Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]1([CH3:17])[O:14][CH:13]([CH2:15][OH:16])[CH2:12][O:11]1.[Na].O>ClCCl>[CH3:9][C:10]1([CH3:17])[O:14][CH:13]([CH2:15][O:16][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:12][O:11]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Nc1cc(Cl)ccn1
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CC1(C)OCC(COc2ccnc(N)c2)O1
Temperature: 145 °C
Yield: 80 %

Procedure:
A sealed tube containing 4-chloro-2-pyridinamine (4 g, 31.2 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (8.4 g, 60.6 mmol), and sodium (1.46 g, 63.5 mmol) was heated at 145° C. for 8 hours. The mixture was cooled to ambient temperature; water (25 mL) and dichloromethane (50 mL) were added. The organic phase was separated, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica-gel to give 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine as a pale yellow solid (5.6 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=3[O:26][CH3:27])=[CH:14][C:13]2=[O:28])[C:3]([OH:29])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2OC)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1OC
Temperature: 23 °C
Reaction time: 2 h
Yield: 128.4 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (600 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (187 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (500 mg, 86%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:11][CH3:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COC(CN)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methoxyethanamine (0.071 g, 0.38 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.060 g, 0.16 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.022 g, 0.16 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.037 g, 0.19 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Biotage SP1 system, eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 67 mg of the title compound (77% yield).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:29])[NH:22][CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH:27]=O)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:20][C:21](=[O:29])[NH:22][CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH2:27][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (0.300 g, 1.2 mmol), Trans-(2-Formyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (0.294 g, 1.2 mmol), in 1, 2 dichloroethane (2 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (0.470 g, 2.2 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 0.288 g (0.74 mmol, 60% yield) of a white solid. MS (m/e): 391.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12]Cl)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1csc(-c2ccccc2)n1
Product: CC(C(=O)O)c1ccc2cc(OCc3csc(-c4ccccc4)n3)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 2-phenyl-4-(chloromethyl)thiazole and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 163°-164° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: COCCl
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Commercially available 7-dehydrocholesterol (18.3 g, 47.6 mmol) was dissolved in dichloromethane (150 mL), and N,N-diisopropylethylamine (24.9 mL, 143 mmol) and chloromethylmethyl ether (7.23 mL, 95.2 mmol) were added thereto at room temperature, followed by stirring overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with chloroform twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain (S)-3-methoxymethoxy-5,7-cholestadiene (18.1 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:11](=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[C:3]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cc(-c2cc(CCOCCC(=O)O)ccc2F)cn1
Reactant: COC(CNC1CCCCC1)OC
Product: COC(CN(C(=O)CCOCCc1ccc(F)c(-c2cnn(C)c2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (3.3 g) was prepared from 3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 13, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.99 and 7.98 (2×s, 1H), 7.86 (and 7.85 (2×s, 1H), 7.47 (m, 1H), 7.09-6.97 (m, 2H), 4.51 and 4.36 (2×t, J=5.4 Hz, 1H), 4.00 and 3.62 (tt, J=3.2 and 12.0 Hz, 1H), 3.920 and 3.918 (2×s, 3H), 3.75-3.63 (m, 4H), 3.34 (s, 3H), 3.33 (d, J=5.6 Hz, 1H), 3.32 (s, 3H), 3.25 (d, J=5.2 Hz, 1H), 2.86-2.79 (m, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.01 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH2:27])[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1
Reactant: CC(N)c1cc(F)cc(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (44 mg), 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 24 (66 mg), DMAP (36 mg), EDC.HCl (120 mg), and Et3N (120 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification of the crude product by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 78 mg of the title compound as a solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([CH2:9]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CO>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[O:28][CH:9]=[N:7][CH:8]=2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(-c2cnco2)cc1
Yield: 82.9 %

Procedure:
To a round bottom flask was added K2CO3 (5.09 g, 36.8 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.95 g, 20.25 mmol), MeOH (30 mL) and 4-(trifluoromethoxy)benzaldehyde (2.63 mL, 18.41 mmol). The reaction was refluxed for 2 hrs. After this time, the reaction mixture was concentrated under reduced pressure. The remaining residue was dissolved in water (50 ml). The aqueous solution was extract with EtOAc (50 ml). The EtOAc layer was washed with saturated aqueous NaCl (30 ml), dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 5-(4-(trifluoromethoxy)phenyl)oxazole, (3.5 g, 15.27 mmol, 83% yield) as an off white solid. Anal. Calcd. for C10H6F3NO2 m/z 229.1, found: 230.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.94 (s, 1H), 7.70 (d, J=8.80 Hz, 2H), 7.37 (s, 1H), 7.29 (d, J=8.25 Hz, 2H).
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: CN(C)C=O
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccccc1COC(=O)N(C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C1C(=O)N([Br:37])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:37][CH2:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncccc1C(F)(F)F
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccnc1CBr
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-pyridine (0.850 g, 5.28 mmol) (Ashimori, A. et al. Chem. Pharm. Bull. 1990, 33, 2446-2458) in CCl4 (30 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (0.193 g, 0.79 mmol) and NBS (1.96 g, 11.0 mmol). The mixture was stirred and heated at reflux for 24 h, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3×40 mL), and the extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording 2-bromomethyl-3-trifluoromethyl-pyridine as a pale yellow liquid (0.180 g, 14%). 1H NMR (CDCl3) δ 4.69 (s, 2H), 7.37 (dd, 1H, J=4.5, 7.8 Hz), 7.96 (d, 1H, J=7.8 Hz), 8.78 (d, 1H, J=4.5 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)[CH:44]=1)[C:39]([OH:41])=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[CH3:66][O:67][CH2:68][C:69]1[N:70]=[C:71]([NH2:74])[S:72][CH:73]=1>CN(C=O)C>[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:44]=1)[C:39]([NH:74][C:71]1[S:72][CH:73]=[C:69]([CH2:68][O:67][CH3:66])[N:70]=1)=[O:41])([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27]
Reactant: COCc1csc(N)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 4 h
Yield: 57 %

Procedure:
HATU (446 mg, 1.17 mmol) was added to 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]benzoic acid (450 mg, 0.94 mmol) followed by addition of DMF (4.5 mL), DIPEA (0.42 mL) and 4-(methoxymethyl)-1,3-thiazol-2-amine (160 mg, 1.11 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:2 to 2:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (325 mg, 56%).
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:23])[N:13]([CH2:24][CH3:25])[C:12]=2[N:11]=[C:10]1Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:27]([OH:29])[CH3:28]>>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:23])[N:13]([CH2:24][CH3:25])[C:12]=2[N:11]=[C:10]1[O:29][CH2:27][CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Reactant: CCO
Agent: [Na]
Product: CCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A solution of sodium (50 mg, 2.17 mmol) in ethyl alcohol (10 mL) was stirred at 40° C. under nitrogen until the sodium was consumed. Then 7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.414 mmol) was added at 0° C. and the mixture was stirred at 40° C. for 4 h. The mixture was quenched with ice-water (15 mL) and concentrated. The aqueous residue was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 77.9% yield) as yellow solid. LCMS retention time 1.488 min; LCMS MH+ 373.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([Br:12])=[CH:5][C:4]=1[F:13].[C:14](O)(=O)C.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([F:13])[CH:3]=[CH:8][C:7]=1[NH:9][O:10][CH3:14]
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1F
Reactant: CC(=O)O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CONc1ccc(F)cc1Br
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenyl methyl ether (25.5 g, 102 mmol), acetic acid (250 mL), ethanol (250 mL) and iron powder (22.7 g, 408 mmol) was heated to 100 C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralised by addition of potassium carbonate and filtered through Celite. The aqueous layer was extracted thrice with DCM. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (15 g, 67%) as a white solid. LC-MS (ES) (M+H)+ m/z=220.
Reaction SMILES: BrC1N=C2C=CN(COCC[Si](C)(C)C)C2=NC=1.CN.[CH3:21][NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1.[CH:40]1([N:46]=[C:47]=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CS(C)=O.ClCCCl>[CH:40]1([NH:46][C:47](=[O:48])[N:22]([CH3:21])[C:23]2[N:24]=[C:25]3[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]3=[N:27][CH:28]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C=NC1CCCCC1
Reactant: CNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Agent: CN
Agent: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CN(C(=O)NC1CCCCC1)c1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 150 °C
Yield: 27 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (0.328 g, 1.00 mmol) was dissolved in DMSO (2.5 mL). A solution of methylamine (33 wt % in EtOH, 2.5 mL, 20 mmol) was added and the resulting solution was heated at 150° C. in the sealed tube overnight, then cooled to RT. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to give a mixture of impure Methyl-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine, which was dissolved in 1,2-dichloroethane (3 mL). Cyclohexylisocyanate (0.38 mL, 3.00 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, concentrated, purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 0.110 g of 3-cyclohexyl-1-methyl-1-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (27% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (2.76 g), 4-chlorophenylboronic acid (2.113 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.920 g), sodium carbonate (3.58 g), toluene (43.3 mL) and water (13 mL) was stirred at 100° C. overnight. To the reaction mixture was added water at room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was fractionated by HPLC(C18, mobile phase: water/acetonitrile (10 mM ammonium hydrogencarbonate-containing system)), the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.242 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:20]I>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:20])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1ncccc1C(=O)Nc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-(2-chloro-3-pyridinyl)-2-methylnicotinamide (1.48 g) in DMSO (20 mL) was added NaH (60% in oil, 0.26 g). After 20 minutes, methyl iodide (0.45 mL) was added, and stirring was continued for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.51 g).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6]
Reactant: CC/C=C/CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C/CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.