Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[N:13]([CH2:14][C:5]=2[C:4](Cl)=[C:3](Cl)[CH:2]=1)CC(=O)[NH:9]3.O.Cl.C(N(CC1C(N)=CC=C(Cl)C=1Cl)CC(O)=O)C.N#CBr>>[NH:9]=[C:8]1[N:13]=[CH:14][C:5]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:7]1
Reactant: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Agent: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl
Agent: Cl
Agent: N#CBr
Solvent: O
Product: N=c1ncc2ccccc2[nH]1

Procedure:
Commercially, as discussed in U.S. Pat. No. 5,801,245 and as shown in FIG. 1, Anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent to give the iminoquinazoline intermediate (compound II) which is isolated and then reacted with a base in a hot solution of alcohol to form Anagrelide base (compound III).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Na].[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[SH:29]>>[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[S:29][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CN1CCC(NC(=O)Nc2cc([N+](=O)[O-])c(Cl)s2)CC1
Reactant: Sc1c(Cl)cncc1Cl
Agent: [Na]
Product: CN1CCC(NC(=O)Nc2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step A of example 18 from 1-(5-chloro-4-nitrothiophen-2-yl)-3-(1-methylpiperidin-4-yl)urea (100 mg, 0.31 mmol) and 3,5-dichloropyridine-4-thiol sodium salt (62 mg, 0.35 mmol). The title compound was obtained as a white solid (120 mg, 85% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.01 (1H, m), 8.92 (2H, m), 6.91 (1H, m), 3.43 (2H, m), 2.87 (2H, m), 2.33 (3H, m), 1.91 (1H, m), 1.74 (2H, m), 1.46 (2H, m). MS m/z: 459.94, 461.94 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CC(C)(N)CO
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-2-methyl-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a cream-colored solid: 1H NMR (d6-DMSO) δ 10.35 (1H, s), 8.49 (1H, d, J=1.3 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.6, 5.6 Hz), 7.12 (2H, t, J˜9 Hz), 5.11 (2H, s), 5.09 (1H, m), 4.10 (2H, s), 3.44 (2H, d, J=5 Hz), 3.12 (3H, s), 2.82 (3H, s), 1.32 (6H, s); HRMS calcd for C24H27FN4O5+H+: 471.2044. Found: 471.2040.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][OH:24])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.S([O-])(O)=O.[Na+]>CN(C)C=O>[Br:25][C:20]1[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)(=[O:12])=[O:13])=[N:16][CH:17]=[N:18][C:19]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(OCCO)ncn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 4-tert-butyl-N-[6-(2-hydroxyethoxy)pyrimidin-4-yl)benzenesulfonamide (210 mg) in dimethylformamide (4 ml) is added N-bromosuccinimide (116 mg), and the mixture is stirred at room temperature for one hour. The mixture is treated with aqueous sodium hydrogen sulfite solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=40:1), and recrystallized from hexane/ethyl acetate to give N-[5-bromo-6-(2-hydroxyethoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (169 mg).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][OH:9])[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH2:1]([O:4][CH2:5][C@H:6]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:7]([O:10][Si:11]([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:12])[CH3:13])[CH:8]=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude material from Step 4 (0.040 g) was dissolved in CH2Cl2 (3 mL) and treated with Dess-Martin periodinane (0.07 g, 0.2 mmol). The mixture was stirred at ambient temperature for 4 h then diluted with EtOAc (10 mL), sat'd NaHCO3 (5 mL), and aqueous Na2S2O3 (5 mL). The biphasic mixture was stirred until it was colorless. The organic layer was washed with brine, dried (Na2SO4), filtered, and conc in vacuo. The crude aldehyde was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:20])=[N:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:4][CH:3]=1>O>[CH3:20][C:10]1[C:9]2[N:8]=[C:6]([C:5]3[CH:21]=[CH:22][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]=2[NH:12][N:11]=1
Reactant: Cc1ccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(-c2nc3c(C)n[nH]c3c3ccccc23)cc1

Procedure:
The preparation took place in analogy to example 33 (B), using 192 mg of 4-methyl-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except the reaction mixture was diluted with water and extracted with dichloromethane. The organic portion was concentrated under reduced pressure and purified by MPLC (4 g SiO2, dichloromethane/methanol, gradient=99/1→50/50) to give the title compound.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:15]=[C:16]=[S:17])[CH:13]=[CH2:14].C>>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:15]([CH:12]=[CH:13][CH3:14])[C:16]2=[S:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: C=CCN=C=S
Product: CC=CN1C(=O)CN(c2ccccc2)C1=S
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of N-phenyl glycine (15.1 grams, 0.1 moles) and allylisothiocyanate (12.0 grams, 0.12 moles) was refluxed for 6 hours and allowed to stand overnight at room temperature (21° C.). The reaction mixture became a solid mass which was ground and crystallized from ethanol using charcoal, 7.26 grams (31% yield) of the above-identified product was recovered having a melting point of about 74° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([CH3:23])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[O:15][C:14]=2[CH:22]=1)(=[O:9])=[O:8])[CH3:5].[OH-].[Na+]>O1CCCC1>[CH3:23][C:4]([NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[O:15][C:14]=2[CH:22]=1)(=[O:9])=[O:8])([CH3:5])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1ccc2c3c(oc2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(NS(=O)(=O)c1ccc2c3c(oc2c1)CCCC3)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The 2-methyl-2-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)-propionic acid methyl ester (586 mg, 1.67 mmol) was suspended in aqueous tetrahydrofuran (1:1, 22 mL) and treated with aqueous sodium hydroxide (1 M, 7 mL). The reaction mixture was stirred at room temperature for 3 days. The tetrahydrofuran was concentrated in vacuo. The aqueous suspension was diluted with water (40 mL) and washed with diethyl ether. The aqueous phase was separated from the organic phase, and acidified (to a pH of 1). The resulting precipitate was collected by filtration and oven dried to give 2-methyl-2-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)-propionic acid (a compound of general Formula VIII) (457 mg, 81%), the structure of which is shown below. The melting point of this compound was determined to be 237-240° C. 1HNMR (DMSO-d6): δ8.0 (s, 1H), 7.8 (s, 1H), 7.6 (m, 2H), 2.7(m, 2H), 2.6 (m, 2H), 1.8 (m, 4H), 1.1 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2ccc(C(C)(C)C)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 36.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 4-tert-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-tert-butyl-benzylamide (41.8 mg, 36.25%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=O)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=1>>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH3:15])[C:12]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCC(C)C(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCC(C)C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-N-[4-(3-pyridinyl)butyl]butanamide, the title compound as an oil in 89% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[CH:9]=2)=[CH:4][CH:3]=1.[Br:16][C:17]1[C:18](B(O)O)=[N:19][CH:20]=[CH:21][CH:22]=1.BrC1C=NC=C(Br)C=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([CH3:14])[N:11]=2)[CH:20]=[N:19][CH:18]=1
Reactant: OB(O)c1ncccc1Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(I)n1
Agent: Brc1cncc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cncc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-methyl-pyridine (example A.29) (2.15 g, 6.5 mmol) and commercially available 3-bromo-pyridine-boronic acid [CAS-No. 452972-09-07] (alternatively prepared from commercially available 3,5-dibromopyridine according to Tetrahedron 2002, 58(17), 3323 or Synthesis 2003, (7), 1035) (1.448 g, 7.1 mmol) according to the general procedure IVb. Obtained as a white solid (1.35 g, 57%). MS (ISP) 358.9 [(M+H)+], 360.9 [(M+2+H)+] and 363.0 [(M+4+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9](=[O:12])[CH2:10][CH2:11][O:8]2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)O
Reactant: Oc1cccc(F)c1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
Following the same procedure established in Example 1, the reactor was charged with meta-fluorophenol (28 grams), acrylic acid (27 grams), and phenothiazine (0.02 grams). The reactor was sealed, evacuated and cooled to -78° C. before the anhydrous hydrogen fluoride (125 grams) was added. The mixture was stirred and warmed to 40° C. for one hour then to 100° C. for 4.5 hours as the pressure was recorded at 140 psig. After venting the excess hydrogen fluoride the reactor was cooled to 5° C. and the mixture washed with D.I. water. Analysis by HPLC indicated no 4-Chromanones to be present. A mixture of by-products were seen.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:11]([S-])[S-:12])(=[O:9])=[O:8].[K+].[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
77 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate prepared in accordance with Example 2 was suspended in 100 ml of toluene, and 37 ml of thionyl chloride was added to the suspension at 0° to 10° C. over the course of 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Distillation at reduced pressure gave 2-phenylbenzenesulfonyl isothiocyanate. On the other hand, 12.3 g of 2-amino-4,6-dimethylpyrimidine was suspended in 300 ml of dry toluene, and 27.5 g of 2-phenylbenzenesulfonyl isothiocyanate prepared as above was added. The mixture was heated under reduced pressure for 8 hours. After cooling, the resulting white precipitate was collected by filtration, and recrystallized from ethanol to give 31 g of the desired 1-(2-biphenylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)thiourea of the following formula, mp. 203°-204° C.: ##STR20##
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Oc2ncc(Cl)cn2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Oc2ncc(Cl)cn2)cc1
Reaction time: 0.08 h

Procedure:
2-(4-Aminophenoxy)-5-chloropyrimidine (20 g), was dissolved in acetic acid (100 ml), and acetic anhydride (20 ml) was added to the solution. After standing for a period of 5 minutes the solution was heated on a steam bath and hot water (100 ml) was slowly added. On cooling the product crystallised and was collected and dried. Yield 20 g, m.p. 202° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[O:9][CH:28]=[N:27][CH:26]=2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cccc(-c2cnco2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a stirred solution of 6-bromopyridine-2-carboxaldehyde (5.90 g, 31.7 mmol) in methanol (150 ml) was added K2CO3 (5.25 g, 38.0 mmol) and TosMIC (7.43 g, 38.0 mmol). After stirring at ambient temperature for 1.5 h, the mixture was concentrated under vacuum and the product precipitated by addition of water. The solid was collected by filtration and dried in a vacuum dessicator at 50° C. to afford 2-bromo-6-oxazol-5-ylpyridine compound as a beige solid (6.81 g, 95% yield). 1H NMR (CDCl3, 300 MHz): δ=7.97 (s, 1H), 7.76 (s, 1H), 7.65-7.57 (m, 2H), 7.48-7.37 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][C:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)=[O:22])[C:4](=[O:19])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:32][CH:33]([CH3:37])[CH:34]([NH2:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:35][CH:34]([NH:36][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([C:21](=[O:22])[CH2:20][N:3]2[C:4](=[O:19])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:24][CH:25]=1)[CH:33]([CH3:37])[CH3:32]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)C(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(C(=O)NC(C)C(C)C)cc1
Reaction time: 12 h
Yield: 48.7 %

Procedure:
4-[2-(2-Methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid (120 mg, 0.29 mmol) and (+/−)-3-methyl-2-butylamine (45 uL, 0.44 mmol) and N,N′-dicyclohexylcarbodiimide (97 mg, 0.47 mmol) and 4-(dimethylamino)-pryridine (58 mg, 0.47 mmol) are dissolved in 5 mL methylene chloride. The reaction mixture is stirred for 12 hours, filtrated and the filtrate evaporated. The residue of the filtrate is purified by preparative HPLC (Method 1) to yield (+/−)-N-(1,2-dimethyl-propyl)-4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-benzamide (68 mg, 48%). LCIMS at 354 nm; [M+H] 482; Rt 3.304 min.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:5]([C:8]#[N:9])[C:6]#[N:7]>C(O)C>[NH2:7][C:6]1[NH:2][N:1]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[C:8]#[N:9]
Reactant: CC(C)(C)C(Cl)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Product: CC(C)(C)c1n[nH]c(N)c1C#N

Procedure:
Hydrazine (40 g) was dissolved in ethanol (100 ml) and was placed in a flask equipped with a condenser, a dropping funnel, a thermometer and a magnetic stirrer. A solution of the above pentenenitrile intermediate (b) (80 g) in ethanol (300 ml) was added with stirring at a rate that the temperature did not rise above 35° C. The reaction mixture was then gently refluxed for 90 minutes, the solvent was partially removed and the residue was treated with water. The product was filtered off and dried.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[O:20]=[C:19]1[C:18]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][N:15]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CCCCCC(=O)OCc1ccccc1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCCCN1CN(c2ccccc2)C2(CCNCC2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(6-(benzyloxy)-6-oxohexyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.08 g, 0.15 mmol) was added 4M solution of HCl in dioxane (1.5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain benzyl 6-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate as a hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[N:52]=[CH:51][N:50]=[C:49]([NH2:53])[CH:48]=1)[CH3:39]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:53][C:49]2[CH:48]=[C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[O:40][CH2:38][CH3:39])[N:52]=[CH:51][N:50]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCOc1ccccc1-c1cc(N)ncn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.12 h
Yield: 39.8 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (V), (1.27 g, 5.54 mmol) in dry dichloromethane, HOBt (1.27 g, 9.30 mmol) and EDCI (1.78 g, 9.30 mmol) were added at 0° C. and the reaction mixture was stirred for 5-10 minutes. Then 6-(2-ethoxy-phenyl)-pyrimidin-4-ylamine (III) (1.00 g, 4.65 mmol) was added and the reaction mixture was heated to reflux under an atmosphere of nitrogen for 48 hours. The reaction mixture was diluted with dichloromethane and washed with 1N HCl, aqueous sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to obtain 4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (IV) (0.79 g, 40%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: COc1ccc(N)cc1O
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cccs5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39.2 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 57% (75 mg, 0.147 mmol) of the title compound.