Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:3]=1.C[O:19]C(OC)N(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:19])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-methylpyridin-2-yl)-2-nitrotoluene (3.42 g) in N,N-dimethylformamide (20 ml) was added N,N-dimethylformamide dimethyl acetal (2.59 ml), and the mixture was stirred at 150° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (80 ml) and water (80 ml). Sodium metaperiodate (10.59 g) was added to the solution, and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 0-1% ethanol in dichloromethane) to give 4-(4-methylpyridin-2-yl)-2-nitrobenzaldehyde (3.58 g).
Reaction SMILES: C1(O[C:8](=[O:33])[CH2:9][C@H:10]([O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C=CC=CC=1.Cl[Si](C)(C)C>[Zn].CCOCC>[CH2:25]([C:24]1[C:23](=[O:32])[O:22][C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:8]=1[OH:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)OC(=O)C(Br)CCCCCC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
In a flame-dried flask under N2 a mixture of 336 mg (5.14 mmol) zinc and 510 mg (0.99 mmol) (R)-3-[(2-bromo-1-oxoocty)oxy]tetradecanoic acid phenyl ester in 5.0 ml 20% v:v Et2O:chlorotrimethylsilane was heated at reflux with rapid stirring for 20 minutes. The mixture was cooled to room temperature and suction filtered through a coarse fritted funnel, using a pad of celite, and washing with 5 ml Et2O. The homogenous filtrate was cooled in an ice/H2O bath and 5 ml tap H2O was added with stirring. After 10 min, the mixture was poured into 50 ml tap H2O and extraction with 3×25 ml Et2O was performed. The combined organic layers were washed with 25 ml brine and dried over MgSO4. The Et2O was removed by rotary evaporation, giving a white solid. The solid was stirred with 6.0 ml hexanes for 30 min, followed by suction filtration through a medium fritted funnel. The product was washed with 2.0 ml hexanes and dried under 26" vacuum at room temperature for 1.5 h, giving 235 mg (67%) (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one as a white powder, mp=109°-111° C.; [α]20D=-43.5° (1% in dioxane).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH2:3][CH3:4])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH:1]([NH:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH:9]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)Cc1cccc(N)c1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCC(C)NC(=O)Cc1cccc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
20.6 g (0.1 mol) of 3-amino-phenylacetic acid sec.-butylamide were dissolved in 100 ml of pyridine. 10.75 g (0.1 mol) of dimethylcarbamic acid chloride were added thereto. The mixture was stirred for a further 2 hours at room temperature and 2 hours at 50° to 60° C. The residue which remained after distilling off the pyridine under reduced pressure was stirred with very dilute hydrochloric acid, filtered off and then recrystallized from butyl acetate. 17 g (61.5% of theory) of 3-(N',N'-dimethylureido)-phenylacetic acid sec.-butylamide of melting point 170-171° C were obtained.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[OH:16])[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[N:6]=[CH:7][CH:8]=[CH:9]2
Reactant: Oc1cccc2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2cccnc12
Temperature: 25 °C
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.58 mL, 1 equiv) and quinolin-8-ol (Aldrich, 900 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.86 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow syrup (870 mg, 54%). This crude product was used for next step directly.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:12]([CH:11]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH3:14]
Reactant: CCCCC(=O)OCC
Reactant: CC(=O)c1ccccc1
Product: CCCC(C(=O)OCC)C(C)(O)c1ccccc1

Procedure:
A 10 milligram sample of the prepared hydroxy-ester is pyrolyzed in an open tube at 250° C. for 5 minutes. Examination of the pyrolyzate by G.C., L.C. and T.L.C. indicates >90% decomposition to form a 1:1 mixture of acetophenone and ethyl valerate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1>CCO.N1C=CC=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of 2-amino-4-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 118, Step B) (20 mg, 0.07 mmol) in EtOH (1.0 mL), pyridine (0.1 mL) and 10% Pd/C (6 mg) under H2 (atmospheric pressure) was stirred overnight at room temperature. The mixture was filtered through a Celite pad which was thoroughly washed with EtOH. The combined filtrate was evaporated and purified on a silica gel column with CH2Cl2/MeOH, 20/1 and 10/1, as eluent to give the title compound as a white solid (16 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][CH2:24][OH:23])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as a brown solid. MS 512 (MH+).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([OH:42])[CH:41]=1)[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:36](=[O:37])[C:35]1[CH:34]=[C:33]([OH:32])[CH:41]=[C:40]([OH:42])[CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(O)cc(O)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 37.6 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 87 mg (0.562 mmol) of 3,5-dihydroxybenzoic acid, 143 mg (0.561 mmol)of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (99 mg, 38%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.41, FD-MS: M+ =563.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Br:16]Br>O1CCOCC1>[Br:16][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a stirred 60° C. dioxane (35 mL) solution of 1-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethanone (2.06 g, 8.7 mmol) was rapidly added Br2 (1.48 g, 9.2 mmol). After one hour, the solution was cooled, concentrated and diluted with H2O. After filtration, the product was washed thoroughly with H2O, then with i-PrOH (9 mL), and air-dried to obtain the title compound (2.43 g, 84%).
Reaction SMILES: [Li]CCCC.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:21][CH:22]=2)[N:17]=1.[C:30](=[O:32])=[O:31]>C1COCC1>[Cl:15][C:16]1[C:25]([C:30]([OH:32])=[O:31])=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:28])([F:27])[F:29])=[CH:21][CH:22]=2)[N:17]=1
Reactant: FC(F)(F)c1ccc2ccc(Cl)nc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
11 ml of BuLi (1M in hexane) were added dropwise at −78° C. to a solution of 1.9 ml (11 mmol) of DIPEA in THF (77 ml). After stirring for 30 min at −78° C., a solution of 2.31 g (10 mmol) of 2-chloro-7-(trifluoromethyl)quinoline in THF (30 ml) was added and stirring was carried out for a further 30 min at −78° C. The reaction solution was then poured onto finely divided, solid CO2. After heating to RT, most of the THF was removed in vacuo. A 1M aq. NaOH soln. was then added and the phases were separated. The aqueous phase was acidified with 10% hydrochloric acid and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 2.12 g (7.7 mmol, 71%) of 2-chloro-7-(trifluoromethyl)quinoline-3-carboxylic acid, which was reacted further without additional purification.
Reaction SMILES: [C:1](=O)=O.[CH:4]1([C:7]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1.C[Mg]Br>C1COCC1.CCOCC>[CH:4]1([C:7]2[C:12]([CH:13]([OH:14])[CH3:1])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: O=C=O
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dry ice chilled solution of 0.75 g (2.57 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde in 5 ml THF was dropped a solution of 1.11 ml (3.33 mmol) 3M methylmagnesium bromide in 2.5 ml THF. The reaction mixture was allowed to warm to RT and it was stirred for 15 min at this temperature. The reaction mixture was then taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/dichloromethane 1:6, to give 384 mg of pure [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][O:19][CH:20]3[CH2:25][N:24]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH2:23][CH:22]([OH:36])[CH:21]3[C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:54]=[CH:53][C:47]5[N:48]([CH3:52])[CH2:49][CH2:50][O:51][C:46]=5[CH:45]=4)=[CH:39][CH:38]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O[CH2:65][CH2:66][N:67]([CH3:78])[S:68]([C:71]2[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][CH:72]=2)(=[O:70])=[O:69])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][O:19][CH:20]3[CH2:25][N:24]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:27])=[O:28])[CH2:23][CH:22]([O:36][CH2:65][CH2:66][N:67]([CH3:78])[S:68]([C:71]4[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][CH:72]=4)(=[O:70])=[O:69])[CH:21]3[C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:54]=[CH:53][C:47]5[N:48]([CH3:52])[CH2:49][CH2:50][O:51][C:46]=5[CH:45]=4)=[CH:39][CH:38]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)CC(O)C3c3ccc(Oc4ccc5c(c4)OCCN5C)cc3)cc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)CC(OCCN(C)S(=O)(=O)c4ccc(C)cc4)C3c3ccc(Oc4ccc5c(c4)OCCN5C)cc3)cc21
Temperature: 25 °C

Procedure:
95 mg of sodium hydride dispersion (60%) are added to a solution of 145 mg of 5-[4-(3-methoxypropyl)3,4 -dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(4-methyl-3,4-dihydro-2 H-benzo[1,4]oxazin-7-yloxy)phenyl]-1-(toluene-4-sulphonyl)piperidin-3-ol and 740 mg of 2-[methyl(toluene-4 -sulphonyl)amino]ethyl toluene-4-sulphonate in 5 ml of tetrahydrofuran while stirring at room temperature. The reaction mixture is stirred at 45° C. for 72 hours. The mixture is poured into 1M aqueous sodium bicarbonate solution (5 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed successively with water (2×10 ml) and brine (1×10 ml), dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO2 60F). Rf=0.08 (EtOAc/heptane 1:1); Rt=5.83.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[F:32].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:27]([C:26]1[CH:25]=[C:24]([F:32])[C:23]([CH2:22][NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=3)[N:3]=2)=[C:30]([F:31])[CH:29]=1)#[N:28]
Reactant: CC(C)NC(=O)Cn1cc(Nc2nccc(Cl)n2)cn1
Reactant: N#Cc1cc(F)c(CN)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(C#N)cc3F)n2)cn1

Procedure:
A solution of 2-(4-(4-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide (120 mg, 0.41 mmol) (II-1, prepared by Procedure D), 4-(aminomethyl)-3,5-difluorobenzonitrile (68 mg, 0.41 mmol) (III-1, prepared by Procedure E) and TsOH (56 mg, 0.33 mmol) in dioxane (2 mL) was heated to 160° C. for 2 h then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with Na2CO3(aq), dried (Na2SO4), concentrated in vacuo and purified by prep. TLC (5-10% v/v MeOH/DCM) to afford 2-(4-((4-((4-cyano-2,6-difluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-N-isopropylacetamide I-1 (50 mg, 29%) as a white solid. LC-MS (Method A), RT=8.02 min. (ES+) 427.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1.Br[CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:21][C:20]#[CH:19])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1
Reactant: C#CCBr
Reactant: CCn1nnn(-c2cc(O)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2nnn(CC)c2=O)c(Cl)cc1F
Yield: 65.2 %

Procedure:
In the manner of Example 8, Step B, the reaction of 0.8 g (0.0031 mole) of 1-(2-chloro-4-fluoro-5-hydroxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one with 0.9 g (0.0062 mole) of 1-bromo-2-propyne and 0.63 g (0.0046 mole) of potassium carbonate in 25 mL of acetone produced 0.6 g of 1-[2-chloro-4-fluoro-5-(2-propynyloxy)phenyl]-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, mp 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[N:30]([C:32](ON1N=NC2C=CC=NC1=2)=[N+:33](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:33][C:32]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetic acid (95 mg, 0.23 mmol, 1 eq.), cyamide (15 mg, 0.36 mmol, 1.5 eq.), HATU (130 mg, 0.36 mmol, 1.5 eq.), diisopropylethylamine (90 mg, 0.69 mmol, 3 eq.) and DMF (1 ml). The resulting mixture was stirred at rt overnight until the starting acid was consumed. The mixture was added to NaHCO3 aq. (5 ml) and extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using a preparation TLC plate and 2% of MeOH in DCM as mobile phase to give the title compound as a white solid (20 mg, 20% yield). MW=435.93. 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.43 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 3.69 (s, 2H), 3.18 (t, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.27 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[C:18](=[O:19])[NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:20])#[N:2].N[CH2:22]CNCCCNCCN>>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[C:7](=[O:20])[NH:8][CH2:9][CH2:10][NH:11][CH2:22][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]1=[O:19])#[N:2]
Reactant: NCCNCCCNCCN
Reactant: N#CCCCC1C(=O)NCCNCCNCCNC1=O
Product: N#CCCCC1C(=O)NCCNCCCNCCNC1=O
Yield: 30 %

Procedure:
The procedure of (2) of Example 1 was repeated with the exception that N,N'-bis(2-aminoethyl)-1,3-propylenediamine was used in place of triethylenetetramine. Thus, 3-(3-cyanopropyl)-2,4-dioxo-1,5,8,12-tetraaza-cyclotetradecane (C-substituted cyclic diamide) was obtained in a yield of 30%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.Cl[S:12]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13]>C1COCC1>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:13])=[O:14])[CH2:6][CH2:7]1
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCN1CCOCC1
Reaction time: 20 h
Yield: 100.4 %

Procedure:
A solution of 4-(3-aminopropyl)morpholine (1.04 g, 7.2 mmol) in THF (25 ml) was added slowly to a cooled solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (1.0 g, 3.6 mmol) in THF (75 ml). After stirring at 20°-25° C. for 20 hours, THF was removed under reduced pressure and the residue partitioned between EtOAc and a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue and elution with 2% MeOH-98% CHCl3 gave 1.4 g of product as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>[Ag]=O>[C:1]([O:5][C:6]([C@:8]1([C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][O:18][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)[C@]1(C(=O)OC(C)(C)C)[C@H](CO)[C@@H]1c1ccccc1
Reactant: CI
Agent: O=[Ag]
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(C(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The above (1R*,2R*,3R*)-2-hydroxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (0.050 g, 0.15 mmol) was dissolved in 1 mL of methyl iodide. To this solution was added silver oxide (0.69 g, 3.0 mmol) and the mixture was stirred overnight at room temperature under N2 (in the dark). This reaction was incomplete and additional methyl iodide and silver oxide were added. After stirring overnight, the reaction appeared stalled. The catalyst was filtered off through celite and the residue was rinsed with ether. The filtrate was concentrated to a clear oil and purified by prep-TLC using 1:1 hexanes/EtOAc to afford 30 mg of the desired product (58%). This reaction was repeated numerous times to bring up more material. Note: If a huge excess of silver oxide was not used, the reaction often led to a reversion to the lactone product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.[OH-].[K+].Br[CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C=O)C>[CH2:20]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (0.5 g, 2.2 mmol) in DMF (4 ml) was added 10% aqueous potassium hydroxide (1.23 ml), followed by dropwise addition of 1-bromobutane (0.24 ml, 2.2 mmol). The mixture was stirred at room temperature for 12 h, then water (12 ml) was added. The product was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded the residue which was purified by flash chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to give the title compound (0.41 g, 59%) as a colorless solid.