Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=4)[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH2:35][C:36]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:37]([OH:39])=[O:38])=[C:15]([F:46])[CH:14]=1.FC(F)(F)C1CCNCC1>>[CH2:40]([C:36]([CH2:35][C:19]1[N:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:13]([N:7]3[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]3)=[CH:14][C:15]=2[F:46])[C:22]2[CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)[CH:25]=[CH:26][C:21]=2[N:20]=1)([CH2:42][CH3:43])[C:37]([OH:39])=[O:38])[CH3:41]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1F)C(=O)O
Agent: Cl
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1F)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting 4-(trifluoromethyl)piperidine hydrochloride and 2-((1-(4-bromo-2-fluorobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C32H37F4N5O3, 615.28; m/z found, 615.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.68 (d, J=9.0, 1H), 7.56 (d, J=2.3, 1H), 7.40 (d, J=2.3, 1H), 7.26 (dd, J=9.0, 2.3, 1H), 7.24-7.18 (m, 1H), 6.80-6.73 (m, 2H), 6.33 (d, J=2.3, 1H), 5.68 (s, 2H), 5.09 (s, 2H), 3.88 (s, 3H), 3.87-3.84 (m, 2H), 3.46 (s, 2H), 2.80 (td, J=12.7, 2.6, 2H), 2.43-2.30 (m, 1H), 1.97-1.88 (m, 2H), 1.87-1.68 (m, 4H), 1.68-1.53 (m, 2H), 0.88 (t, J=7.4, 6H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23])[CH3:20]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[N:21]([CH2:19][CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(C(=O)Cl)c1ccccc1
Product: CCN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.O>CN(C)C=O>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol) produced in Example A18(iv) and 2-chloro-2-oxoethyl acetate (137 mg, 1.00 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with acetone to give the title compound (22 mg, 21%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:16])[CH:15]=1)[CH3:9])=[O:6].[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32]>>[Cl:16][C:14]1[CH:15]=[C:10]([CH:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([NH:32][C:28]3[O:27][CH:31]=[CH:30][N:29]=3)[N:25]=[C:24]([CH3:26])[CH:23]=2)[CH3:9])[CH:11]=[N:12][C:13]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20]
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Br)n1
Reactant: Nc1ncco1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 2-bromo-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylisonicotinamide (25 mg, 0.06 mmol, Step-1, single enantiomer) and oxazol-2-amine (16 mg, 0.19 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:13]>ClCCl>[Br:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution in dichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) is added. Triphenylphosphne (11.8 g, 45 mmoles) is added in portions to the medium at 0° C. Then the mixture is agitated for 2 hours at ambient temperature. Th e solvent is evaporated off and the product obtained is purified on silica gel in an ethyl acetate/heptane mixture (1/2). It is obtained in the form of white needle-shaped crystals (7.2 g; 85%). Melting point: 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:18][C:19]([F:20])([F:21])[F:22])=[C:11]([Cl:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-trifluoromethoxyaniline gave 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.61 (dd, 1H, J=2.1 and 8.7 Hz), 7.35 (dd, 1H, J=1.2 and 8.7 Hz), 6.98 (bs, 1H); LCMS: purity: 97%; MS (m/e): 342 (M+2H).
Reaction SMILES: [CH2:1]([S:3]([O:6][C:7]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[O:9][N:8]=1)(=[O:5])=[O:4])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(Cl)Cl>[CH2:1]([S:3]([O:6][C:7]1[CH:11]=[C:10]([CH2:12][C:13]([Cl:17])=[O:15])[O:9][N:8]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)Oc1cc(CC(=O)O)on1
Solvent: ClCCl
Product: CCS(=O)(=O)Oc1cc(CC(=O)Cl)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
650 mg of (3-ethanesulphonyloxyisoxazol-5-yl)acetic acid were dissolved in 7 ml of methylene chloride, 577 mg of phosphorus pentachloride were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and the residual (3-ethanesulphonyloxyisoxazol-5-yl)acetyl chloride thus obtained was dissolved in 5 ml of methylene chloride. This solution was added to a solution of 300 mg of benzhydryl 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and 207 mg of N,N-diethylaniline in 4 ml of methylene chloride. The reaction mixture was stirred in an ice bath for 1 hour and then the solvent was distilled off. The residue was dissolved in ethyl acetate and the solution was washed with, in turn, dilute aqueous potassium bisulphate, aqueous sodium chloride, aqueous sodium hydrogen carbonate and aqueous sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was distilled off and the residue was adsorbed on a silica gel preparative thin layer chromatograph and developed with a 1:1 by volume mixture of benzene and ethyl acetate. The portion having an Rf value of 0.63 was extracted with ethyl acetate. The solvent was distilled under reduced pressure from the extract to give 422 mg (100%) of the benzhydryl ester of the desired Compound No. 15.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(O)C>[NH2:14][C:10]1[CH2:11][CH:12]([CH3:13])[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: C/C=C/C#N
Agent: [Na]
Solvent: CCO
Product: CC1CC(N)=NN1c1ccccc1
Reaction time: 0.17 h

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 200 ml. of absolute ethanol, then 32.4 g. of phenylhydrazine in 50 ml. of ethanol is added followed in 10 minutes by 20.1 g. of crotononitrile. The reaction mixture is refluxed for 5 hours. Most of the ethanol is removed in vacuo, water is added and the product is collected by filtration. The solid is dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The column effluent is then refluxed on a steam bath with the gradual addition of hexane to crystallize a product. The product is collected and recrystallized from acetone-hexane to give 26.9 g. of the product of the Example as colorless prisms, m.p. 103.5°-106° C.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][O-].[Na+]>CO>[CH3:13][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:1][OH:12]
Reactant: CCCCCCCCCCCO
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCC(C)CO

Procedure:
Another synthesis starts from n-undecanol, which is reacted with methanol in the presence of sodium methylate. 2-methyl-undecanol is formed, which is then dehydrogenated to form the aldehyde. (Chemical Abstracts Vol. 74 [1971], 12552 X.)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCNCc2ccccc2)CC1
Reaction time: 48 h
Yield: 43 %

Procedure:
Benzylamine (345 μl, 3.22 mmol, 1.1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (0.9 g, 2.93 mmol, 1 eq) and triethylamine (0.8 ml, 5.86 mmol, 2 eq) in toluene (50 ml), and refluxing was carried out for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in ethyl acetate (100 ml), washed with water (30 ml) and sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, ethyl acetate), a yellow solid was obtained. Yield: 43% (400 mg, 1.25 mmol).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]>N1CCCCC1.C(O)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 105.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.6 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole, and 2 drops piperidine in 2 mL ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 227 mg of the title compound (−100%) as a brown solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11](Br)([F:13])[F:12].O>CN(C=O)C>[Br:10][C:11]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:13])[F:12]
Reactant: Sc1ccccc1
Reactant: FC(F)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(Br)Sc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a three-necked round-bottomed flask placed under a nitrogen atmosphere, topped with a dry-ice condenser and a dropping funnel, thiophenol (10.2 ml, 100 mmol) was added dropwise, over 40 min at 0° C., to a suspension of NaH (6 g, 150 mmol) in anhydrous DMF (100 ml). The mixture was then stirred at 0° C. for 30 min then cooled to −50° C. Dibromodifluoromethane (27 ml, 300 mmol) was then added at −50° C. The mixture was then stirred for 3 h at this temperature, then 30 min at ambient temperature. Water (100 ml) was added to the reaction mixture, then the product was extracted with ethyl ether (3×100 ml). The organic phases were washed with water (3×100 ml) and dried over MgSO4. After evaporation of the solvent, the residue was purified by distillation under reduced pressure (97° C./34 mmHg) to give the product [(bromodifluoromethyl)sulfanyl]benzene in the form of a colorless liquid (15.3 g, 60%).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C.Cl>O1CCCC1>[N:18]1([CH2:2][C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: C1CCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CN2CCCC2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(2-bromoacetyl)piperidinecarboxylate (0.85 g, 2.8 mmol) was dissolved in tetrahydrofuran (8.5 mL), and the solution was mixed with pyrrolidine (0.46 mL, 5.6 mmol) and triethylamine (0.78 mL, 5.6 mmol) with stirring at room temperature, followed by stirring for twenty-four hours. The reaction mixture was mixed with diluted hydrochloric acid (0.5 mol/L, 27 mL) and washed with ethyl acetate. The aqueous layer was adjusted to be basic with an aqueous potassium hydroxide solution added under ice-cooling and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dried under reduced pressure and thereby yielded tert-butyl 4-(2-pyrrolidin-1-ylacetyl)piperidinecarboxylate (0.72 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
2-Chloro-4-(6-nitropyridin-3-yloxy)pyridine (0.540 g, 2.146 mmol) was dissolved in THF (54 ml) and MeOH (54 ml). Ammonium chloride (1.148 g, 21.46 mmol) was then added, followed by zinc dust (1.403 g, 21.46 mmol). The reaction was stirred at RT for 45 minutes, filtered over Celite® and concentrated under reduced pressure to yield 5-(2-chloropyridin-4-yloxy)pyridin-2-amine as a brown solid (0.49 g, 99%). It was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, 1H), 7.81 (d, 1H), 7.30 (dd, 1H), 6.90 (m, 2H), 6.50 (d, 1H), 6.08 (s, 2H); MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25])=[O:9]
Reactant: O=C(O)c1cnc(OCCCCCO)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(Br)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31b, using 5-bromo-6-(5-hydroxy-pentyloxy)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials to give the product as white solid, MS (ISP): 403.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.CO[CH:29]1[CH:33]([CH2:34][N:35]([CH3:37])[CH3:36])[CH2:32][CH:31](OC)O1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:36][N:35]([CH2:34][C:33]1[CH:32]=[CH:31][N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH:29]=1)[CH3:37]
Reactant: COC1CC(CN(C)C)C(OC)O1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(CN(C)C)c2)cc1

Procedure:
10 millimoles of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazinone in toluene were refluxed with 13 millimoles of toluenesulfonic acid and 12 millimoles of 2,5-dimethoxy-3-dimethylaminomethyltetrahydrofuran with the addition of a little dimethylformamide, this procedure being carried out under a water separator. When the reaction was complete, which was determined by thin layer chromatography, the major part of the solvent was stripped off, the residue was taken up in dimethylformamide and the solution was poured into saturated NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 and the organic extract was dried over Na2SO4 and evaporated down in a rotary evaporator. The crude product was purified by column chromatography (SiO2, CH2Cl2 /CH3OH). 6-[4-(3-Dimethylaminomethylpyrrol-1-yl)-phenyl]-4,5-dihydro-5-methylpyridazinone was obtained, this substance being identical to that synthesized in Example 3A.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCc2ccccc2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)Nc1nc(C)cc(OCc2ccccc2)n1

Procedure:
Acetic anhydride (15.3 g, 0.15 mole) is added to a stirred suspension of 2-amino-4-methyl-6-benzyloxypyrimidine (23.6 g, 0.11 mole) in 150 ml of benzene. The mixture is heated at reflux for 4 hours. It is cooled, neutralized with aqueous sodium carbonate and the benzene layer separated. The benzene solution is concentrated under vacuum to an oil from which 2-acetamido-4-methyl-6-benzyloxy-pyrimidine melting at 121°-122° C. is isolated by crystallization from hexane n-butyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([NH:19][CH2:20][C:21]#[CH:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:12]([O:11][C:9]([NH:19][CH2:20][C:21]#[C:22][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][NH:19][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: O=C(NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)nc1)OCc1ccccc1
Temperature: 65 °C
Yield: 86.4 %

Procedure:
A mixture of 2,5-dibromopyridine (3.00 g), N-Cbz-propargylamine (5.99 g), PdCl2(PPh3)2 (89.8 mg), and CuI (6.0 mg) in diisopropylamine (51 ml) was heated at 65° C. for 7 hours under nitrogen atmosphere. The mixture was cooled to room temperature, and the precipitates were filtered, washed with water, and dried under reduced pressure to give 8-1 (4.96 g) as a crystalline compound; m.p. 156-158° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][NH:21][CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(Nc2ccc3c(c2)CCC3)c2c3c([nH]c2n1)CCNC3
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)CCC5)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
Indan-5-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (102 μL, 0.74 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 64 (21 mg, 25% yield) as an oily residue. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16](O)[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:7])=[O:6].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[F:24][CH:2]([F:1])[O:3][CH:4]([C:9]1[CH:23]=[CH:22][C:12]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][CH:16]([CH2:27][CH:26]=[CH2:25])[C:11]=2[CH:10]=1)[S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)C(OC(F)F)c1ccc2c(c1)C(O)Oc1ccccc1-2
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1Oc2ccccc2-c2ccc(C(OC(F)F)S(N)(=O)=O)cc21
Reaction time: 1 h

Procedure:
A solution of Example 27G (0.14 g, 0.39 mmol) in dichloromethane (10 mL) at −78° C. was treated with allyltrimethylsilane (0.13 g, 1.16 mmol) and borontrifluoride etherate (0.156 g, 1.16 mmol), stirred for 1 hour, and treated with saturated sodium bicarbonate (10 mL) to provide two laters. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)Q1MS) m/z 380 (M−H)−.