Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11](#[N:13])[CH3:12].[O:14]1[CH2:19][CH2:18][CH:17]([C:20](OC)=[O:21])[CH2:16][CH2:15]1.Cl>C1COCC1>[O:21]=[C:20]([CH:17]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)[CH2:12][C:11]#[N:13]
Reactant: COC(=O)C1CCOCC1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
26.8 ml of a 1M solution of LiHMDS in THF are introduced into 25 ml of anhydrous THF under an argon atmosphere. The mixture is maintained at a temperature of about −78° C., and then 1.47 ml of acetonitrile in solution in 3 ml of anhydrous THF are added. The reaction mixture is kept stirring at −78° C. for 40 minutes and then a solution of 3.0 g of methyl tetrahydropyran-4-carboxylate in 3 ml of THF is added. After stirring for 2 hours at −78° C., the mixture is left to return to ambient temperature for 15 hours and it is then diluted with 200 ml of a water/ice mixture. The pH is adjusted to a value of about 3 by adding 2N HCl, and then the mixture is extracted three times with 150 ml of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to give 3.18 g of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile in the form of a light brown oil.
Reaction SMILES: C([O:4][C@@H:5]([CH3:27])[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:19]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:27])=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](O)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Yield: 81.7 %

Procedure:
A solution of (S)-(−)-3-(2-acetoxypropionylamino)-2-benzoyl-6-chloroindole (Example 58, 580 mg, 1.5 mmol) and potassium carbonate (2.0 g, 14 mmol) in ethanol (30 ml) and water (10 ml) was stirred for 2 h. The mixture was concentrated and extracted with ethyl acetate (50 ml×2). The organic extracts were dried (MgSO4) and concentrated to give a yellow amorphous solid. Recrystallization from ethyl acetate/hexane gave 420 mg (81%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]1[C:38]([CH2:43]Br)=[CH:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:6]3[O:5][N:4]=[C:3]([CH2:2][N:1]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36]4)[N:7]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Reactant: BrCc1ccccc1CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CN4Cc5ccccc5C4)no3)c2[C@@H]2CCN12
Yield: 62.3 %

Procedure:
5 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 50 ml of methylene chloride, 12 ml (70 mmol) of N-ethyldiisopropylamine and 3.7 g (14 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 72 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 70 g of silica gel while eluting with methylene chloride/ethyl acetate 7/3. There were obtained 4.0 g (62%) of (S)-8-chloro-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 170°-175°.
Reaction SMILES: C(N(CC)CC)C.O[C@@H]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[NH:13][C:12]1=[O:32])C.C(C1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(O)=O>C(#N)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([C:17](=[N+:45]=[N-:46])[C:16](=[O:31])[CH2:15][CH:14]2[NH:13][C:12](=[O:32])[CH2:11]2)=[O:19])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (263 mg, 2.6 mmol) is added by syringe to a mixture of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (253 mg, 0.72 mmol) and p-carboxybenzene sulfonylazide (196 mg, 0.84 mmol) in dry acetonitrile (6 ml) at 0° C. When addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is then diluted with ethyl acetate (50 ml) and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed on a short silica gel column (ethyl acetate) to yield 222 mg, (81% overall from (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyl dimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one) of (3S,4R)-3-(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one as a white solid m.p. (dec.) 163° C. IR(CHCl3, CM-1) 3410, 2132, 1756, 1718, 1650, 1350, 1280, 1120; n.m.r. (CDCl3) δ7.9(2d-aromatic,4), δ5.4(s,2), δ6.2(brs,1), δ4.1(m,2), δ2.6-3.6(m,4), δ1.32(d,3,J=6.2).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:11]([NH:19][N:20]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=CC=Cc1ccccc1
Solvent: CO
Product: O=C(NN=CC=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To 200 ml of methanol solution containing 13.2 g of cinnamaldehyde was added 13.6 g of benzoylhydrazine, followed by stirring for 30 minutes at room temperature, for the precipitation of crystals. The crystals were filtered off and dried. Thus there was obtained 22 g of cinnamaldehyde benzoyl hydrazone (mp. 192°-194° C.).
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([OH:32])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:40])=[N-]>CO.C(OCC)C>[CH2:33]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([O:32][CH3:40])=[O:31])[CH2:10]1)=[O:8])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 368 mg (0.725 mmole) of (S)-4-(dipentylcarbamoyl)-1-(diphenylacetyl)piperazine-2carboxylic acid (from Example 9) in 5 ml of methanol was treated at 0° C. with 20 ml of diazomethane solution in diethyl ether (prepared by the procedure above). The solution was stirred at 0° C. for 30 minutes and at 25° C. for 30 minutes. The excess diazomethane was destroyed by the dropwise addition of acetic acid until the solution became colorless. The resulting solution was concentrated in vacuo and the residue was chromatographed over an 85×2.5 cm LH-20 column and concentrated in vacuo to 225 mg (59%) of pale colored oil which was homogeneous by TLC (1:1 hexane-ethyl acetate, Rf =0.7).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 3-methoxyaniline by a procedure similar to Example 28 (80% yield). 1H NMR (CDCl3): 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H), 6.76 (dd, J=8.4 and 2.1 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[CH:23][N:22]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[CH:23][N:22]=1
Reactant: Cc1cnc(N=C=S)c(C)n1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(C)nc2C)c1NCCCO
Temperature: 60 °C
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (500 mg, 1.94 mmol) and 2-isothiocyanato-3,5-dimethylpyrazine (866 mg, 5.24 mmol) in tetrahydrofuran (4.0 mL) was stirred at 60° C. for 6 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(3,5-dimethylpyrazin-2-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a yellow solid (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:22])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 81 %

Procedure:
As described for example 3, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (86 mg, 81%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:18]3[NH:19][N:3]=[N:2][N:1]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc(COc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride (1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)benzonitrile (8.0 g, 28.04 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. To the cooled reaction mixture water (100 mL) was added and the reaction mixture stirred for 0.75 hour. The precipitate was filtered off and washed with water, 96% ethanol (2×50 mL), and dried in vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([F:32])([F:31])C(OCC)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH:25]([F:32])[F:31])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(OC(F)F)cc2C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture containing 0.68 mmol 5-Hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethyl chlorodifluoroacetate in 1.5 ml DMF was stirred overnight at 65° C. The mixture was then partitioned between ethyl acetate and water and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: n-heptane/ethylacetate) to afford the title compound as a white solid (40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2.[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2
Reactant: Fc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(F)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-fluoroacridine (J. Med. Chem. 1985, 28. 940-944) and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=358).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][CH:31]=[N:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:34][C:33]3[N:29]([CH3:28])[N:30]=[CH:31][CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Cn1nccc1N
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccnn3C)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2-methyl-2H-pyrazol-3-ylamine according to procedure B followed by deprotection yielded the title compound as a pale brown waxy solid. MS (ESI): m/z=359.2 [M+H]+.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:17]=2)=[CH:13][CH:12]=1.[NH2:34][C:35]1[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=1>O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20]([C:39]3[N:38]=[CH:37][N:36]=[C:35]([NH2:34])[CH:40]=3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:32])[CH3:33])[N:17]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)Cn1cc(-c2cc(N)ncn2)c(-c2ccc(Cl)s2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To a degassed solution of acetonitrile (4 mL) and water (1 mL) were added potassium carbonate (4 eq, 2.8 mmol), 3-(5-chloro-2-thienyl)-1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq, 0.7 mmol), 4-amino-6-chloropyrimidine (1.1 eq, 0.77 mmol) and 1,1′-bis(diphenylphosphinoferrocene)palladium(II)dichloride (0.1 eq, 0.07 mmol). The mixture was stirred at 130° C. in the microwave for 60 min. At room temperature, the mixture was filtered over celite and the filtrate was evaporated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 1:0 to 9:1) to afford 12 mg of 6-[3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazol-4-yl]pyrimidin-4-amine (5% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:29])C>>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([OH:29])[C:5]=2[N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:12]2=[O:26])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c[n+]([O-])ccc1C1CC1
Product: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c(C2CC2)ccnc1O
Yield: 8 %

Procedure:
4-Cyclopropyl-3-(2-oxo-3-(2-(trifluoromethyl) pyridin-4-yl)imidazolidin-1-yl)pyridine 1-oxide (I-50b: 100 mg, 0.273 mmol) was heated with acetic anhydride (5 mL) at 120° C. for 3 hours. The resulting mixture was concentrated, basified with dilute sodium bicarbonate solution, and diluted with DCM. The organic layer was dried over sodium sulphate and concentrated to afford the crude product. Purification by column chromatography on silica gel (3% methanol in chloroform), followed by preparative HPLC afforded 8 mg of the product (8% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:3](=[CH:13][N:14]([CH3:16])[CH3:15])[C:4]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)c1nccs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1nccs1

Procedure:
2-Cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one was prepared from 2-cyanoacetyl thiazole (400 mg,2.94 mmol) and dimethylformamide dimethylacetal (1.5 mL) as a yellow solid, m.p. 126° δH (CDCl3) 8.89 (1H, s), 7.96 (1H, d, J 3.3 Hz), 7.60 (1H, d, J 3.1 Hz), 3.54 (3H, s) and 3.35 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=3)[CH:19]=[CH:20][N:21]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[CH:19]=[CH:20][N:21]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide (250 mg, 0.534 mmol) in CH2Cl2 (5 mL) at −78° C. was added a solution of boron tribromide (1M in CH2Cl2, 0.80 mL, 0.80 mmol) dropwise. After 4 h, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was then slowly poured into H2O, extracted 3 times with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by column chromatography (SiO2, CHCl3, then 2% MeOH/CHCl3) to yield a clear oil in 58% yield.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[N:8]1([C:17](=[O:31])/[CH:18]=[CH:19]/[C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[N:8]1([C:17](=[O:31])/[CH:18]=[CH:19]/[C@@H:20]([NH2:23])[CH2:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TFA (25 mL, 324 mmol) was added to a solution of 1,1-dimethylethyl [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]carbamate (7.21 g, 21.82 mmol) in CH2Cl2 (25 mL). The reaction was stirred at RT. After 3.5 h, CH2Cl2 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperdine-4-carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder, mp 208° C.; MS: 404.5 (M+H)+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>O1CCCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH3:30])[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 93 %

Procedure:
This compound is obtained by reacting 1-trityl-4-hydroxymethylpyrazole (555 mg; 1.63 mmol) in dry tetrahydrofuran with sodium hydride (98 mg; 2.44 mmol) and iodomethane (0.5 mL; 8.15 mmol). Yield: 93% (536 mg, 1.51 mmol).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:17]1([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1cnc2cc(-c3ccccc3)ccn12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1

Procedure:
Tetrakis(triphenylphosphoine)palladium(0) (16 mg, 0.014 mmol, 0.050 equiv) was added to a deoxygenated mixture of 3-iodo-7-phenylimidazo[1,2-a]pyridine (1-5, 88 mg, 0.28 mmol, 1 equiv), phenyl boronic acid (50 mg, 0.41 mmol, 1.5 equiv), and aqueous saturated sodium carbonate solution (0.42 mL, 3.0 equiv) in dioxane (5 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled, then concentrated, and the residue was partitioned between half-saturated aqueous NaCl solution (50 mL) and EtOAc (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (dichloromethane, initially, grading to 40% EtOAc in dichloromethane) to give 3,7-diphenylimidazo[1,2-a]pyridine (1-6) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 8.41 (dd, 1H, J=7.2, 0.6 Hz), 7.90 (dd, 1H, J=1.8, 0.6 Hz), 7.74 (s, 1H), 7.69 (m, 2H), 7.62–7.39 (m, 8H), 7.12 (dd, 1H, J=7.0, 1.8 Hz).