Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Li]CCCC.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26]>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]([CH:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[OH:26])[CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
Under nitrogen, cool a THF (300 mL) solution of dibenzosuberane (23.9 g, 123 mmol) to 0° C. and add n-BuLi (1.6M, 90 mL, 144 mmol). Remove the cooling bath and the reaction stir at ambient temperature for 1 h. Cool the orange solution to 5° C. and add a solution of 3-bromobenzaldehyde (22.8 g, 123 mmol) in THF (100 mL). After 30 min., quench the reaction with saturated NH4Cl (200 mL) and remove most of the THF under reduced pressure. Shake the residue with brine/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 49.2 g colorless oil. HPLC shows 86% purity. The compound is sufficiently pure to carry on to the next reaction. Purify a small portion on silica gel using EtOAc/hexane to give a colorless oil that rapidly crystallized, mp 93.9° C., 1H NMR (CDCl3) δ3.00 (m,2H), 3.57 (m,2H), 3.94 (d,1H), 5.30 (d,1H), 6.38 (d,1H), 6.76-7.34 (m,12H); MS (EI) 360 (M−H2O).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:14][CH2:15]O)=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1>O.ClCCl>[CH:1]1([C:4]2[C:5]([CH:14]=[CH2:15])=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C1OCc2cc(CCO)c(C3CC3)cc21
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc2c(cc1C1CC1)C(=O)OC2
Reaction time: 0.33 h

Procedure:
To a 100 ml flask containing a stir bar was added compound 6-cyclopropyl-5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one, (0.5 g, 2.29 mmol), TEA (20 mL) followed by addition of dichloromethane (25 mL). The flask was placed in a cool bath of ° C., and slowly treated with methanesulfonyl chloride (6.5 mL, 83 mmol). The resulting mixture was then stirred for 20 min. TLC (hexanes/EtOAc=1/1) indicated completion of the reaction. The mixture was poured into saturated ammonium chloride and extracted with DCM. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated in vacuo. The residue (LC/MS: [(M+1)]+=297; tR=1.01 min) was dissolved in dichloromethane (25 mL) and treated with DBU (0.7 mL, 4.72 mmol) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated in vacuo. The material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:45]([Si:48]([CH:66]([CH3:68])[CH3:67])([CH:63]([CH3:65])[CH3:64])[O:49][C:50]1[CH:59]=[C:58]2[C:53]([CH:54]=[CH:55][CH:56]=[C:57]2[C:60](O)=[O:61])=[CH:52][CH:51]=1)([CH3:47])[CH3:46].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:60]([C:57]1[C:58]2[C:53](=[CH:52][CH:51]=[C:50]([O:49][Si:48]([CH:63]([CH3:65])[CH3:64])([CH:66]([CH3:68])[CH3:67])[CH:45]([CH3:46])[CH3:47])[CH:59]=2)[CH:54]=[CH:55][CH:56]=1)=[O:61])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)NCCNC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Reaction time: 4 h

Procedure:
To 2-(tert-butoxycarbonylamino)ethylamine (70 mg, 0.44 mmol) in dry THF (1 mL) under argon were added PYBOP (226 g, 0.43 mmol), 7-(triisopropylsilyloxy)-1-naphthoic acid, as described above in Step D, (148 mg, 0.43 mmol), and N,N-diisopropylethylamine (0.115 mL, 0.66 mmol). The reaction mixture was stirred for 4 hrs, then partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2 −10% to 15% EtOAc to yield the desired product as a white solid.
Reaction SMILES: [C:1]([CH:3](N1CCOCC1)[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])#[N:2].[H-].[Na+].[Cl:20][C:21]1N=C(Cl)[CH:24]=[CH:23][N:22]=1.CN(C=[O:32])C>>[Cl:20][C:21]1[N:2]=[C:1]([C:3]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:32])[CH:24]=[CH:23][N:22]=1
Reactant: CN(C)C=O
Reactant: Clc1ccnc(Cl)n1
Reactant: N#Cc1cccc(C(C#N)N2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cccc(C(=O)c2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
3-[cyano(morpholin-4-yl)methyl]benzonitrile (5 g, 22.0 mmol) was dissolved in 175 mL dry DMF and cooled to 0° C. Add sodium hydride (Aldrich, 0.58 g, 24.2 mmol) in one portion and stir for 25 minutes at 0° C. Add 2,4-dichloropyrimidine (Aldrich, 9.83 g, 66.0 mmol) in one portion. After 10 minutes, additional sodium hydride (1.16 g, 48.4 mmol) was added in one portion and the bath allowed to warm to room temperature. After 15 h, the reaction was quenched with water and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was dried over sodium sulfate and concentrated in vacuo. The crude material was taken up in 175 mL of 70% (v/v) acetic acid/water and refluxed for 45 min. The reaction mixture was cooled to room temperature, diluted with water, then extracted with ethyl acetate (2×). The combined organic portion was washed with saturated sodium bicarbonate (1×), dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by silica gel chromatography (3-35% ethyl acetate in hexanes) and the product-containing fractions concentrated in vacuo to give 3-[(2-chloropyrimidin-4-yl)carbonyl]benzonitrile (3.0 g, 56%). LRMS m/z (M+H) Calcd: 244.7, found 244.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:57]1([CH2:63][CH2:64][CH2:65]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:65][CH2:64][CH2:63][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.2 %

Procedure:
Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (333 mg, 0.66 mmol), PS—PPh3 resin, (loading=2.33 mmol/g, 797 mg, 1.86 mmol), 3-morpholinyl-propan-1-ol (0.26 ml, 1.88 mmol), and DEAD (0.31 ml, 1.91 mmol) were combined in CH2Cl2 (10 ml) and stirred at room temperature for 1-2 hrs. The reaction mixture was filtered and the resin thoroughly washed with CH2Cl2. The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with H2O (4×) and sat'd NaCl (1×) and then extracted with 1N HCl (3×). The combined 1N HCl extractions were washed with EtOAc (2×). The acidic aqueous phase was then basified with 1N NaOH and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25 mM NH4OAc/acetonitrile) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide (42.6 mg, 10%). 1HNMR (400 MHz, DMSO-d6): d 10.37 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m, 2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s, 3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2. found 634.1.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@:8]1([C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:14]([OH:16])=[O:15])=[O:6])[CH:2]=[CH2:3].C(N=C=N[CH2:25][CH2:26][CH2:27]N(C)C)C.CN(C1C=CC=CN=1)C.C(O)C=C>C(Cl)Cl>[CH2:27]([O:15][C:14]([C@@H:10]1[C@@H:9]2[C@H:11]1[CH2:12][CH2:13][C@@:8]2([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:17]([OH:19])=[O:18])=[O:16])[CH:26]=[CH2:25]
Reactant: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: C=CCO
Solvent: ClCCl
Product: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)OCC=C)[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (13.4 g, 49.81 mmol, 1.0 equiv) was suspended in methylene chloride (400 mL). N-Ethyl-N′-dimethylaminopropylcarbodiimide (9.55 g, 49.81 mmol, 1.0 equiv) and dimethylaminopyridine (0.608 g, 4.98 mmol, 0.1 equiv) were added at room temperature under nitrogen. After a solution formed, allyl alcohol (3.4 mL, 2.89 g, 49.81 mmol, 1.0 equiv) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as an oil (44% yield).
Reaction SMILES: [H-].[Na+].[CH:3]([SH:6])([CH3:5])[CH3:4].[H][H].Cl[C:10]1[CH:15]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[Cl:22][C:21]1[CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=[C:17]([Cl:27])[C:16]=1[C:14]1[CH:13]=[CH:12][C:11]([N+:28]([O-:30])=[O:29])=[C:10]([S:6][CH:3]([CH3:5])[CH3:4])[CH:15]=1
Reactant: [H][H]
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
0.33 g (8.3 mmol) of 60% sodium hydride was stirred in 50 ml of N,N-dimethylformamide at room temperature while 0.7 g (9.2 mmol) of isopropyl mercaptan was added dropwise. After generation of hydrogen was over, 3.0 g (8.1 mmol) of 1-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrobenzene was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into about 200 ml of ice-cold water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate was washed with 100 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 3.0 g of [5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrophenyl]isopropyl sulfide (yield 90.0%) as a yellow dough (nD20 1.5881).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[N:53]=1>CN(C=O)C.O>[Cl:51][C:52]1[N:53]=[C:54]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)[CH:55]=[CH:56][CH:57]=1
Reactant: Clc1cccc(OC2CCNCC2)n1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(Cl)n2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 18.27 %

Procedure:
DIPEA (271 mg, 2.1 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (162 mg, 0.7 mmol) in DMF (2 mL) followed by HOBt (94 mg, 0.7 mmol) and EDCI.HCl (134 mg, 0.7 mmol). After 2 minutes 2-chloro-6-(piperidin-4-yloxy)-pyridine hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) (140 mg, 0.7 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 53 mg (18.27% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(6-chloro-pyridin-2-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 90%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (b, 1H), 7.8 (m, 3H), 7.4 (m, 3H), 7.1 (m, 1H), 6.8 (m, 1H), 5.2 (m, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.7 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][CH2:15][NH2:16].[Cl:20][CH2:21][C:22](O)=[O:23].C(Cl)CCl.O>ClCCl>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: NCCCOc1cccc(CC2CCCCCN2)c1
Reactant: O=C(O)CCl
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCl)NCCCOc1cccc(CC2CCCCCN2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.22 g of 3-{3-(1-perhydroazepinylmethyl)phenoxy}propylamine was dissolved in 10 ml of dichloromethane, and cooled in an ice bath. 0.1 g of monochloroacetic acid and 0.2 g of EDC were added to this solution, and stirred at 0° C. for 30 minutes then at room temperature overnight. 10 ml of water and 10 ml of dichloromethane were added to the reaction solution, and the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to obtain colorless oily N-[3-{3-(1-perhydroazepinylmethyl)phenoxy}propyl]-2-chloroacetamide. Yield: 0.15 g. ##STR159##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
In a 25 ml round-bottomed flask, 1H-indazole-5-carbonitrile (400 mg, 2.79 mmol) was dissolved in DMF (7 ml). Potassium hydroxide (607 mg, 10.8 mmol) was added followed by iodine (1.42 g, 5.59 mmol). The dark brown suspension was stirred at room temperature for 3 h then was quenched with 10% aqueous NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 396 mg (53%) of 3-iodo-1H-indazole-5-carbonitrile as a light yellow powder.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH2:14].C(N(CC)CC)C.O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:18]1[CH:19]=[CH:20][C:15](/[CH:13]=[CH:14]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1/C=C/c1ccncc1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
50 g (0.22 mol) of ethyl 2-bromobenzoate, 30 g (0.29 mol) of 4-vinylpyridine and 75 ml (0.54 mol) of triethylamine were dissolved in 750 ml of dimethylformamide. Then 0.36 g of palladium(II) acetate, 0.96 g of tri(o-tolyl)phosphine and 1 ml of water were added and the mixture was refluxed for 3 h. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo. The residue was recrystallized [lacuna] cyclohexane/petroleum ether, resulting in 45.3 g (83%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH:40]([NH2:42])=[O:41]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:42]([CH2:16][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:40]=[O:41])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: COc1cc(CN(C=O)S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A mixture of Example 1A (22.3 g, 0.15 mol), 3,4,5-trimethoxybenzaldehyde (35.32 g, 0.18 mol), and camphorsulfonic acid (3.48 g, 15 mmol) in formamide (40 mL) was stirred vigorously at 65° C. for 16 hours, cooled to room temperature, and filtered. The resulting solid was washed several times with methanol and dried to provide 13.4 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.CCOC(C)=O>[Pd].CO>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:19])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a stir bar was charged with N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 (300 mg, 1.1 mmol), 10% Pd/C (˜150 mg), EtOAc (24 mL) and MeOH (6 mL). The mixture was purged with H2 (3× evacuation and back-fill cycles) then allowed to stir under an H2 balloon. After 24 h, TLC and LCMS indicated that the starting material was completely consumed. The mixture was filtered through a pad of Celite, washing with MeOH and CH2Cl2. Recrystallization from MeOH/CH2Cl2 afforded 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 as a pale yellow crystalline solid.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[CH3:6]C(C)([O-])C.[K+].[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>O>[CH:2]([C:1]1[CH2:4][CH2:16][CH2:12][CH2:13][CH2:14][CH:3]=1)=[CH2:6]
Reactant: CC(C)(C)O
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C=CC1=CCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The latter compound (6.7 g) was dissolved in 40 mL of 1:9 THF:tert-butanol and added dropwise to an ice cold solution of potassium tert-butoxide (8.44 g) in 100 mL of 1:9 THF:tert-butanol. The reaction mixture was stirred in ice for 0.5 hours and at room temperature for 0.5 hours. The reaction mixture was diluted with water (200 mL) and extracted with pentane (2×50 mL). The combined organic layer was washed with water (7×150 mL). organic layer was separated, dried with anhydrous magnesium sulfate, filtered and the solvent removed at atmospheric pressure using a Vigreaux column to give a liquid. Distillation gave 2.6 g (85% yield) of 1-vinyl cycloheptene as established by NMR and IR analyis.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35]C1N=C(NCCC)N=C(C(O)=O)C=1.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH3:34][C:15]1[CH:16]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH2:33][CH3:35])[N:25]=3)[O:21][N:20]=2)[CH:18]=[C:3]([CH3:1])[C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12]
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CCCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{2,6-Dimethyl-4-[5-(6-methyl-2-propylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.92 min, [M+H]+=471.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:15]=[CH:14][N:13]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccnc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-chloropyridin-4-ol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]1[OH:12].[Cl:13][C:14]1[C:19]([NH2:20])=[C:18](Cl)[N:17]=[C:16]([S:22][CH2:23][CH2:24][CH3:25])[N:15]=1.C(N(CC)CC)C>C(OCC)(=O)C.CCCCCC>[NH2:20][C:19]1[C:18]([NH:1][C@@H:2]2[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]2[OH:12])=[N:17][C:16]([S:22][CH2:23][CH2:24][CH3:25])=[N:15][C:14]=1[Cl:13]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: N[C@@H]1C[C@H](OCCO)[C@@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Temperature: 75 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A mixture of (1S,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLA; 1.06 g, 6 mmol), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (CLINA; 1.43 g, 6 mmol), triethylamine (1.09 g, 7.8 mmol) and polyethyleneglycol PEG400 (2 mL) was stirred for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) and evaporated under reduced pressure to give a resinous material which solidified upon trituration in n-hexane (25 mL). After filtration there was obtained OLACINA as a grey powder (2.0 g, 88% yield): 13C NMR (DMSO-d6, 125 MHz) δ13.3, 22.8, 32.2, 34.7, 54.8, 60.4, 69.8, 72.4, 75.2, 82.4, 119.9, 137.5, 152.5, 155.1.