-ethyl acetate solvent mixture.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[C:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
tert-Butyl acetoacetate (23.8 ml) was added dropwise over 15 minutes to a stirred suspension of sodium hydride (8.9 mg) in tetrahydrofuran at 0° C. under nitrogen atmosphere. After stirring for 20 minutes n-butyl lithium in hexane (111 ml) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-bromobenzyl bromide (14.19 g) in tetrahydrofuran (100 ml) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with HCl (6M, 5 ml). The resulting mixture was extracted with diethyl ether. The organic phases were combined, washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. The residue was thus obtained was purified via flash chromatography using 5% ethyl acetate in hexane as eluant to furnish the title compound (37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH3:24].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH3:24])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: CNC
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added dimethylamine in THF (0.65 ml, 1.29 mmol, 2.0M THF) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (112 mg, 52% yield). Rf=0.65 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C18H25Cl N2 O2, 336.8, found, 337.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ (d, J=1.7 Hz, 1H), 7.46 7.40 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 3.68 (s, 2H), 3.06-2.96 (m, 1H), 2.92 (s, 6H), 2.78-2.68 (m, 2H), 2.62-2.46 (m, 6H), 1.76-1.68 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 175.5, 146.2, 135.5, 133.9, 130.7, 126.5, 123.7, 72.9, 56.8, 54.3, 40.9, 37.4, 36.1, 28.5, 23.7.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.7 %

Procedure:
(+/−)-Cis-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (5.43 g, 19.65 mmol) was dissolved in THF (50 mL) and added triphenylphosphine (5.41 g, 20.64 mmol) and stirred at RT overnight. Added water (6 mL) and warmed to 60 deg. C. for ˜6 hrs. THF was removed in vacuo and the aqueous portion was diluted with 1N HCl (50 mL) and extracted 5× with EA (20 mL) to remove all of triphenylphosphine and triphenylphosphine oxide. The aq. portion was cooled to ˜5 deg. C. and adjusted to pH of 10 by dropwise addition of 1N NaOH. Extracted with DCM (5×) and the organic extractions were combined, dried (Na2SO4) and concentrated. This material was combined with another similar reaction performed on 22.8 mmol scale to afford a total of 8.0 g (75%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.36 (5 H, m), 5.34 (2 H, m), 3.45-3.73 (5 H, m), 3.42 (3 H, s), 3.13-3.22 (1 H, d, m), 1.28-1.31 (2 H, br s). LCMS: M+1=251, Rt=1.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:6]=[C:5]2[C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.[OH-].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:5]2[C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 4-[5-chloro-3-(3-nitrobenzoyl)indol-1-yl]butyrate (2.00 g), 1N aqueous sodium hydroxide (7.5 ml), methanol (35 ml) and 1,4-dioxane (35 ml) was stirred at 25° C. for 6 hours. After evaporation of the organic solvent, 1N hydrochloric acid (15 ml) was added to the aqueous solution and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with hot ethanol to give 4-[5-chloro-3-(3-nitrobenzoyl)indol-1-yl]butyric acid (1.77 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:6]=2[CH:18]=1.[H-].[Na+].[CH2:22](I)[CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([N:12]([CH:7]1[C:6]2[CH:18]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:19])[C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)[S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCI
Reactant: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C1CCCOc2c(C)cc(Cl)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of 0.8 g (2.6 mmol) of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 ml of DMF was added dropwise under nitrogen to a suspension of 0.1 g (2.7 mmol) of 80 percent sodium hydride in 8 ml of DMF. After stirring at RT for 30 min, 0.68 g (3.7 mmol) of butyl iodide was added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. After washing the organic phase with dil. hydrochloric acid in water, and drying over magnesium sulfate, it was concentrated in vacuo. 0.9 g of 5-(N-butyl-N-ethylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 83-87° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[NH2:34][CH:35]([CH3:38])[CH2:36][OH:37].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:34][CH:35]([CH3:38])[CH2:36][OH:37])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC(C)CO
Yield: 64.6 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (200 mg, 0.40 mmol), 2-amino-1-propanol (0.06 mL, 0.80 mmol), WSC hydrochloride (230 mg, 1.20 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol), to obtain 144 mg of the title compound as a white solid (65%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C>C(O)=O>[NH2:7][C@@H:8]([C@H:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:17]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1)=[O:27]
Reactant: C#Cc1ccc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)cc1
Solvent: O=CO
Product: C#Cc1ccc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)cc1
Temperature: 50 °C
Yield: 97.3 %

Procedure:
A suspension of [(1S,2S)-1-(4-ethynyl-phenylcarbamoyl)-2-phenyl-propyl]-carbamic acid tert-butyl ester (300 mg, 0.79 mmol) in formic acid (5 mL) was heated to 50° C. for 1 hour. The reaction was concentrated in vacuo, basified with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (2S,3S)-2-amino-N-(4-ethynyl-phenyl)-3-phenyl-butyramide as a foam (214 mg, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1)O.S(Cl)([Cl:19])=O>>[Cl:19][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1)[C:2]([CH3:16])([CH3:15])[CH3:1]
Reactant: CC(C)(C)c1ncc(C(O)C(C)(C)C)cn1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)c1ncc(C(Cl)C(C)(C)C)cn1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propan-1-ol (19.37 g) in thionyl chloride (125 cm3) was heated at the reflux temperature for 30 minutes. After cooling to the ambient temperature, the excess thionyl chloride was removed by evaporation under reduced pressure, and the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulphate, concentration of the organic solution by evaporation of the solvent under reduced pressure gave 1-chloro-2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propane (20.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.[CH3:24]I>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: COc1ccc(N(C)CCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of (4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and methyl iodide (0.49 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4 methoxyphenyl)-N-methyl (3-(naphthalen-2-yloxy)propyl) amine, crystallized as yellow solid, m.p. 112° C., (yield 0.69 gm, 94%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C[Si](C)(C)[O-:28].[K+]>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=2)[C:12]([C:15]([NH2:16])=[O:28])=[N:13][CH:14]=1
Reactant: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)n1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)n1
Temperature: 100 °C

Procedure:
A suspension of 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carbonitrile (51 mg, 0.152 mmol) and potassium trimethylsilanolate (486 mg, 3.79 mmol) in dioxane (3 mL) was heated to 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO, filtered, and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C19H27N6O[M+H]+ 355. found 355. 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.56 (s, 1H), 7.92 (s, 1H), 7.88-7.80 (m, 2H), 7.70 (d, J=2.5 Hz, 1H), 7.58-7.54 (m, 1H), 7.34 (s, 1H), 6.76 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 3.81 (br s, 1H), 2.68 (q, J=7.5 Hz, 2H), 1.86-1.79 (m, 2H), 1.73-1.67 (m, 1H), 1.67-1.54 (m, 3H), 1.45-1.35 (m, 2H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 180 parts of isopropanol and 300 parts of water and 200 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C. resulting in the evolution of nitrogen. The mixture is cooled, 400 parts of water are added and the product is filtered off. 192 parts (a practically quantitative yield) of 3,5-dichloro-nitro-benzene, of melting point 60°-62° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].N>[Ni].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
A slurry of Raney nickel in methanol was added to a solution of 3,5-difluorobenzonitrile (12.0 g, 0.0863 mole) in methanol (100 ml) saturated with ammonia and the mixture was hydrogenated for 2.5 hours at 50 pounds pressure. The solution was decanted from the catalyst and the catalyst washed four times with methanol and decanted. The combined decanted solvent was evaporated and the residue dissolved in ethyl acetate and extracted twice with lN hydrochloric acid (50 ml). The acid solution was made basic with 10% sodium hydroxide and extracted with three portions of ethyl acetate. The ethyl acetate was washed with water, brine, dried over sodium sulfate and the solvent removed to give 3,5-difluorobenzylamine as an oil (12.3 g, 100%).