Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl>>[NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(CCC(=O)O)C(=O)O
Agent: Cl
Product: N[C@H](CCC(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
An experiment for resolution of D,L-glutamic acid.HCl by a device composed of two compartments separated by a membrane is described. A round perspex piece of 9 cm exterior diameter, 6 cm internal diameter and 0.9 cm thickness was connected to another piece of perspex of the same dimensions via a membrane with cut-off of 10000-15000, and mechanically shaken for 48 h. Into each compartment a solution of 4 g D,L-glutamic acid in 20 ml of HCl 5N was introduced (total 8 g/40 ml). Poly-(Nε -acryloyl-L-lysine) or poly-(Nε -methacryloyl-L-lysine) was dissolved in one compartment (A) while poly-(Nε -acryloyl-D-lysine) or poly-(Nε -methacryloyl-D-lysine) was dissolved in the second compartment (B). Each compartment was seeded with 0.5 mg of D,L-glutamic acid.HCl. After 48 h the solid from each compartment was filtered to give from compartment (A) 605 mg of D-glutamic acid.HCl with (α)D=-24° C. and from compartment (B) 575 mg of L-glutamic acid.HCl with (α)D=+24° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]3[N:15]([CH3:18])[N:16]=[CH:17][C:12]3=[C:11]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=2)[CH:6]=[CH:5][N:4]=1.I[Si](C)(C)C>C(#N)C>[CH3:18][N:15]1[C:13]2=[N:14][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([OH:2])[CH:8]=3)=[CH:10][C:11]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:12]2[CH:17]=[N:16]1
Reactant: COc1cc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3ccnc(O)c3)nc21
Temperature: 70 °C

Procedure:
To 6-(2-methoxypyridin-4-yl)-1-methyl-4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-b]pyridine 118 (100 mg) in acetonitrile (1 mL) was added iodotrimethylsilane (140 μl). The resulting mixture was heated 3 h at 70° C. and purified by reverse phase HPLC to provide 120. MS (ESI) m/z 397.1 (M+1)+
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Brc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-bromo-4-ethynylbenzene (Alfa Aesar, 80 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.95 (m, 5H), 9.32 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 304 (M+H)+, 302 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[C:6](S(O)(=O)=O)(S(O)(=O)=O)[CH:5]=1)([O-])=O.[NH2:27]C1C=C(S(O)(=O)=O)C2C(C=1)=CC=CC=2.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1>>[NH2:27][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1
Reactant: Nc1ccc(C=CC2C=CC([N+](=O)[O-])=CC2(S(=O)(=O)O)S(=O)(=O)O)cc1
Reactant: Nc1cc(S(=O)(=O)O)c2ccccc2c1
Agent: c1c[nH]nn1
Product: Nc1ccccc1C=Cc1ccccc1

Procedure:
Diazotized 4-nitro-4′-aminostilbene-2,2-disulfonic acid and 3-aminonaphthalene-1-sulfonic acid were subjected to coupling. The resultant was turned into a triazole, and a nitro group of the triazole was reduced to an amino group by means of a conventionally known method to produce aminostilbene-triazole. Aminostilbene-triazole was dissolved into water, and sodium nitrite and hydrochloric acid were added dropwise to the solution to perform diazotization. The resultant was added dropwise to an aqueous solution of a compound represented by Compound (4) below, and the whole was subjected to coupling, followed by dialysis with sodium chloride. The compound was diazotized with an aqueous solution of sodium nitrite, and was turned into a triazole by adding an aqueous solution of 6-aminonaphthalene-2-sulfonic acid. The triazole was dialyzed with sodium chloride to prepare a coloring material represented by Exemplified Compound 1 below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([OH:16])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([O:16][C:17](=[O:19])[CH3:18])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CSC(COCc2ccccc2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CSC(COCc2ccccc2)CO1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
5-Benzyloxymethyl-1,4-oxathian-2-ol (3.46 g) was dissolved in pyridine (37 ml), and the solution was cooled to 5° C. Acetic anhydride (3.27 ml) was added dropwise thereto, and the solution was stirred at the same temperature for 4 hours to complete the reaction. After removing the solvent by evaporation under reduced pressure, the residue was azeotroped with toluene to completely remove pyridine to obtain pale brown syrup. The syrup was purified on a silica gel column (eluent: n-hexane/ethyl acetate=3/1) to provide the desired product (2.94 g) as colorless syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[F:17][C:12]([F:16])([CH:13]([F:15])[F:14])[CH2:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(F)(F)C(F)F)nc1
Yield: 446.1 %

Procedure:
A solution of 5-nitro-2-(2,2,3,3-tetrafluoro-propoxy)pyridine (1.5 g, 0.6 mmol) in methanol (30 ml) was hydrogenated over 10% Pd—C (150 mg) at atmospheric pressure until no further gas was absorbed. The reaction mixture was filtered over celite and the filtrate concentrated to dryness to yield 6-(2,2,3,3-tetrafluoro propoxy)-pyridin-3-ylamine (600 mg, 50%) as solid.
Reaction SMILES: BrC1C(C)(C)CC2C(C=1)=CC=C(OC)C=2.BrC1C=CC=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-])=O)[C:34]([CH3:39])([CH3:38])[CH2:35]2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31](=[CH:30][CH:29]=1)[CH:32]=[C:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46])[C:34]([CH3:39])([CH3:38])[CH2:35]2
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1[N+](=O)[O-])=C2
Agent: COc1ccc2c(c1)CC(C)(C)C(Br)=C2
Agent: O=[N+]([O-])c1ccccc1Br
Product: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1N)=C2
Yield: 53.5 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-1,2-dihydronaphthalene and 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-2,2-dimethyl-3-(2-nitrophenyl)-1,2-dihydronaphthalene (1.4 g) was used according to an analogous synthetic method to Example 57 to provide the title compound (676 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=2)=[N:3][CH:2]=1.[OH-].[Na+].[ClH:19]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: Cl
Reactant: COC(=O)c1ccc(-c2ccncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cl)c1ccc(-c2ccncn2)cc1

Procedure:
Methyl 4-(4-pyrimidinyl)benzoate (0.41 g, 1.9 mmol) was stirred at room temperature in ethanol (20 mL) and 2N NaOH(aq) (20 mL) for 1 hour. 2N HCl(aq) was added until a precipitate formed. The resulting suspension was concentrated in vacuo and azeotroped with toluene. Thionyl chloride (100 mL) and DMF (1 drop) were added and the reaction mixture refluxed for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped twice with dichloromethane to yield 4-(4-pyrimidinyl)benzoyl chloride. The acid chloride was suspended in dichloromethane (100 mL) and 1-(6-bromonaphth-2-ylsulphonyl)piperazine hydrochloride (0.545 g, 1.5 mmol) added as a solid in two portions followed by triethylamine (2.2 mL, 15 mmol). The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The resulting solid was separated between ethyl acetate (100 mL) and water (2×100 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to yield a black oil which was subjected to chromatography (SiO2: 40%, 50%, 60% Ethyl acetate/Hexane) to yield 1(6-bromonaphth-2-ylsulphonyl)4-[4-(4-pyrimidinyl)benzoyl]piperazine as a white solid; 1H NMR (250 MHz, DMSO-d6) δ=2.94 to 3.18 ppm (m,4H), δ=3.40 to 3.83 ppm (m,4H), δ=7.49 ppm (d,2H), δ=7.83 ppm (m,2H), δ=8.10 ppm (dd,1H), δ=8.14 to 8.23 ppm (m,4H), δ=8.43 ppm (d,1H), δ=8.49 ppm (s,1H), δ=8.89 ppm (d,1H), δ=9.26 ppm (s,1H); MS (M+H)+ 536.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:10][C:11](N)=[O:12].S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.Cl>C(OCC)(=O)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:10][C:11]([NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])=[O:12]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(N)=O
Agent: Cl
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: C[Si](C)(C)NC(=O)N[Si](C)(C)C

Procedure:
10 ml of hexamethyldisilazane (48 mmoles) were added to 2.4 g (40 mmoles) of urea and 73 mg (0.4 mmole) of saccharin in 15 ml of refluxing ethyl acetate and evolution of ammonia started immediately and was completed after refluxing for 20 minutes established by titration with 1 N HCl. The volatile material was evaporated under vacuum and the residue was vacuum dried to obtain 8.06 (99%) of N,N'-bis-(trimethylsilyl)-urea melting at 219°-222° C. Without the addition of saccharin as a catalyst, evolution of ammonia was slow and the reaction had to be carried out for at least 24 hours for completion.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21](Cl)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([S:29][CH3:28])[CH:31]=3)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)c1cc(F)cnc1Cl
Reactant: CSc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid benzyl ester (2.14 g, 5.5 mmol), 3-methylsulfanylphenol (844 mg, 6.02 mmol) and caesium carbonate (2.67 g, 8.21 mmol) were suspended in dimethylformamide (50 ml) and the reaction was heated to 65° C. and stirred at this temperature under nitrogen for 18 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (50 ml). It was then extracted with ethyl acetate (3×40 ml) and the combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane:ethyl acetate (2:8 changing to 1:3 then 3:7, by volume) to give cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (2.0 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20]/[C:21](=[N:32]/O)/[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:32]=[C:21]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[N:20]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COC(=O)c1cccc(/C(N)=N\O)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(C(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (128.15 mg; 0.5 mmol) and methyl 3-[(E)-amino(hydroxyimino)methyl]benzoate, prepared as described in US2004/204461 from methyl 3-cynaobenzoate (Maybridge; RJC00610EA), (97 mg; 0.5 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by FC (c-hex/EtOAc: 9.5/0.5 to 5/5). It was then suspended in MeCN and filtrated, affording the title compound as a white solid. LC/MS (Method B): 415.2 (M+H)+. HPLC (Method A) Rt 6.48 min (Purity: 96.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[C:35]([CH3:42])=[C:36]([CH:40]=O)[NH:37][C:38]=3[CH3:39])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>C(O)C.N1CCCCC1>[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[C:35]([CH3:42])=[C:36](/[CH:40]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:37][C:38]=3[CH3:39])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(CC2CC2)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(CC2CC2)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound. MS m/z 613 [M−1].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH:7]2[O:11][C:10](=[O:12])[N:9]=[N:8]2)[CH2:6][CH2:5]1.[Cl:13][C:14]1[CH:15]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=[C:18]([Cl:21])[C:19]=1Cl.O>CN(C)C=O>[CH3:3][C:4]1([C:7]2[O:11][C:10](=[O:12])[N:9]([C:19]3[C:18]([Cl:21])=[CH:17][C:16]([C:22]([F:23])([F:25])[F:24])=[CH:15][C:14]=3[Cl:13])[N:8]=2)[CH2:6][CH2:5]1
Reactant: CC1(C2N=NC(=O)O2)CC1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(=O)o2)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
After 44 mg (1.1 mmol) of 60% sodium hydride was added to a solution of 0.14 g (1 mmol) of 5-(1-methylcyclopropyl)-1,3,4-oxadiazolin-2-one in 5 ml of N,N-dimethylformamide at room temperature, the mixture was stirred at the same temperature for 15 minutes. To the mixture was added 0.25 g (1 mmol) of 3,4,5-trichlorobenzotrifluoride followed by heating a 80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated under reduced pressure to give the crude product. The crude product was subjected to silica gel column chromatography to give 35 mg of 5-(1-methylcyclopropyl)-3-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazoline-2-one.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 7 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 19.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1cnccn1
Reactant: NCCCN
Product: NCCCNc1cnccn1

Procedure:
Reacting 2-chloropyrazine with 1,3-diaminopropane by the procedure of Example 93 gives 2-(3-aminopropylamino)-pyrazine and reacting this intermediate with methyl isothiocyanate gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]1[CH2:12]CC[CH2:9]1.CC(C)([O-])C.[K+].COCCl>CN(C)C=O>[CH3:9][O:8][CH2:12][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: COCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Reaction time: 0.42 h
Yield: 75 %

Procedure:
To a mixture of 3-hydroxypyridine (50.0 g, 0.525 mol), tetrahydrofuran (107 mL) and N,N-dimethylformamide (285 mL), potassium t-butoxide (65 g, 0.579 mol) was added at −15° C. After 25 minutes, chloromethyl methyl ether (44.4 g, 0.552 mol) was slowly added at −15° C. The reaction temperature was elevated over 2 hours and the reaction mixture was concentrated. The resulting oil was poured into saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 3-(methoxymethoxy)pyridine (54.7 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17]O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][I:43])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(N2CCN(CCCI)CC2)cc1Cl

Procedure:
Compound 7p was mixed with triphenylphosphine resin, imidazole and iodine in DCM as described in General Procedure B. The product compound 11p was used without further purification for the next reaction. MS (LC/MS, ESI): 399 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc(SC)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(/C=C/c2ccc(C(=O)O)cn2)cc1
Temperature: 0 °C
Yield: 98.7 %

Procedure:
Methyl 6-{(E)-2-[4-(methylsulfanyl)phenyl]ethenyl}nicotinate (80 mg, 0.280 mmol; see step (i) above) was suspended in methanol (4 mL) and a solution of sodium hydroxide (250 mg, in water 10 mL) and the reaction mixture was heated under reflux for 4 h. The solvent was removed under reduced pressure and the aqueous layer was extracted with DCM. The aqueous layer was cooled to 0° C. with ice then HCl(conc.) was added dropwise with stirring until pH4, where a precipitate formed. The solid material was filtered, washed with water and dried under reduced pressure to give the title compound as pale yellow solid (75 mg, 99%).
Reaction SMILES: CN1CCOCC1.[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)[CH2:37][CH2:36]3)=[CH:29][CH:28]=2)=[CH:11][C:12](=[O:26])[N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[CH:14]=1.ClC1N=C(OC)N=C(OC)N=1.[O:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH:60]1[O:65][NH2:66]>CC1CCCO1.O>[F:8][C:9]1[C:10]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)[CH2:37][CH2:36]3)=[CH:31][CH:32]=2)=[CH:11][C:12](=[O:26])[N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([NH:66][O:65][CH:60]2[CH2:61][CH2:62][CH2:63][CH2:64][O:59]2)=[O:19])[CH:14]=1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC1CCCO1
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl morpholine (340 uL, 3.09 mmol) was added to a suspension of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}-phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (1.28 g, 2.21 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (510 mg, 2.87 mmol) in 2-methyltetrahydrofuran (30 mL) and the reaction was stirred for 1 h at rt. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (61 mg, 0.52 mmol) was added, and the reaction was stirred overnight at rt. Water (50 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (75-100%) to afford the title compound as a light brown residue (700 mg, 46%). MS (LCMS) m/z 677.4 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH:6]([C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)=O>C(O)C>[OH:3][N:2]=[CH:6][C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
0.60 g of hydroxylamine hydrochloride and 3.0 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.00 g (2.93 mmol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-cloroquinazoline in 30 ml of ethanol. The obtained mixture was stirred at 60° C. for 30 minutes and cooled by allowing to stand. The crystal thus precipitated was recovered by filtration, washed with ethanol and n-hexane and air-dried to give 1.00 g of the title compound as a white crystal.