Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35](O)=[O:36])=[CH:33][C:32]([S:38][CH3:39])=[N:31]2)=[CH:26][CH:25]=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>CN(C=O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35]([NH:2][C:3]3[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][N:14]([CH3:20])[C:13]5=[O:21])[CH:8]=3)=[O:36])=[CH:33][C:32]([S:38][CH3:39])=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: CSc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(C(=O)Nc2ccc(C)c(Nc3ccc4ncn(C)c(=O)c4c3)c2)n(-c2ccc(F)cc2)n1
Reaction time: 20 h
Yield: 55.5 %

Procedure:
6-(5-amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (110 mg, 0.28 mmol) was dissolved in DMF (5 mL) with 2-(4-fluoro-phenyl)-5-methylthio-2H-pyrazole-3-carboxylic acid (125 mg, 0.5 mmol) at RT. HATU (150 mg, 0.39 mmol) was added, followed by DIEA (0.5 mL, 2.87 mmol). The mixture was stirred for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 80 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 514.2.
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1CCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CCl

Procedure:
A solution of ammonia (5.2 ml) in tetrahydrofuran (250 ml) at -70° was contacted rapidly with a solution of 2-(chloromethyl)benzenesulfonyl chloride (21.8 g) in tetrahydrofuran (125 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under vacuum. The residue was contacted with ethyl acetate and a small volume of water. The organic layer was dried (MgSO4) and evaporated to give 19.8 g of white solid, m.p. 156°-157.5°. Recrystallization from toluene/ethyl acetate gave a sample with m.p. 157°-160°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH:13]1([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: Cl[Mg]C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)[PH](=O)C1CCCCC1

Procedure:
Following a procedure analogous to that of Example 1, but using 9.81 g of ethyl diethoxymethylphosphinate and 50 ml of a 2 molar solution of cyclohexylmagnesium chloride in diethyl ether and adding 20.7 g of potassium carbonate in 25 ml of water to precipitate inorganic salts, cyclohexyl(diethoxymethyl)phosphine oxide is obtained as colourless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](OCC)(OCC)([O:14][CH2:15][CH3:16])[CH3:13]>>[C:1]([C:2](=[C:12]([O:14][CH2:15][CH3:16])[CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Temperature: 159 °C
Yield: 73 %

Procedure:
160 g (1 mol) of diethyl malonate, 649 g (4 mol) of triethyl orthoacetate and 0.5 g of catalyst from Example 1 were heated to 130° C. in a glass apparatus having a distillation column. The metering-in of 102 g of acetic anhydride over the course of 7 h was then begun. The bottom temperature was increased to 159° C. with the distillation of low-boiling components at a head temperature of 72° to 73° C. After the end of the reaction, the residual low-boiling components were distilled off under a low vacuum and the excess triethyl orthoacetate was removed at 15 mbar. The desired product was then distilled over at 0.3 mbar and a head temperature of 100° to 102° C. Ethyl 2-carboethoxy-3-ethoxy-2-butenoate was obtained in a yield of 73% of the theoretical yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[O:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]2[CH:14]=[C:15]3[N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)=[CH:9][C:8]=1[C:32]([F:35])([F:34])[F:33])#[N:2]>CN(C=O)C.CCOC(C)=O.O>[O:19]=[C:17]1[N:16]2[CH2:20][CH2:21][NH:22][C:15]2=[CH:14][C:13]([O:12][CH2:11][C:10]2[CH:30]=[CH:31][C:7]([O:6][C:5]3[CH:4]=[C:3]([CH:38]=[CH:37][CH:36]=3)[C:1]#[N:2])=[C:8]([C:32]([F:34])([F:35])[F:33])[CH:9]=2)=[N:18]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(C(F)(F)F)c1)nc2=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4)cc2C(F)(F)F)c1
Yield: 13.7 %

Procedure:
To a solution of tert-butyl 7-((4-(3-cyanophenoxy)-3-(trifluoromethyl)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (27 mg, 0.051 mmol) in DMF (2 mL) was added silica gel. The reaction mixture was sealed in a microwave vial and irradiated with a microwave at 120° C. for 4 h, and then diluted with EtOAc and water. Separated organic portions were dried over anhydrous Na2SO4, filtered and concentrated. Purification via MDAP afforded the title product (3 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OCCOC)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COCCOc1ccn2c(C(=O)O)cnc2c1
Temperature: 40 °C
Yield: 90.6 %

Procedure:
Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (6.0 6 g; 22.9 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred under an atmosphere of nitrogen and heated at 40° C. for 22 hours. The mixture was allowed to cool and then concentrated under reduced pressure to give a yellow gum. Water (50 mL) was added and the mixture was stirred until homogeneous. Hydrochloric acid (2N) was added with stirring to adjust to pH3. The mixture was cooled with an ice/water bath. The resulting precipitate was collected by filtration and washed with a small amount of water (10 mL). The material was dried under vacuum to give 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (4.90 g).
Reaction SMILES: F[C:2]1[C:9]([Si](C)(C)C)=[C:8]([I:14])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:2]2[CH:9]=[C:8]([I:14])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:21])[CH3:16]
Reactant: C[Si](C)(C)c1c(I)ccc(C=O)c1F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(I)cc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 2-fluoro-4-iodo-3-trimethylsilanyl-benzaldehyde (14.2 g, 44.1 mmol) (Tetrahedron Letters 1992, p7499-7502) in DMF (50 mL) is treated with mercapto-acetic acid ethyl ester (5.80 mL, 52.9 mmol) and K2CO3 (12.2 g, 88.2 mmol). The resulting suspension is stirred at 75° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (3×50 mL,) and the organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (5-20% EtOAc/Hex), to give the title compound as an oil (9.40 g, 64%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.S(Cl)([Cl:21])=O.[CH3:23]O>>[ClH:21].[CH3:23][O:17][C:16](=[O:18])[CH:14]([CH2:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[NH2:15]
Reactant: CO
Reactant: COc1ccc(S(=O)(=O)CC(N)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C(N)CS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Part B: To an ice cooled solution of (8.87 g, 30 mmol) of β-(4-methoxyphenylsulfonyl)-D,L-alanine hydrochloride in 200 mL of dry methanol was added dropwise over 20 minutes (10.7 g, 90 mmol) of thionyl chloride, and the solution was refluxed overnight under nitrogen atmosphere. The contents were cooled to room temperature and concentrated by rotory evaporation and triturated with ether. The product was collected by filtration to yield 6.2 grams of β-(4-methoxyphenylsulfonyl)-D,L-alanine methyl ester hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(Cl)Cl>C1COCC1>[Br-:9].[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of 4-nitrobenzylbromide (25.0 g, 0.116 mol), triphenylphosphine (30.4 g, 0.116 mol) and chloroform (120 ml) was refluxed for 2 hours with stirring. The mixture was cooled to room temperature, diluted with THF (250 ml) and cooled in a freezer for 4 hours. The solid was collected and dried under vacuum to give p-nitrobenzyl triphenylphosphonium bromide (54.8 g, 99%).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>>[F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][O:6][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: OCC1CC1(F)F
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1OCC1CC1(F)F

Procedure:
Prepared analogously to example XII.1 using (2,2-difluorocyclopropyl)methanol and 2-fluoro-3-nitro-pyridine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(OCC)(=O)C.O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (2 g, 0.0116 mol) in acetone (40 ml) was treated with potassium carbonate (1.91 g, 1.2 equivalents) and benzyl bromide (1.44 ml, 1.05 equivalents). The reaction was refluxed under nitrogen. After 5-6 hours of reflux, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This was diluted further with water and the organic layer was separated, dried over magnesium sulfate and evaporated to dryness to afford a white fluffy powder. Yield=2.36 g (73%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:33])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:33])=[O:22]
Reactant: CNC(=O)c1c(C)[nH]c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)[nH]c2cc(Oc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2,-b]pyridine 4a with 6-hydroxy-2-methyl-1H-indol-3-carboxylic acid methylamide and Cs2CO3 in a manner as previously described for Example 1. 1H NMR (300 MHz, CD3OD) δ8.48 (1H, d, J=5.5 Hz), 7.91 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.6 Hz), 7.21 (1H, s), 7.00 (1H, d, J=8.6 Hz), 6.69 (1H, d, J=5.5 Hz), 4.50 (1H, m), 4.05-3.70 (4H, m), 2.97 (3H, s), 2.63 (3H, s), 2.40-1.90 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 451, found 451.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:14])[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][Br:19]>>[BrH:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:18][CH2:17][O:16][CH3:15])[C:10](=[NH:14])[S:11][C:12]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Cc1sc(N)nc1-c1ccc(Cl)cc1
Product: Br
Product: COCCn1c(-c2ccc(Cl)cc2)c(C)sc1=N

Procedure:
A mixture of 4-(4-chlorophenyl)-5-methyl-thiazol-2-ylamine (420 mg, 1.87 mmol) and 2-bromoethyl methyl ether (600 μL, 6.40 mmol) was processed according to the method of Example 12A to provide the title compound: MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=2)[C:23]([O:25]C)=[O:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[N:10]1)#[N:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=2)[C:23]([OH:25])=[O:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[N:10]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(-n3cc(-c4ccccc4)nn3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1-n1cc(-c2ccccc2)nn1
Yield: 34.6 %

Procedure:
12 mg of methyl 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinate was dissolved in a mixture of 234 μl of methanol and 351 μl of THF, then 61 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating under reflux for 3 hours. The reaction mixture was cooled, and neutralized with 61 μl of 1 M hydrochloric acid, then extracted with a mixture of 2-propanol and chloroform (1:4). The organic layer was washed with brine. The solvent of the organic layer was removed under reduced pressure, and the resulting residue was recrystallized from a mixture of 2-propanol and chloroform (1:4) to obtain 4 mg of 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=O)[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([CH:30]2[CH2:32][CH2:31]2)[OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:34]=[C:35]1[NH:40][C:39]2[CH:41]=[C:42](C=O)[CH:43]=[CH:44][C:38]=2[S:37][CH2:36]1>>[CH:30]1([CH:28]([O:29][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=3)[N:3]=2)[CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([NH:20][CH2:19][C:42]3[CH:43]=[CH:44][C:38]4[S:37][CH2:36][C:35](=[O:34])[NH:40][C:39]=4[CH:41]=3)[CH2:26][CH2:25]2)[CH2:31][CH2:32]1
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(O)C2CC2)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Product: COc1ccc2ncc(OC(CN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)C3CC3)nc2c1

Procedure:
The title compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Examples 1 and 9 using 2-chloro-7-methoxy-quinoxaline, [1-(2-cyclopropyl-2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([C:18]5[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][CH:3]=1.F[C:26]1[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30]([OH:32])[CH:31]=1.[C:36]([O-:39])([O-])=O.[K+].[K+].Cl>O.CN(C=O)C>[OH:32][C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][C:29]=1[N+:33]([O-:35])=[O:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:15][CH:14]4[CH2:13][CH:12]([CH2:11][C:10]([C:18]5[CH:19]=[CH:20][C:21]([O:24][C:26]6[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:36]([OH:39])[CH:31]=6)=[CH:22][CH:23]=5)([CH2:16]4)[CH2:9]2)[CH2:17]3)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)cc2)(C4)C3)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C34CC5CC(C3)CC(c3ccc(Oc6ccc([N+](=O)[O-])c(O)c6)cc3)(C5)C4)cc2)cc1O
Yield: 93 %

Procedure:
A mixture of 2.00 g (6.26 mmol) of 1,3-bis(4-hydroxyphenyl)adamantane, 2.00 g (12.7 mmol) of 5-fluoro-2-nitrophenol, 1.70 g (12.3 mmol) of anhydrous K2CO3, and 50 mL of dry DMF was reflux for 12 h under nitrogen. The mixture was allowed to cool and subsequently poured into 500 mL of distilled water. The resulting solution was acidied by concentrated hydrogen chloride to PH=3.5˜4.0. The precipitated product was collected, washed thoroughly with water until neutral, and then dried to give 3.46 g (93.1%) of 1,3-bis(4-(3-hydroxy-4-nitrophenoxy)phenyl)adamantane. mp 118˜122° C.; Elemental Anal. Calcd. for C34H30N2O8: C, 68.69; H, 5.05; N, 4.71. Found: C, 68.56; H, 5.12; N, 4.65. MS (EI) m/z 594 (M+, 100); IR (KBr): 3416, 2890, 2857, 1556, 1342 cm−1.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].S(=O)(=O)(O)O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][CH:16]=[CH:15]2.[Cl-].[Na+]>CN(C=O)C.O>[CH3:3][N:4]([CH2:1][C:15]1[C:14]2[C:18](=[CH:19][C:20]([Cl:21])=[C:12]([Cl:11])[CH:13]=2)[NH:17][CH:16]=1)[CH3:5]
Reactant: Clc1cc2cc[nH]c2cc1Cl
Reactant: CNC
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 5 °C
Yield: 89.3 %

Procedure:
19.6 kg of 37% aqueous formaldehyde solution and 16.3 kg of DMF were added to a reactor and then the reactor was cooled to 5° C. 33.3 kg of 33% aqueous dimethylamine solution was added. The reaction mixture was stirred for an additional hour at 0-5° C. upon completion of addition. 11.8 kg of concentrated sulfuric acid was added slowly to the mixture while the temperature was maintained below 10° C. The mixture was stirred for an additional 15 minutes and cooled to 5° C. A solution of 30 kg of 5,6-dichloroindole in 30 kg of DMF was added slowly to the reactor and stirred for an additional hour at 5° C. The mixture was allowed to warm to room temperature and stirred for 24 hrs. The mixture was then added to a reactor containing a solution of 50 kg industrial sodium chloride in 1600 L water. To this reactor was added 10 kg activated carbon and the mixture stirred for 30 minutes. Upon filtration, the filtrate was adjusted to pH>12 with 20% aqueous sodium hydroxide solution. The precipitate was filtered, washed with water until pH=7-8, centrifuged, and dried to yield crude 35 kg 5,6-dichlorogramine. Recrystallization in 70% ethanol produced the pure product with melting point of 150-154° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[O:15]1C2(CCNCC2)O[CH2:17][CH2:16]1.C12OC1CCCC2>C(O)C>[O:15]1[C:11]2([CH2:12][CH2:13][N:8]([C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[OH:1])[CH2:9][CH2:10]2)[O:14][CH2:17][CH2:16]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C1CCN([C@@H]2CCCC[C@H]2O)CC1
Agent: C1CCC2OC2C1
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 91 %

Procedure:
Preparation of (+/−)-trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-one. To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (14.7 g, 100 mmol) in ethanol (75 ml) was added cyclohexene oxide (10.0 g, 100 mmol). The reaction mixture was refluxed for 40 hours then cooled to room temperature and concentrated. The residue was chromatographed over silica gel (hexane/ethylacetate 4:1) to provide (+/−)-trans-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-cyclohexanol (22.1 g, 91%) as a white solid, MS (ISP): m/e=241.2 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19]C)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)O)cc1
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a stirring solution of methyl 3-[(4-t-butylbenzoyl)amino]-2-thiophenecarboxylate (9.67g, 30 mmol) in dioxane (75 mL) was added 2 M sodium hydroxide (75 mL). After 16 h, the mixture was acidified to pH 2 with 5 M hydrochloric acid, then diluted with ethyl acetate. The phases were separated and the aqueous layer was extracted a total of 3 times with ethyl acetate. The combined ethyl acetate fractions were dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to afford the product (8.09 g, 89% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16](Cl)=[O:17])[CH3:2].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:17])[CH3:2]
Reactant: CCOc1nc2c(nc1C(=O)Cl)c(C)nn2CC
Reactant: Nc1nccs1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1nc2c(nc1C(=O)Nc1nccs1)c(C)nn2CC
Reaction time: 1 h

Procedure:
15.75 g. of 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]-pyrazine-5-carbonyl chloride (0.058 mol.) are dissolved in 150 ml. of dry toluene. To this well cooled solution (ice/sodium chloride) a solution of 6.4 g. of 2-aminothiazole (0.638 mol.) and 6.5 g. of triethylamine (0.638 mol.) in 260 ml. of dry toluene is added dropwise under stirring. The reaction temperature is kept at -5° to -10°. Then stirring is continued at room temperature for 1 hour and at 50° for 1 hour. The precipitated triethylamine hydrochloride is filtered off and the toluene filtrate is removed in vacuo. Recrystallization of the residual 6-ethoxy-1-ethyl-3-methyl-N-2-thiazolyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxamide gives 15.4 g. of product (78%), m.p. 158°-159°.