Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C@:5]2([NH:22][S@@](C(C)(C)C)=O)[C:17]([F:21])([F:20])[CH2:18][OH:19]>CCCCCCC.C(OCC)(=O)C>[NH2:22][C@@:5]1([C:17]([F:21])([F:20])[CH2:18][OH:19])[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[O:13][C@:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6]1
Reactant: CC(C)(C)[S@@](=O)N[C@]1(C(F)(F)CO)CC2(CCCOC2)Oc2ccc(Br)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N[C@]1(C(F)(F)CO)C[C@@]2(CCCOC2)Oc2ccc(Br)cc21
Yield: 47 %

Procedure:
Starting from (R)—N-((4R)-6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2-methylpropane-2-sulfinamide (intermediate B4.7), and after chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to =:100 as the eluent the 2-((2R,4R)-4-amino-6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2,2-difluoroethanol (47% yield) (intermediate B5.7A) was obtained as the first eluting isomer as a white foam; MS (ISP): m/z=378.0 [M+H]+ and 380.0 [M+2+H]+. The second eluting isomer, 2-((2S,4R)-4-amino-6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-yl)-2,2-difluoro ethanol (27% yield) (intermediate B5.7B) was also obtained as a white foam; MS (ISP): m/z=378.0 [M+H]+ and 380.0 [M+2+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:30])C(=O)C1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[C:21]=1[I:30])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2ccncc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1I
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-a]pyrazin-2-yl-ethyl)-carbamic acid benzyl ester (1.7 g, 5.74 mmol) in acetonitrile (10 mL) was added n-iodosuccinimide (1.3 g, 5.74 mmol) at rt and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)=[O:24]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([OH:24])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(CCCCO)cccc1C(=O)c1ccc(F)cc1
Reactant: CC(C)=O
Product: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
14 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml were added over 25 minutes at 10°C to a solution of 3.47 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol in 35 ml of acetone and after returning the mixture to room temperature, the mixture was stirred overnight. The mixture was poured into ice water and vacuum filtered, was washed with water until the wash water was neutral and the precipitate recovered was dried over phosphoric acid and crystallized from cycloxane to obtain 3.02 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 94°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:39]=[CH:40][CH:41]=1)[C:15]([NH:17][CH2:18][C:19]1[C:20]([NH:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:21]2[CH:29]=[N:28][N:27]([CH2:30][CH3:31])[C:22]2=[N:23][C:24]=1[CH2:25][CH3:26])=[O:16])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:30]([N:27]1[C:22]2=[N:23][C:24]([CH2:25][CH3:26])=[C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:39]=[CH:40][CH:41]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[CH:13]=3)[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]2[CH:29]=[N:28]1)[CH3:31]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCBr)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCN(C)CCO)c1
Temperature: 60 °C

Procedure:
A solution of 3-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (42 mg, 0.067 mmol, e.g. which can be as prepared in Intermediate 47) in N,N-dimethylformamide (3 ml) was treated with 2-(methylamino)ethanol (0.011 ml, 0.13 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.0235 ml, 0.13 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (33 mg). LCMS showed MH+=622; TRET=2.21 min.
Reaction SMILES: [N:1]1([CH:6]([C:8]#[CH:9])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>O1CCCC1>[C:18]1([C:15]([OH:17])([C:9]#[C:8][CH:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:7])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CC(C)N1CCCC1
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C#CC(C)(O)c1ccccc1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(pyrrolidin-1-yl)-but-3-yne (0.1.23 g) in dry tetrahydrofuran (20 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 4.4 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of acetophenone (1.2 g) in tetrahydrofuran (5 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5-10% methanol in dichloromethane was used as the eluant) to afford the product as an oil that solidified on standing. MS(+ES), m/z: 244 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:10][N:11]([C:13]4[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccccc2)ccn1
Reactant: O=C(Cl)C1CC1
Product: O=C1CCC(n2cc(-c3ccnc(NC(=O)C4CC4)c3)c(-c3ccccc3)n2)=NN1
Yield: 80.8 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 56.0 mg (0.17 mmol) of 4-(2-aminopyridin-4-yl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole obtained in Example 49 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 19.3 mg (0.19 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 55.0 mg of the title compound as a white powder. (Yield: 82%)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCCl)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCS(=O)(=O)Cc2ccccc2)CC1
Yield: 41.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (8.00 g) as a starting compound, 3-benzylsulfonylpropyl chloride (6.03 g) and potassium carbonate (13.4 g) were reacted and purified in the same manner as in Example 199 to give 4.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-benzylsulfonylpropyl)piperidin-4-yl)methyl)-benzamide, m.p. 166°-168° C.
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[O:5][CH:4]=3)[CH2:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: OCc1coc2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Clc1ccc(C2=CCN(Cc3coc4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
3-Hydroxymethylfuro[2,3-b]pyridine (101.5 mg, 0.681 mmol) was treated with thionyl chloride (2 ml) and the solution stirred at room temperature for an hour. The mixture was concentrated in vacuo, toluene added (5 ml) and evaporated to dryness. The residue was dissolved in anhydrous dimethylformamide (5 ml), potassium carbonate (0.47 g, 3.40 mmol) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (173.3 mg, 0.753 mmol) were added and the mixture stirred at room temperature, under nitrogen, overnight (19 hours). The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The extracts were washed with brine (25 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 1:1 then 2:1 ethyl acetate/hexane, to afford the title compound (118.3 mg, 54%) as a pale yellow solid. Recrystallisation from ethyl acetate/hexane gave yellow plates, m.p. 115.5°-116.5° C.; (Found: C, 70.06; H, 5.19; N, 8.52. C19H17ClN2O requires C, 70.26; H, 5.28; N, 8.62%); δH (CDCl3) 2.54 (2H, br s, tetrahydropyridinyl CH2), 2.78 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.23 (2H, m, tetrahydropyridinyl CH2), 3.78 (2H, s, ArCH2N), 6.06 (1H, t, J 3.5 Hz, tetrahydropyridinyl CH), 7.21-7.32 (5H, m, ArH), 7.68 (1H, s, 2-H), 8.12 (1H, dd, J 7.6, 1.7 Hz, 4-H), 8.34 (1H, dd, J 4.8, 1.7 Hz, 6-H); m/z (ES+) 325/327 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][CH2:9][CH:10]([CH3:13])[CH:11]=[CH2:12])[CH2:3][CH2:4][CH:5]=O.[NH2:14][OH:15]>>[CH3:1][C:2](=[CH:7][CH2:8][CH2:9][CH:10]([CH3:13])[CH:11]=[CH2:12])[CH2:3][CH2:4][CH:5]=[N:14][OH:15]
Reactant: C=CC(C)CCC=C(C)CCC=O
Reactant: NO
Product: C=CC(C)CCC=C(C)CCC=NO

Procedure:
As described above, for example, the oximation reaction can be carried out using 4,8-dimethyl-4,9-decadienal and hydroxylamine to yield 4,8-dimethyl-4,9-decadienal oxime (an oxime intermediate).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH:40](C)C(=O)C.C([O-])([O-])=O.[Ca+2].CN1C(=O)CCC1>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][C:21]([CH3:40])=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:37][CH:38]=1)(=[O:3])=[O:4]
Reactant: Cc1coc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)oc1C
Temperature: 140 °C
Yield: 12.8 %

Procedure:
6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 4-methanesulfonyl-benzylamide (see Example 60, 0.05 g, 0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 140° C.) for 2 h. The reaction was stopped and the crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC, giving the title compound (0.007 g, 13%) as a slightly brownish solid after freeze-drying the pure fractions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:17].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:17][CH2:20][CH:19]=[CH2:18])[CH:4]=[CH:5][C:6]=1[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: C=CCBr
Reactant: Cn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)c2ccnn2C)c(Cl)c1Cl
Yield: 87.2 %

Procedure:
A suspension of 8.35 g of 2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol, 5.59 g of allyl bromide and 10.64 g of potassium carbonate in acetone is refluxed for 3 hours. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is dissolved in toluene, and the solution is treated with activated charcoal and then evaporated to give 8.36 g of (2,3-dichloro-4-allyloxyphenyl)(1-methyl-5-pyrazolyl)methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16][C:17]1C=CNN=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:17]=[CH:16][C:14]([CH3:13])=[N:15]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cc[nH]n1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 3-methyl-1H-pyrazole. MS (ESI) 217 (M+H).
Reaction SMILES: CO[C:3](OC)([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:4].[S-:18][C:19]#[N:20].[K+].Cl>C(O)C.O>[F:15][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH2:6][N:5]1[CH:3]=[CH:4][N:20]=[C:19]1[SH:18]
Reactant: COc1ccc(CNC(C)(OC)OC)cc1F
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2ccnc2S)cc1F
Yield: 60.7 %

Procedure:
To a solution of 1-(3-fluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal (6.68 g, 0.0275 mole) in ethyl alcohol (40 ml) was added potassium thiocyanate (2.94 g, 0.0302 mole) in water (65 ml) followed by 12 N hydrochloric acid (6 ml) and the reaction mixture was heated under reflux for 3 hours. The solvent was partially removed under reduced pressure and the mixture was cooled in ice and the product filtered. The product was recrystallized from ethyl alcohol to give 1-(3-fluoro4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 156-157° (3.98 g, 61%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OCC1C=CC=CC=1)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][N:14]([C:42](=[O:43])[C@H:40]([CH3:41])[NH2:39])[CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1cc2c(cc1OC)C(NCC(=O)OC(C)(C)C)CC2
Agent: O=C(O)C(=O)O
Product: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Yield: 48.5 %

Procedure:
By reacting 7 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate with 4.8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 5, there is obtained 4 g of L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate as colorless amorphous powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:39]1([CH2:38][CH2:37][NH:36][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)[CH:28]=2)(=[O:35])=[O:34])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1)(355 mg, 1.0 mmol) and 3-Bromo-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (example B.20)(454 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow amorphous solid (60 mg, 10%). MS (ISP) 624.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[O:31]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:40]4[CH2:41][CH2:42][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C1COCCOCCOCCN1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCOCCOCCOCC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH2:20][OH:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:21][CH2:20][CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OCCn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCO)nc2-3)cn1

Procedure:
Following the procedure for 114, 2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 442. MS (ESI+) 453.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.42 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.94 (t, J=5.5, 1H), 4.89 (t, J=5.9, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.04 (s, 2H), 3.91 (q, J=5.8, 2H), 3.44 (t, J=5.0, 2H), 1.10 (s, 6H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]([F:19])([F:18])[C@@H:15]([OH:17])[CH3:16]>>[F:13][C:14]([F:19])([F:18])[C@H:15]([CH3:16])[O:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: C[C@H](O)C(F)(F)F
Reactant: OC1(c2cnccc2Cl)CCC1
Product: C[C@H](Oc1ccncc1C1(O)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 108b, using 1-(4-Chloro-pyridin-3-yl)-cyclobutanol (Example 108a) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (3.22 g, 57%) as yellow oil; MS (ESI, m/z): 262.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:46](Br)(=[O:49])[CH2:47][CH3:48]>>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:17][CH:16]=2)[C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:46](=[O:49])[CH2:47][CH3:48])[CH:3]=2)[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nn(-c2cccc(N)c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCC(=O)Br
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(-c2cccc(NC(=O)CC)c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 60 %

Procedure:
This material was prepared from 2-(3-aminophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step E), sodium hydride, and propionyl bromide according to the procedure of Example 61. The crude product was flash chromatographed over silica gel to afford the title compound in 60% yield as a cream-colored solid, mp 105°-107° C., homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 672 (M+1)+.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([O:12][O:13][C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([O:20][OH:21])([CH3:19])[CH3:18])([CH3:11])([CH3:10])[CH3:9]>>[CH3:6][C:5]([O:21][O:20][C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]([O:13][O:12][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:23])[CH3:22])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(C)(C)OOC(C)(C)CCC(C)(C)OO
Reactant: CC(=O)C=C(C)C
Product: CC(=O)CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 19.62 g. (0.20 mole) of mesityl oxide, 61.40 g. (0.22 mole) of 4-t-butylperoxy-1,1,4,4-tetramethylbutyl hydroperoxide (84%) and 10.0 g. of Amberlyst 15® sulfonic acid type ion exchange resin was stirred for 16 hours at 28°-30° C. and then at 35° C. for 4 hours. The resin was separated by filtration and the filtrate subjected to steam distillation at 20 torr in the presence of sodium bicarbonate to maintain a slightly alkaline pH during the distillation. The distillation was ended when the removal of unreacted mesityl oxide was complete. The product was taken up in ether, the ether solution dried over anhydrous magnesium sulfate and the ether removed under reduced pressure. The product weighed 55.9 g. and was obtained in 84.4% yield.