Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([CH:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1>CS(C)=O.CCOC(C)=O>[C:27]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:28]=[CH:29][C:30]([C@H:33]([NH:35][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:34])=[CH:31][CH:32]=1.[C:27]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:28]=[CH:29][C:30]([C@@H:33]([NH:35][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:34])=[CH:31][CH:32]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(-c3ccccc3)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2ccc(-c3ccccc3)cc2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (90 mg, 0.37 mmol), iPr2NEt (0.455 mL, 2.61 mmol, 7.0 equiv) and 1-(biphenyl-4-yl)ethanamine hydrochloride (87 mg, 0.37 mmol) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-3-(2-((R)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([OH:38])=O)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:43]=[CH:42][N:41]=[C:40]1[NH2:44].Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:44][C:40]3[O:39][CH:43]=[CH:42][N:41]=3)=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncco1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ncco1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and oxazol-2-amine instead of indole-2-carboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.Cl>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:11][C:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:10])[CH3:13]
Reactant: BrCCCCBr
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-bromophenylacetate (2 g, 8.2 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.72 g, 18.1 mmol), and the mixture was stirred for 10 minutes. 1,4-Dibromobutane (1.07 mL, 9.0 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was worked up with EtOAc and aqueous 10% HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]2[O:13][C@:12]([C:15]([OH:17])=O)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35].C(N(CC)C(C)C)(C)C>C1COCC1.CN(C=O)C>[OH:8][C:7]1[C:6]([CH3:9])=[C:5]2[C:4](=[C:3]([CH3:18])[C:2]=1[CH3:1])[O:13][C@@:12]([CH3:14])([C:15]([NH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35])=[O:17])[CH2:11][CH2:10]2
Reactant: N[C@H]1CCOC1=O
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)N[C@H]1CCOC1=O)O2
Temperature: 23 °C
Reaction time: 15 h

Procedure:
A solution of 1.82 g (7.27 mmoles) of (R)-Trolox and 1.18 g (7.27 mmoles) of 1,1′-carbonyldiimidazole (CDI) in 15 ml of anhydrous THF is stirred for 1 hour at 23° C., before adding a solution of 1 g (7.27 mmoles) of (S)-2-amino4-butyrolactone hydrochloride and 1.27 ml (7.27 mmoles) of N,N-diisopropylethylamine (DIEA) in 15 ml of anhydrous DMF. The reaction mixture is stirred for 15 hours at 23° C. and finally concentrated to dryness under vacuum. The residue is dissolved in 100 ml of AcOEt and the organic solution is washed successively with 50 ml of 1N aqueous HCl, 50 ml of H2O, 50 ml of a saturated aqueous solution of NaHCO3, 50 ml of H2O and finally 50 ml of salt water. After drying over MgSO4, the organic solution is filtered and concentrated to dryness under vacuum. The residue is taken up in 50 ml of Et2O, followed by agitating and filtering. After rinsing with 2×25 ml of Et2O, the white powder, obtained is dried under vacuum. Melting point: 195-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Br)c1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine methyl ester (Example 306; 195 mg, 0.348 mmol) in methanol (2 mL) at 25° C. was added 1 N NaOH (350 μL, 0.348 mmol). The reaction mixture was stirred for 24 h and TLC (10% methanol in dichloromethane) revealed that starting material was still present. 1 N NaOH (350 μL) was added at room temperature and the reaction was stirred for 24 h. The solvents were evaporated under reduced pressure, the residue was placed under vacuum for 1 h, and then purified by HPLC (gradient of acetonitrile, water, 0.075% TFA). The pure fractions were combined, concentrated under vacuum and then freeze dried for 24 h to yield N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (144 mg, 76%) as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]I)=[C:20]([Cl:27])[CH:19]=1.O>O1CCCC1>[CH2:1]([C@:4]1([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][C:20]=2[Cl:27])[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1N=C(OC)[C@@H](C(C)C)N=C1OC
Reactant: Clc1cc(Br)ccc1CCI
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@]1(CCc2ccc(Br)cc2Cl)N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under an argon atmosphere, an n-butyllithium-hexane solution (1.60 mol/L, 11.16 mL) was added at −78° C. to a solution of (5R)-2-allyl-3,6-dimethoxy-5-isopropyl-2,5-dihydropyrazine (3.64 g) in tetrahydrofuran (60 mL) to form a reaction solution. This reaction solution was then stirred at −78° C. for 30 minutes. A solution of 4-bromo-2-chloro-1-(2-iodoethyl)benzene (6.73 g) in tetrahydrofuran (20 mL) was added to the reaction solution, and the reaction solution was stirred at −78° C. for 30 minutes and then at 0° C. for 1 hour. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=70:1) to obtain the target product (6.04 g) as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH3:25])[C:19]3=[O:26])[C:11]1=[O:27])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:35]([O:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH3:25])[C:19]3=[O:26])[C:11]1=[O:27])[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])(=[O:36])[CH3:34]
Reactant: CN1Cc2ccc(N3CCO[C@H]([C@@H](O)C(=O)OC(C)(C)C)C3=O)cc2C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound 70-2 (80 mg) in CH2Cl2 (2 ml) at 0° C. was added pyridine (26 μL), Ac2O (30 μl), and DMAP (4 mg). The mixture was stirred for 1 hour at 0° C., warmed to rt, and stirred for an additional 12 h. The mixture was diluted with EtOAc and the organic layer was washed sequentially with sat. aq. CuSO4 solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford compound 70-3 (85 mg) as a light yellow semisolid. LC-MS: M+H=419. This material was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22]([NH:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4])=[O:23]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COc1ccc2ccc([C@@H](N)CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc([C@H](CO)NC(=O)C=Cc3c(F)cccc3F)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
A mixture of (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol (0.1 mmol), 2,6-difluorocinnamic acid (0.1 mmol), EDC·HCl (0.2 mmol), DMAP 0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the title compound as a solid (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OS(C1C=CC(C)=CC=1)(=O)=O)[C@H:12]1[O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]2[CH2:13][O:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OC[C@@H]1CO1
Yield: 107.6 %

Procedure:
Preparation according to Preparation 1 using 5-bromo-2-hydroxybenzaldehyde (6 g, 30 mmol), (S)-glycidyltosylate (8.2 g, 36 mmol), K2CO3 (4.9 g, 36 mmol) and DMF (12 ml). Water (100 ml) was added and the solution was extracted with EtOAc (3×100 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1 N, 100 ml), brine, were dried and concentrated to give the crude title compound (8.3 g). MS m/z (rel. intensity, 70 eV) 257 (M+, 38), 256 (M+, 39), 200 (bp), 199 (87), 57 (88).
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[CH:13]1([NH:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[N+:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O-:20])=[CH:4][C:3]=2[O:2]1
Reactant: ONC1CCCCC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: [O-][N+](=Cc1ccc2c(c1)OCCO2)C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4ethylenedioxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 74.5% yield as a solid, m.p. 96.7° C.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[CH:6][C:7]([C:15]#[N:16])=[C:8]([Cl:14])[N:9]=[CH:10][N:11]([CH3:13])[CH3:12].Cl[C:19](N=CN(C)C)=[C:20](C=NNC=O)C#N>>[Cl:14][C:8]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[C:7]([CH:6]=[N:5][NH:4][C:3]([CH2:19][CH3:20])=[O:2])[C:15]#[N:16]
Reactant: COC(=O)NN=CC(C#N)=C(Cl)N=CN(C)C
Reactant: CN(C)C=NC(Cl)=C(C#N)C=NNC=O
Product: CCC(=O)NN=CC(C#N)=C(Cl)N=CN(C)C

Procedure:
Following the same procedure and replacing the methyl-3-(3-chloro-2-cyano-5-dimethylamino-4-aza-2,4-pentadienylidene)carbazate by an equivalent of 3-chloro-5-dimethylamino-2-formylhydrazonomethyl-4-aza-2,4-pentadienenitrile or of 3-chloro-5-dimethylamino-2-ethylcarbonylhydrazonomethyl-4-aza-2,4-pentadienenitrile results in the similar preparation of the corresponding compound of formula I.
Reaction SMILES: CC1C2NC(=O)OC=2C=CC=1.[Cl-:12].[Cl-].[Cl-].[Al+3].Cl[C:17]1[C:22]([CH3:23])=[C:21]([C:24]([C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:20]=[CH:19][N:18]=1>>[Cl:12][C:19]1[CH:20]=[C:21]([C:24]([C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[C:22]([CH3:23])=[CH:17][N:18]=1
Reactant: Cc1c(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)ccnc1Cl
Reactant: [Cl-]
Agent: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Product: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Temperature: 125 °C

Procedure:
1.53 g (10.0 mmol) 3-methyl-1-oxy-isonicotinic acid were stirred with 9.32 mL (100 mmol) phosphorus oxychloride and boiled for 4 h. The reaction mixture was evaporated to dryness i. vac. and coevaporated twice with toluene. The crude product thus obtained (which was present in admixture with 2-chloro-3-methyl-isonicotinic acid chloride) was combined with 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride and heated to 125° C. for 1.5 h with stirring. Then the mixture was mixed with ice water and the precipitated grease was separated from the solvent by decanting. The residue was triturated with MeOH. The precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried i. vac. The product thus obtained, which was present in admixture with 6-(2-chloro-3-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, was reacted further without further purification.
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].[C:21]([N:28]1[CH:32]=[CH:31]N=C1)(N1C=CN=C1)=[O:22].C(O)(=O)C.[Cl:37][C:38]1[CH:43]=[CH:42]C(CN)=[CH:40][CH:39]=1>O1CCCC1>[Cl:37][C:38]1[CH:43]=[CH:42][C:31]([CH2:32][NH:28][C:21](=[O:22])[O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7]3)=[CH:40][CH:39]=1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NCc3ccc(Cl)cc3)ccc21
Reaction time: 24 h
Yield: 95.9 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 60 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.83 g) and this mixture was stirred for 24 hours. Then 4.5 ml of glacial acetic acid was added to the reaction mixture followed by 4-chlorophenylmethylamine (1.5 g) in 10 ml of tetrahydrofuran. This mixture was then stirred for 24 hours, quenched with water and basified with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (3.9 g), which was eluted with 5% methanol in dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid (3.05 g), m.p. 149°-151° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]([NH2:11])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:12]NC(NC(N)=O)=O>>[CH2:1]([N:5]1[CH:12]=[N:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CNC(=O)NC(N)=O
Reactant: CCCCNC(=O)NC(N)=O
Product: CCCCn1cnc(=O)[nH]c1=O
Yield: 92 %

Procedure:
Following the procedure described in Preparation 2, Part B, above, but substituting the n-butylbiuret prepared in Part A, above, for the methylbiuret, there is prepared 60 gm. (92% yield) of 1-n-butyl-5-azauracil.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[N:19]#[C:20]Br>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][N:7]1[C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[N:8]([CH2:13][C:12]2[CH:15]=[CH:16][C:17]([F:18])=[C:10]([F:9])[CH:11]=2)[C:20]1=[NH:19]
Reactant: N#CBr
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Product: N=C1N(Cc2ccc(F)c(F)c2)[C@@H]2CCCC[C@H]2N1Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared from (±)-trans-1,2-cyclohexanediamine and 3,4-difluorobenzaldehyde by Procedure C. After reacting with cyanogen bromide, the reaction mixture was evaporated to dryness and the crude product washed with ether and recrystallized from MeOH to give the title compound as the hydrogen bromide salt (mp 238-240° C.). MS (ES+) m/z 392 ([M+1]+, 100).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].C(N(CC)CC)C.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>C1COCC1>[CH2:28]([O:27][C:26]([NH:13][C@@:8]12[C:7]3[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=3[CH2:5][C@@H:4](/[C:3]/1=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]2)=[O:30])[CH3:29]
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(NC(=O)OCC)c1ccc(=O)[nH]c1C2
Temperature: 0 °C
Yield: 61.7 %

Procedure:
Dissolved 10 mg huperzine A and 10 mg triethylamine in 5 mL dry THF; cooled the solution down to 0° C.; added ethyl chlorocarbonate (6 mg) and stirred the resultant reaction mixture for 4 hours; filtered to remove solid residues; after concentrating the filtrate, purified on prep TLC (chloroform:methanol=9:1) to yield 8 mg of pure title compound. MS: 315 (M+1).
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29]CC1C=CC=CC=1)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:22](=O)[CH2:23][CH3:24])C(=O)CC)C1C=CC=CC=1.[OH:37][C:38]1C=C(C=[CH:56][C:57]=1O)OCCCCC(C(=O)CC)C(=O)CC>>[OH:29][C:28]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][CH2:23][CH:24]([C:11](=[O:12])[CH2:10][CH3:9])[C:38](=[O:37])[CH2:57][CH3:56])=[CH:26][CH:27]=1
Reactant: CCC(=O)C(CCCCOc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)CC
Reactant: CCC(=O)C(CCCCOc1ccc(O)c(O)c1)C(=O)CC
Product: CCC(=O)C(CCCCCCCOc1ccc(O)cc1)C(=O)CC

Procedure:
By a similar hydrogenolysis procedure 4-[4-(3,4-dibenzyloxyphenoxy)butyl]-3,5-heptanedione can be coverted to 4-[4-(3,4-dihydroxyphenoxy)butyl]-3,5-heptanedione [I; Ar is 3,4-(HO)2C6H3, Alk is CH2CH2CH2CH2, R and R' are CH3CH2CO].
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:37])C.C(O)(=O)C.IC1C=CC=CC=1.C(O)(=O)C.C(OC(=O)C)(=O)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:34][C:2]([F:33])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:31][CH3:32])[C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:37])[CH:12]=1)(=[O:4])=[O:5]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Ic1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(O)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 50 °C

Procedure:
A mixture of 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (2.6 g, 5.17 mmol), Pd(OAc)2 (58 mg, 0.259 mmol), and iodobenzene diacetate (2.33 g, 7.24 mmol) in 1:1 acetic acid/acetic anhydride (42 mL) was heated at 50° C. for 8 h. The mixture was cooled to RT and concentrated under reduced pressure. Flash chromatography (10-100% EtOH in DCM, followed by 7:1 EtOH/7 N ammonia in MeOH elution) provided a mixture of the title compound and the corresponding acetate (3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(((trifluoromethyl)sulfonyl)oxy)phenyl acetate). After concentration, the mixture was taken up in methanol and heated at 70° C. for 4 h. The solvent was evaporated to provide 3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoro-methanesulfonate as a tan-colored solid (1.25 g). MS (M+1)=519.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (d, J=10.1 Hz, 1H), 7.23 (d, J=10.1 Hz, 1H), 6.57 (s, 2H), 5.16 (t, J=12.1 Hz, 1H), 3.89 (s, 3H), 3.02 (s, 3H), 1.69-1.77 (m, 2H), 1.56-1.67 (m, 2H), 1.41 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCNC1
Product: O=C(NCc1ccc(Br)cc1)N1CCCC1
Yield: 99.7 %

Procedure:
A solution of 4-bromobenzylisocyanate (408 mg, 1.92 mmol) in acetonitrile (15 ml) was treated with triethylamine (390 mg, 3.86 mmol) followed by pyrrolidine (137 mg, 1.93 mmol) at room temperature with stirring under argon. The reaction was stirred at 20° C. for 30 minutes and then partitioned between ethyl acetate (10 ml) and water (20 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless solid (542 mg, 99%).