Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of n-butylithium (50.97 cm3, 0.1274 mol, 2.5M in hexane) was added dropwise to a cooled (−78° C.) stirred solution of 4-bromo-4′-octyloxybiphenyl (40.00 g, 0.1108 mol) in THF (400 cm3). After 1 h, trimethyl borate (23.05 g, 0.2216 mol) was added dropwise to the reaction mixture maintaining a temperature of −78° C. The reaction mixture was allowed to warm to room temperature overnight. 20% hydrochloric acid (350 cm3) was added and the resultant mixture stirred for 1 h. The product was extracted into diethyl ether (3×300 cm3). The combined organic layers were washed with water (300 cm3), dried (MgSO4), filtered and the filtrate evaporated down under partially reduced pressure. The crude product was stirred with hexane for 30 minutes and filtered off to yield a white powder (26.20 g, 73%, m.pt. 134–136° C.).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]#[N:18].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[C:3]=1[C:17]([NH2:18])=[O:20]
Reactant: N#Cc1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carbonitrile in DMSO (20 mL), added potassium carbonate (0.50 eq), then added hydrogen peroxide solution (1.8 mL of 30% solution in H2O) dropwise over ice bath over the course of 10 minutes. After the final addition, kept on ice bath for 2 hrs, then heated to room temperature and stirred until complete by TLC. After 24 hrs, reaction had not come to completion, so the amount of hydrogen peroxide was doubled (additional 3.6 mL). Still incomplete, though progressing, the reaction was stirred at room temperature over the weekend. Reaction was complete by TLC after 3 days of stirring and was poured into 100 mL of ice water. After precipitate formed, solution was filtered and washed with water to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a gray powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:10][C@@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][NH:13]C(=O)OC(C)(C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[ClH:27]>O1CCOCC1>[ClH:27].[NH2:13][CH2:12][C@@H:11]([S:10][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(C#N)c(S[C@H](CNC(=O)OC(C)(C)C)c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C#N)c(S[C@H](CN)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from step (c) (45 mg) was dissolved in 4M HCl in dioxane (5 ml). The resulting solution was stirred at room temperature for 15 minutes, then the solvent was evaporated off. The residue was recrystallised from diethyl ether/ethanol to give the title compound as a white solid (19 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([OH:26])[CH2:23][NH:24][CH3:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([OH:26])[CH2:23][N:24]([CH3:25])[S:11]([C:10]2[C:6]3[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=3[S:8][CH:9]=2)(=[O:13])=[O:12])=[CH:20][CH:21]=1
Reactant: CNC[C@@H](O)c1ccc(F)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: CN(C[C@@H](O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (285 mg) and (1S)-1-(4-fluorophenyl)-2-(methylamino)ethanol (the compound of Preparation Example 38) (230 mg), the title compound (370 mg) was obtained as a light brown solid, in the same way as Preparation Example 41. The NMR data matched the racemic mixture described in Preparation Example 48. The optical purity as measured by high performance liquid chromatography (ChiralPak AD-H, hexane:2-propanol=8:2) was >99% e.e.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[C:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:31]=[C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]#[N:21])[N:30]=2)=[CH:8]1)[CH3:17]
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N#Cc1cccc(NC(=N)N)c1
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(C#N)c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-cyanophenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.48 (t, 3H, J=7.2 Hz, CH3), 4.39 (q, 2H, J=7.2 Hz, CH2), 7.27 (m, 1H, Ar—H), 7.36 (d, 1H, J=4.4 Hz, Pyrimidin-H), 7.42 (m, 1H, Ph-H or Ar—H), 7.51 (m, 1H, Ph-H or Ar—H), 7.98 (m, 1H, Ar—H), 8.38 (m, 1H, Ph-H or Ar—H), 8.46 (m, 2H, Pyrimidin-H or Ar—H), 8.63 (s, 1H, Ar—H), 8.94 (m, 1H, Ph-H or Ar—H), 9.85 (s, 1H, NH). MS (ESI+) m/z 341.1489 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21]O)=[CH:18][CH:17]=1)[CH3:14]>Cl.O.C(=O)([O-])[O-].[K+].[K+]>[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:1][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CNC(=C[N+](=O)[O-])NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 168 h

Procedure:
N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (2 ml) was added dropwise to 5-(dimethylamino)methyl-2-furanmethanol (428 mg) at 0°. After standing at 0° for 7 days the reaction was diluted with water (3 ml), excess potassium carbonate was added and the solid extracted with ethyl acetate (50 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide(0.247 g, 1 mmol) in dichloromethane (10 mL) and pyridine (0.5 mL) was added a solution of 4-biphenylcarbonyl chloride (0.217 g, 1 mmol) in dichloromethane (5 mL). After stirring overnight the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL). Separate the layers and wash the organic layer with water (2×10 mL), saturated sodium bicarbonate (2×20 mL), hydrochloric acid (0.2 N, 1×20 mL). Dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified by RPHPLC (30% ethyl acetate/hexane) to give 0.4 g (94%) of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[CH:8]2.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Cl-].[Cl-].[Al+3]>>[C:15]([C:6]1[CH2:7][CH2:8][C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OC)c2c1C=CCC2
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(OC)c2c1C=C(C(C)=O)CC2

Procedure:
In spite of the fact that in literature the attempts of acylating the compound II were reported as fruitless or non interesting because of the low yields, the 5,8-dimethoxy-3,4-dihydronaphthalene II is treated with acetyl chloride in the presence of an excess of aluminium trichloride, preferably 5-9 moles of aluminium trichloride for one mole of acyl chloride, at the temperature of −35°+25° C., preferably at 0° C. After the usual work-up and crystallisation with ethyl acetate, the product, 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene is obtained in yields higher than 70%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=2)[C:7]=1O.O=P(Cl)(Cl)[Cl:21]>ClCCl>[Cl:21][C:7]1[N:6]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:5]2[N:4]=[C:3]([CH3:18])[C:2]=1[F:1]
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(O)c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccccc3)nn2c(Cl)c1F
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133 (25 mmol, 1 eq, 6.2 g) in POCl3 (150 ml) is heated at 125° C. overnight. After cooling to room temperature, the solution is diluted in dichloromethane and quenched on ice (temperature must be kept under 25° C.). After separation of the organic layer, the aqueous phase is extracted twice with dichloromethane. The cumulated organic-layers are dried over MgSO4, filtered, evaporated under reduced pressure and the residue purified by chromatography on silicagel (CH2Cl2) to afford 6.6 g of 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[OH:15]>>[Cl:4][C:9]1[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=[C:7]([Cl:6])[C:8]=1[OH:15]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Product: Oc1c(Cl)cc(Cl)c(Cl)c1Cl

Procedure:
As the concentration of sulfuryl chloride increases, over-chlorination occurs, i.e., the 2,4,5-trichlorophenol becomes chlorinated to form more 2,3,4,6-tetrachlorophenol. The 2,3,4,6-tetrachlorophenol present becomes unacceptably high when the ratio of sulfuryl chloride to dichlorophenol significantly exceeds 1.3 to 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 5-chloro-2-(4-methoxy-phenoxy)-benzaldehyde (13 g, 49.7 mmol) in methanol (100 mL) was added pyrrolidine (4.1 mL, 49.5 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:5]#[N:6].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][C@H:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[C:5]#[N:6])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC[C@@H](O)CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCC[C@H](CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 186 mg (0.53 mmol) of (4R)-4-hydroxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile in 10 ml of pyridine were added a solution of 303 mg (1.6 mmol) of p-toluenesulfonyl chloride in 20 ml of pyridine and 10 mg of DMAP. The resulting mixture was stirred at room temperature overnight. The pyridine was then removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (hexane/ethyl acetate=4/1), thereby obtaining 130 mg (yield 49%) of (4R)-4-p-toluenesulfonyloxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]2[CH2:20][O:19]2)[C:11]=1[O:21][CH3:22])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>>[Cl:16][C:14]1[C:13]([CH3:17])=[C:12]([CH:18]([OH:19])[CH2:20][NH:30][CH:28]([CH3:29])[CH3:27])[C:11]([O:21][CH3:22])=[C:10]([CH:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:9])[CH:15]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CO1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C(O)CNC(C)C
Temperature: 80 °C
Yield: 4.9 %

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate (100 mg, 0.29 mmol, from Example 190, Step 1) was stirred in ethanol (2.0 mL, 34 mmol), 2-propanamine (120 μL, 1.5 mmol) and DIPEA (260 μL, 1.5 mmol) was added. The mixture was stirred at 80° C. over the weekend. Purification by preparative LC/MS (pH 10) gave the desired compound (5.7 mg, 5%). LCMS calculated for C20H34ClN2O4 (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Cl:19][CH2:20][S:21]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(Cl)CCl
Solvent: Clc1ccccc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(CCl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
10 g (0.034 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole are dissolved in 35 ml of pyridine. 21.4 g (0.068 mole) of 47% chloromethanesulphonyl chloride, dissolved in 1,2-dichlorobenzene, are added dropwise at 0° C. to 5° C. The mixture is stirred for five hours, during which the temperature slowly rises to 20° C. The mixture is then poured into ice-water and extracted with methylene chloride. The organic phase is separated off, washed with dilute hydrochloric acid and extracted three times with 100 ml of saturated sodium bicarbonate solution. The combined aqueous phases are brought to pH 1 with 10% strength hydrochloric acid and the product which has precipitated is taken up in methylene chloride. The methylene chloride phase is separated off, washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. 8.7 g (63% of theory) of 5-chloromethanesulphonamido-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 63°-66° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), 4-methoxyphenylsulfonyl chloride (320 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. HR-MS: m/z Calculated for C24H72NO8S2 522.1251; Found 522.1252.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)C(=O)O
Yield: 97.9 %

Procedure:
A mixture of diethyl 3-phenylpropylmalonate (5.5 g) and potassium hydroxide (2.8 g, 2.5 eq) in ethanol (20 ml) and water (30 ml) was refluxed for 5 hours. Work-up as described in Example 37b) gave the title compound (4.3 g, 98%); νmax (CH2Cl2) 2940 (br), 1727 and 1413cm-1 ; δH (CDCl3) 1.73 (2H, m, CH2), 2.00 (2H, m, CH2), 2.66 (2H, t, J 7.5 Hz, CH2), 3.44 (1H, t, J 6.8 Hz, CH), 6.84 (2H, bs, 2×CO2H), 7.26 (5H, m, Ph). EIMS M+ 222, DCIMS MNH4+ 240.
Reaction SMILES: Cl.[C:2]1(=[O:12])[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][NH:3]1>[Pt]=O.C(O)(=O)C>[C:2]1(=[O:12])[CH:11]2[CH:6]([CH2:7][NH:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][NH:3]1
Reactant: O=c1[nH]ccc2c1CCNC2
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1NCCC2CNCCC12

Procedure:
5,6,7,8-tetrahydro-2H-2,6-naphthyridin-1-one hydrochloride (250 mg, 1.339 mmol), platinum oxide (100 mg) and glacial acetic acid (10 mL) are stirred under hydrogen (5 bar) at r.t. for 24 h.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>CO.[C].[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Cc1cc(C)c(C(N)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C(N)=O)c(N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.4 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethylbenzamide (0.42 g, 95%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of 28 (200 mg) in methanol (5.5 ml) containing NaBH4 (28 mg) is stirred for 1 hour at room temperature. 29 (140 mg, 68%) is obtained after hydrolysis and customary extraction.
Reaction SMILES: O[C:2]1([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][CH3:18])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[C:32]2[CH2:31][CH2:30][O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1>CO>[O:29]1[CH2:30][CH2:31][C:32]2[C:24]([O:23][CH2:22][C@@H:20]([OH:19])[CH2:21][N:5]3[CH2:6][CH2:7][CH:2]([C:8]4[S:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[C:9]=4[CH2:17][CH3:18])[CH2:3][CH2:4]3)=[CH:25][CH:26]=[CH:27][C:28]1=2
Reactant: c1cc2c(c(OC[C@@H]3CO3)c1)CCO2
Reactant: CCc1c(C2(O)CCNCC2)sc2ccccc12
Solvent: CO
Product: CCc1c(C2CCN(C[C@H](O)COc3cccc4c3CCO4)CC2)sc2ccccc12
Yield: 35 %

Procedure:
A solution 4-hydroxy-4-(3-ethylbenzo[b]thiophen-2-yl)piperidine (0.069 g, 0.281 mmol) and (S)-(+)-4-(oxiranylmethoxy)-2,3-dihydrobenzo[b]furan (0.054 g, 0.281 mmol) in methanol (3 mL) was heated at reflux for 18 hours, and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/1% methanol in dichloromethane) to give the title compound as a clear colorless oil (0.043 g, 35%). FDMS m/e=438 (M++1). C26H31NO3S.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1>>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2N)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 20 %

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-ylcarbamate and 3-amino-6-bromo-picolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-yl-carbamate, (20%). LCMS (m/z): 623.2 (MH+); LC Rt=4.12 min.