Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:35].[K+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:35])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Reactant: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 85 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]hexyl]urea, 0.74 g of potassium chloride, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-80° C. for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with three 40 ml portions of brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to yield 1.5 g of a brown oil. The oil was purified by chromatography to yield 1.5 g of the desired product as a light yellow oil in 86% yield.
Reaction SMILES: [CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH3:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([NH:19][NH2:20])=[O:18].C([O:31][CH2:32][CH3:33])(=O)C>>[C:17]([C:13]1[CH:12]=[C:7]([CH:8]=[CH:33][C:32]=1[OH:31])[C:6]([NH:20][NH:19][C:17]([C:13]1[O:14][CH:15]=[CH:16][C:12]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[C:21]([CH3:27])=[C:22]([CH3:26])[CH:23]=[C:24]([CH3:25])[C:2]=1[CH3:1])=[O:18])=[O:5])#[N:19]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C)c(C)c(COc2ccccc2-c2ccoc2C(=O)NN)c1C
Product: Cc1cc(C)c(C)c(COc2ccccc2-c2ccoc2C(=O)NNC(=O)c2ccc(O)c(C#N)c2)c1C

Procedure:
In ethyl acetate (10 ml), a mixture composed of 3-[2-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 6, 0.36 g) and the compound of Reference Example 63 (0.33 g) was heated at reflux overnight while stirring. The thus-precipitated crystals were filtered and recrystallized from ethyl acetate, thereby giving 0.18 g of the desired compound. Melting point: 215-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C=O)cc1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To 3-chloro-4-hydroxybenzaldehyde (5.00 g, 31.9 mmol) and pyridine (5.0 mL, 61.8 mmol) in dichloromethane (40 mL) at 0° C. was added acetic anhydride (4.0 mL, 42.3 mmol) over a 20-minute period. The mixture was stirred for 1.5 hours more, warmed to 20° C., then worked up (10% hydrochloric acid wash) to afford 4-acetoxy-3-chlorobenzaldehyde as a pale-yellow solid (6.01 g, 92% yield): m.p. 33-35° C.; Rf0.30 (20% ethyl acetate/hexane); 1H NMR spectrum (400 MHz, CDCl3) δ 2.39 (s, 3, CH3), 7.34 (d, J=8.0 Hz, 1, ArH), 7.82 (dd, J=7.6,2 Hz, 1, ArH), 7.98 (d, J=1.6 Hz, 1, ArH), 9.96 ppm (s, 1, CHO).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:13]([NH:16][NH2:17])(=[O:15])[CH3:14]>>[C:13]([NH:16][NH:17][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:12])(=[O:15])[CH3:14]
Reactant: CC(=O)NN
Reactant: O=C(O)c1ccc2occc2c1
Product: CC(=O)NNC(=O)c1ccc2occc2c1
Yield: 85 %

Procedure:
In the same manner as in Reference Example 5 and using 1-benzofuran-5-carboxylic acid instead of benzothiazole-6-carboxylic acid and acetohydrazide instead of 3-[3-(trifluoromethyl)phenyl]propanohydrazide, the title compound (yield 85%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][CH2:13][OH:14].C([Cl:18])(=O)C>>[ClH:18].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[NH:9])[O:14][CH2:13][CH3:12])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: CCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=N)c1ccc([N+](=O)[O-])cc1
Product: Cl
Temperature: 25 °C
Reaction time: 56 h
Yield: 63.6 %

Procedure:
To a solution of 4-nitrobenzonitrile (27 g, 182 mmol) in EtOH (128 ml, 2187 mmol) under nitrogen was added acetyl chloride (104 ml, 1458 mmol) dropwise at 0° C. over 1 h, and the reaction was warmed to room temperature. The flask was sealed and the reaction was stirred for 56 h. The resulting precipitate (4-nitrobenzamide) was collected by filtration, and the filtrate was treated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and air dried to give the title compound (26.7 g, 58%): mp 198-200° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.30 (m, 2H), 8.21-8.13 (m, 2H), 7.35 (s, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H); EIMS m/z 193 [M+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31]/[N:32]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OCc1ccccc1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 43 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-benzylhydroxylamine (intermediate H) in 43% yield using the same procedure as described in the synthesis of example 22 1H-NMR (400 MHz, CDCl3), δ ppm 9.43 (s, 1H), 8.93 (d, 1H), 8.13 (m, 2H), 7.91 (s, 1H), 7.83 (d, 1H), 7.42 (m, 6H), 6.10 (s, 2H), 5.36 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=410, tR=5.94 min.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:42][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: NC1CCCCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCCC2)no1
Yield: 58.2 %

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclohexylamine (198 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)=O)[CH2:10][C@H:9]1[CH2:42][C:43]([F:46])([F:45])[F:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)[CH2:10][C@H:9]1[CH2:42][C:43]([F:45])([F:46])[F:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(-c2cc(C(=O)N3CCN(Cc4ccccc4)[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cc(CN3CCN(Cc4ccccc4)[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 63.4 %

Procedure:
To a solution of 350 mg of [(R)-4-Benzyl-3-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-[6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone in 6 ml of dry THF 4.4 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 6 h. The reaction was quenched by the addition of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 217 mg (63%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23](Cl)=[O:24].Cl.CCOCC>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:24]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2.07 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid chloride prepared from 1.68 g of the corresponding acid in 30 ml of benzene and 1.7 ml of pyridine were slowly added thereto at 10° C. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extractedwith ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylate.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11]([C:13]1[S:17][C:16]([NH2:18])=[N:15][C:14]=1[CH3:19])=[O:12])(=[O:8])[O:5]CC)C.[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:32]=1)[C:27](O)=[O:28])([CH3:22])[CH3:21]>>[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:32]=1)[C:27]([NH:18][C:16]1[S:17][C:13]([C:11]([NH:10][CH2:9][P:4](=[O:8])([OH:3])[OH:5])=[O:12])=[C:14]([CH3:19])[N:15]=1)=[O:28])([CH3:22])[CH3:21]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Reactant: CCOP(=O)(CNC(=O)c1sc(N)nc1C)OCC
Product: Cc1nc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)sc1C(=O)NCP(=O)(O)O

Procedure:
The title compound is prepared from {[(2-amino-4-methyl-thiazole-5-carbonyl)-amino]-methyl}-phosphonic acid diethyl ester and 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid in a similar manner to Example 21.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][CH:50]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[N+:45]([O-:47])=[O:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([N+:45]([O-:47])=[O:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:50]=[CH:49][CH:48]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c([N+](=O)[O-])c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (360 mg, 1.60 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (172 μL, 2.00 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2.5 mL). N-[6-(3-Aminophenoxy)-7-nitro-1,3-benzothiazol-2-yl]acetamide (460 mg, 1.34 mmol) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and basic silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from 2-butanone/n-hexane to give the title compound (300 mg, 41%) as a white powder.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[Pt]=O>[CH2:1]([C@@H:5]1[CH2:13][CH2:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCCC[C@H]1CC[C@@H](C(=O)O)CC1

Procedure:
4-n-butylbenzoic acid (8, 50 g, 0.28 mol) was dissolved in glacial acetic acid (250 ml ) and the solution was then autoclaved and hydrogented over platinum oxide (2.0 g) at 20° C. for 18 hr. at 5- p.s.i. The catalyst was filtered and the solution evaporated in vacuo to leave a solid residue of predominantly cis-4- n-butylcyclohexanecarboxylic acid (9, 50.89). The solid was dissolved in dry dichloromethane (250ml) containing N,N-dimethylformamide (1 ml). Thionyl chloride (72.69, 0.61 mol) was cautiously added over 30 min and the mixture was then heated at reflux for 3 hr. The resultant solution was cooled to 20° C., anhydrous ethanol (31.5 g, 0.69 mol) was carefully added and the mixture was then heated at reflux for 1 hr. The cooled solution was poured into water (400 ml) and the separated dichloromethane layer was evaporated to give mainly ethyl cis-4-n-butylcyclohexanecarboxylate (13, 56.4 g), as a viscous oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29]>CS(C)=O>[NH3:14].[CH3:28][C:24]1[C:23]([CH3:29])=[C:22]([O:20][CH:17]2[CH2:18][CH2:19][N:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:15][CH2:16]2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1nccc(Cl)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Product: N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (4.70 g, 42 mmol) was added to a solution of 1-Boc-4-hydroxypiperidine (4.05 g, 20.1 mmol) in dimethylsulfoxide (20 mL) and the mixture was stirred at room temperature for 1 hour. 4-Chloro-2,3-dimethylpyridine (3.58 g, 20.1 mmol) was then added and the reaction mixture was stirred at 50° C. for 18 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium hydrogen carbonate solution and brine. The organic solution was then dried over magnesium sulfate concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 94:6:0.6, to afford the title compound as an oil in 39% yield, 2.4 g.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[O-]S([O-])(=S)=O.[Na+].[Na+].[CH2:34]([OH:36])[CH3:35]>>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:7]([C:1]4[CH:6]=[CH:5][C:35]([CH:34]=[O:36])=[CH:3][CH:2]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCO
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: O=Cc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil (143.5 mmol) was freshly prepared as described in Example 1d and dissolved in absolute ethanol (1 L). Terepthaldehyde monodiethylacetal (Aldrich, 28.54 ml, 143.5 mmol) was added and the solution was stirred at room temperature for 3h. The reaction mixture was concentrated at reduced pressure. and residual ethanol was removed by evaporation from dimethoxyethane (400 ml). The resulting yellow solid was dissolved in dimethoxyethane (1 L) and iodine crystals (40.06 g, 157.85 mmol) were added. The reaction mixture was stirred at 50° C. for 4 h and at room temperature overnight. Saturated Na2S2O3 (300 ml) was added and the dimethoxyethane was removed at reduced pressure. The resulting solid was collected by filtration and combined with methanol (300 ml), H2O (100 ml) and conc. Hydrochloric acid (3 ml). After heating at reflux for ten minutes, the solids were collected by filtration and dried to provide the title compound as a tan solid (53.05 g, 82% yield). 1H-NMR (400 MHz, DMSO-d6) δ: 14.13 (s, 1H), 10.05 (s, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.03 (d, J=8.2 Hz, 2H), 3.91 (br d, J=7 Hz, 2H), 3.77 (br d, J=7 Hz, 2H), 1.93 (m, 1H), 1.74 (m, 1H), 1.60 (m, 10H), 1.20-0.90 (m, 10H). MS (ES−): 447 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH2:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: CCNS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred together for 16 hours. 4-bromo-N-ethyl-3-fluorobenzenesulfonamide (0.38 g, 92%) was provided after purification. HRMS: calcd for C8H9BrFNO2S, 280.95214; found (EI, M+.), 280.951. HPLC purity 100.0% at210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39]OS(C)(=O)=O)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]23[CH2:39][CH:29]2[C:28](=[O:30])[N:27]([C:31]2[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:26]3)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(COS(C)(=O)=O)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 560 μL, 1.39 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (216.5 μL, 0.545 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 1-(2,6-dimethyl-phenyl)-3-methanesulfonyloxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 165 mg, 0.465 mmol) in THF (2 mL) was added and stirred for 2 h at 75° C. The reaction mixture was then purified by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-(2,6-dimethyl-phenyl)-4-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (22 mg, 10% yield). LC-MS: R, (retention time): 2.98 min, MS: (ES) m/z 457.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.32 (s, 2H), 7.78 (s, 1H), 7.02-7.18 (m, 3H), 4.18 (d, 1H, J=9.7 Hz), 3.68 (d, 1H, J=9.7 Hz), 2.68-2.75 (m, 1H), 2.18 (s, 3H), 2.08-2.12 (m, 1H), 2.05 (s, 3H), 1.45 (t, 1H, J=3.9 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]
Reactant: CCN1CCNCC1(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1(C)C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-ethyl,2,2-dimethylpiperazine. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 0.79-1.20 (m, 9H) 2.36-2.48 (m, 5H) 2.59 (d, J=6.06 Hz, 2H) 3.15 (br. s., 1H) 3.44 (br. s., 2H) 3.69 (br. s., 1H) 7.53-7.59 (m, 1H) 7.60-7.63 (m, 1H) 7.63-7.66 (m, 1H) 7.75 (s, 1H) 8.01 (br. s., 2H) 8.42 (br. s., 1H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][N:8]=[C:9]=[S:10]>CCO>[OH:1][CH2:2][C:3]([NH:5][NH:6][C:9]([SH:10])=[N:8][CH3:7])=[O:4]
Reactant: CN=C=S
Reactant: NNC(=O)CO
Solvent: CCO
Product: CN=C(S)NNC(=O)CO
Temperature: 60 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of 2-hydroxyacetohydrazide (4.5 g, 50 mmol) in EtOH was added dropwise methyl isothiocyanate (3.7 g, 50 mmol) under ice cooling. After addition was complete the reaction mixture was brought to room temperature and then stirred for 24 hr at 60° C. Ice water was then added and stirring was continued for 15 min. The reaction mixture was concentrated in vacuuo to give the title compound. Yield: 100%. LCMS (ESI) m+H=164.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1.CS(C1C=CC(N2C(C3C=CC(Br)=CC=3)=CC(C(F)(F)F)=N2)=CC=1)(=O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: OB(O)c1ccco1
Agent: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid and Ethyl 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate prepared according to the procedure of EXAMPLE 63, step1) instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.