Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[CH:38]1([CH2:41][O:42][NH2:43])[CH2:40][CH2:39]1.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>[CH:38]1([CH2:41][O:42][NH:43][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:37])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17]2)=[O:36])[CH2:40][CH2:39]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: NOCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NOCC2CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 21.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.15 g, 0.27 mmol) was reacted with O-cyclopropylmethylhydroxyamine (HUHU Tech) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide as a white solid (30 mg, 21%).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([O:1][CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: ClCCN1CCOCC1
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)n(C)c1=O
Yield: 42.4 %

Procedure:
A solution of 7-[4-(4-hydroxybenzoyl)benzyl)-1,3-dimethylxanthine (170 mg), potassium carbonate (200 mg) and 1-chloro-2-morpholinoethane hydrochloride (87 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate: acetone =1:1:1) to provide the title compound (93 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[Cl:8].O.[SH-:18].[Na+].O>CN(C)C=O>[C:9]([N:6]1[C:7]([Cl:8])=[C:3]([CH2:2][SH:18])[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: [SH-]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CS)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to a solution of 21.8 g of sodium hydrosulfide hydrate (purity: 70%, 272.2 mmoles) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.CCN(CC)CC.O>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:7])=[O:6]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloropropane-1-sulfonyl chloride (1.46 g, 8.22 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. is added bis-(4-methoxy-benzyl)-amine (2.22 g, 8.63 mmol) followed by Et3N (1.68 g, 10.69 mmol). After the addition, the mixture is allowed to warm to room temperature and is stirred for 2 h. The mixture is then poured into water (50 mL) and is extracted with CH2Cl2 (3×50 mL). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0%˜50%) to provide 3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide as colorless oil. (2.7 g, 84%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.F[C:24]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=1[C:26]#[N:27].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:30]=[CH:31][C:24]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:25]([CH:28]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (40 mg, 0.13 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (150 mg, 0.78 mmol), acetonitrile (0.4 mL) and N,N-diisopropylethylamine (68 μL, 0.39 mmol). The mixture was subjected to microwave irradiation at 200° C. for 2 h. The mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column to yield a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:21][N:19]([CH3:20])[C:17]([CH:16]([NH:15][C:11]([C:9]1[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[CH:8]=1)=[O:13])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18]
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cnc(Cl)cc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116, 47 mg, 0.24 mmol) in DMF (5 mL, anhydrous) was added 2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride (Preparation 8, 56 mg, 0.25 mmol), DIPEA (131 μL, 0.75 mmol) and HOBt (40 mg, 0.26 mmol) sequentially. The solution was stirred for 5 min prior to the addition of EDCI (55 mg, 0.29 mmol) in one portion. The resulting solution was stirred for 12 h at rt. The reaction mixture was partitioned between ethyl acetate (50 mL) and water/brine (150 mL, 1:1). The layers were separated and the aqueous phase extracted with ethyl acetate (3×50 mL), then the combined organics were washed with dilute HCl solution (1M, 50 mL), dilute NaOH solution (1M, 50 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography eluting with toluene/acetone (3:1) gave the title compound. δH (CDCl3): 2.88, 3.05 (6H, 2s), 3.18, 3.28 (2H, 2 dd), 5.41 (2H, m), 7.02 (1H, s), 7.28-7.34 (6H, m), 8.17 (1H, d), 8.68 (1H, s), 10.58 (1H, br s); m/z (ES+)=371.13 [M+H]+; RT=3.28 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].C(O[C:31](=[O:33])[CH3:32])(=O)C.C([O:37][CH2:38][CH3:39])(=O)C.Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:31](=[O:33])[CH3:32])[CH2:12][O:13][C:38](=[O:37])[CH3:39])=[O:8])[C:5]([I:17])=[C:4]([C:3]=1[I:26])[C:18]([NH:20][CH2:21][CH:22]([O:25][C:12](=[O:13])[CH3:11])[CH2:23][O:24][C:7](=[O:8])[CH3:6])=[O:19]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O

Procedure:
5-Amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (14.08 g, 0.02 mol), which had been prepared according to GB-A-1548594 was suspended in pyridine (200 ml) and acetic anhydride (57.1 g, 0.56 mol) was added dropwise with stirring and cooling. After stirring overnight, the mixture was poured into ethyl acetate (300 ml) and 20% aqueous HCl (200 ml). After extraction, the organic phase was washed with 2M aqueous HCl (20 ml), brine (70 ml), dried (Na2SO4) and evaporated. Yield 17.4 g (100%). The crude material was used without further purification, since analysis by HPLC and 1H NMR indicated, that the product was >97% pure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 706.4 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(NC(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 3-Methoxyphenyl isocyanate (0.03 mL, 0.24 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 30 (28 mg, 30% yield) as a yellow solid. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[NH:46][C:47](=[O:67])[C@H:48]([CH:54]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:49][C:50]([O:52][CH3:53])=[O:51])[O:35][CH2:34][C@H:33]1[C:68](O)=[O:69])=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH2:71]([NH2:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.N1C(C)=CC=CC=1C>CN(C=O)C.CCOC(C)=O>[CH2:71]([NH:78][C:68]([C@H:33]1[N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:37][C@@H:36]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[NH:46][C:47](=[O:67])[C@H:48]([CH:54]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:49][C:50]([O:52][CH3:53])=[O:51])[O:35][CH2:34]1)=[O:69])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (1.4 eq) was added to a stirred mixture a solution of (3S,6R)-4-(tert-butoxycarbonyl)-6-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-3-carboxylic acid (Example 1, step 11) (1 eq), benzyl amine (1.2 eq) and 2,6-lutidine (2 eq) in DMF (0.05 M) and the mixture was stirred at room temperature for 16 hrs. The mixture was diluted in EtOAc, The organic layer was washed with aqueous saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:15][C:13]1[CH:12]=[CH:11][N:10]2[CH:16]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[N:14]=1)=[O:22]
Reactant: COc1ncccc1C(=O)O
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ncccc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (200 mg, 951 μmol, Eq: 1.00), 2-methoxynicotinic acid (146 mg, 951 μmol, Eq: 1.00), diisopropylethylamine (369 mg, 498 μl, 2.85 mmol, Eq: 3) and propylphosphonic anhydride in ethyl acetate 50% (1.21 g, 1.12 ml, 1.9 mmol, Eq: 2) in tetrahydrofuran (10 ml) is stirred for 18 hours at 60° C. The mixture is diluted with ethyl acetate and washed 2 times with water and once with brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 2-methoxy-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)nicotinamide (36 mg, 11%) as a light yellow solid. MS: m/e=346.1 (M+H+), mp: 225-226° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C(#N)C.Cl[C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([S:29][CH3:30])[C:21]=1[C:31]#[N:32]>O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:20]2[N:25]3[N:26]=[CH:27][CH:28]=[C:24]3[N:23]=[C:22]([S:29][CH3:30])[C:21]=2[C:31]#[N:32])=[CH:3][CH:2]=1
Reactant: CSc1nc2ccnn2c(Cl)c1C#N
Reactant: NCc1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc2ccnn2c(NCc2ccncc2)c1C#N
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture comprising 460 mg of 4-picolylamine, 430 mg of triethylamine and 1 ml of acetonitrile was dropwise added to 950 mg of 7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 20 ml of acetonitrile under cooling with ice, followed by stirring for about 1 hour. After completion of the reaction, about 80 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 970 mg of 7-(4-pyridylmethyl)amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 3) having a melting point of from 153 to 154° C.
Reaction SMILES: [NH2:1][C:2](=[N:8]O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C(C)=CC=CC=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[C:19]#[CH:20]>C(N(CC)CC)C>[CH2:6]([O:5][C:3]([C:2]1[NH:8][CH:20]=[C:19]([C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:1]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(N)=NO
Reactant: C#CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(C(=O)OC(C)(C)C)c[nH]1

Procedure:
tert-Butyl 2-ethoxycarbonyl imidazole-4-carboxylate can be prepared as follows: the procedure is as in Example 1 but starting from 15 g of ethyl α-aminooximinoacetate, 500 ml of xylene, 19.1 of triethylamine and 14.3 ml of tert-butyl propiolate. The crude product (19 g) is chromatographed on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) to give 5 g of tert-butyl 2-ethoxycarbonylimidazole-4-carboxylate, employed as such in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:23](=[O:25])[CH3:24])[CH:8]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(Oc1ccnc(O)c1)C(O)C(C)(C)O2
Reaction time: 16 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° for 16 hours. The mixture is evaporated, purified chromatographically and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-acetamido-3-chromanol is obtained.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:59])([CH3:58])[O:6][C@@H:7]([C@@H:45]([CH3:57])[CH2:46][O:47]CC1C=CC(OC)=CC=1)[C@@H:8]([CH3:44])[CH2:9][N:10]([C:12](=[O:43])[C@H:13]([CH3:42])[C@@H:14]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:15]([CH3:33])[C@@H:16]([O:23]CC1C=CC(OC)=CC=1)[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11])([CH3:4])[CH3:3].C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[CH3:1][C:2]([Si:5]([CH3:58])([CH3:59])[O:6][C@@H:7]([C@@H:45]([CH3:57])[CH2:46][OH:47])[C@@H:8]([CH3:44])[CH2:9][N:10]([C:12](=[O:43])[C@H:13]([CH3:42])[C@@H:14]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[C@H:15]([CH3:33])[C@@H:16]([OH:23])[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11])([CH3:4])[CH3:3]
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)COCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution consisting of 1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol (1.9 g, 2.2 mmol), CH2Cl2 (40 mL), and H2O (1 mL) at room temperature, is added 2,3-dichloro-5,6-Dicyano-1,4-benzoquinone (DDQ), (2.53 g, 11.1 mmol). After stirring at room temperature for 10 min, the reaction mixture is purified by column chromatography on silica gel with hexane/EtOAc (90/10) to give the desired product (1.15 g, 82.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[N:38]([CH2:39][CH3:40])[CH2:36][CH3:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNCC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, diethylamine (0.5 ml) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 93%) of the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25](OC)=[O:26]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:26]=[C:25]([CH2:24][CH:18]1[CH2:19][CH:20]2[CH2:23][CH:17]1[CH2:22][CH2:21]2)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CC1CC2CCC1C2
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CC1CC2CCC1C2)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 63.9 g (0.516 mole) dimethyl methylphosphonate (Aldrich) in 645 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 251 ml of 2.2 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose about -65°. After an additional 5 minutes stirring at -78°, 43.5 g (0.258 mole) methyl (2-norbornyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 35 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 100 ml portions of chloroform (4x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, dimethyl 2-oxo-3-(2-norbornyl) propylphosphonate (b.p. 138°-141°/0.3 mm).