Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Br)[CH3:18].B(F)(F)F.CCOCC>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]1([NH2:12])[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccccc1OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccccc2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g).
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=O>CO>[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1/[CH:45]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Br-]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Brc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
To a solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (3.0 g, 6.3 mmol) in methanol (18 mL), DBU (1.4 mL, 9.5 mmol) was added dropwise and 2-bromobenzaldehyde (0.81 mL, 7.0 mmol) was further added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was washed with methanol (15 mL) and dried under reduced pressure to obtain (E)-3-[2-(2-bromophenyl)vinyl]-1H-indazole (0.22 g, 12%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](O)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:20][CH:19]=[CH2:18])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CC[Si](C)(C)C
Reactant: CCOC(=O)CC(O)(CCCl)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(CCCl)(CC(=O)OCC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of ethyl 5-chloro-3-hydroxy-3-phenylpentanoate (1.0 g, 3.9 mmol) in anhydrous CH2Cl2 (20 mL) cooled to −78° C. under nitrogen was added allyltrimethylsilane (4.5 g, 39 mmol) followed by a solution of TiCl4 in CH2Cl2 (16 mL, 1 mol/L) dropwise. The solution was stirred at −78° C. for 30 min, and then was heated to reflux overnight. The reaction was quenched with aqueous Na2CO3 solution. The organic phase was separated and concentrated to give the crude product, which was purified by column chromatography to afford the ethyl 3-(2-chloroethyl)-3-phenylhex-5-enoate (0.5 g, 45%). 1H NMR (CDCl3): δ=1.08 (t, 3H), 2.24 (m, 2H), 2.54 (m, 2H), 2.68 (d, 2H), 3.19 (m, 1H), 3.26 (m, 1H), 3.96 (q, 2H), 5.01 (m, 2H), 5.51 (m, 1H), 7.14 (m, 1H), 7.19 (m, 2H), 7.29 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]3=[O:7])=[N:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: CC1CCC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nc3)CC2)c(C)c1
Yield: 44.9 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (176 mg) was obtained.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[C:29]1([C:35]2[C:36]([O:38][C:39](=O)[CH:40]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:39](=[O:38])[CH:40]=[C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:36]1=[O:37])=[O:8]
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(c2ccccc2)C1=O)OC
Yield: 24.5 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.7 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.29 g of phenylmaleic anhydride, there was obtained 0.21 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[OH:27][C@@H:28]([C@H:30]1[C:50](=[O:51])[N:32]2[CH:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])[C:34](=O)[CH2:35][C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[SH:60][C@@H:61]1[CH2:65][N:64]([C:66]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=2)=[O:67])[C@H:63]([C:79]([N:81]2[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]2)=[O:80])[CH2:62]1>C(#N)C>[OH:27][C@@H:28]([C@H:30]1[C:50](=[O:51])[N:32]2[C:33]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=3)=[O:38])=[C:34]([S:60][C@@H:61]3[CH2:65][N:64]([C:66]([O:68][CH2:69][C:70]4[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=4)=[O:67])[C@H:63]([C:79]([N:81]4[CH2:82][CH2:83][N:84]([CH3:87])[CH2:85][CH2:86]4)=[O:80])[CH2:62]3)[CH2:35][C@H:31]12)[CH3:29]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 1 h
Yield: 61.2 %

Procedure:
85 μl of diisopropylethylamine and 86 μl of diphenyl chlorophosphate were simultaneously added, whilst ice-cooling, to a solution of 161 mg of 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 2 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, 232 μof diisopropylethylamine and a solution of 310 mg of (2S,4S)-4-mercapto-2-(4-methyl-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in Example 1(1)] in 2 ml of anhydrous acetonitrile were added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight, whilst ice-cooling. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was worked up and purified in a similar manner to that described in Example 29(1), to afford 209 mg of the title compound as a powder.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([O:21]C(=O)C)[CH:18]=[CH:17][C:15]=2[CH:16]=1.[C:25](=O)([O-:27])[O-:26].[K+].[K+]>ClCCl>[OH:21][C:19]1[CH:18]=[CH:17][C:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:12]([CH3:11])[O:13][C:14]=2[CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Oc1ccc2cc(C)oc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1oc2cc(O)ccc2c1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a slurry of aluminum trichloride (20.0 g, 150 mmol) in dichloromethane (200 mL) is added oxalyl chloride (13.0 mL, 150 mmol) and the mixture is stirred at 0° C. for 30 minutes. A solution of acetic acid 2-methyl-benzofuran-6-yl ester (9.50 g; 49.9 mmol) in dichloromethane (50 mL) is added over 10 minutes. The ice-bath is removed and the reaction is stirred at room temperature for 2 hours. The reaction mixture is cooled to 0° C. and quenched with MeOH (50 mL). The mixture is concentrated to a residue, dissolved in methanol (250 mL), and treated with potassium carbonate (8.28 g, 59.9 mmol). The mixture is stirred at room temperature for 16 hours, filtered through a pad of celite, and concentrated. The residue is diluted with water (100 mL) and extracted with EtOAc (250 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography (eluted with 25% EtOAc/Hexanes), and the appropriate fractions are concentrated. The material is dried in vacuo to afford 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid (9.56 g, 93%). ES/MS m/e 207.0 (M+1); 205.0 (M−1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br>CN1C(=O)CCC1.CCOCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: BrCCOCCBr
Reactant: COc1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A mixture of NaH (3.1 g, 76 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with the mixture of 2-(4-methoxyphenyl)acetonitrile (4.5 g, 31 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (7.1 g, 31 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+Na=240. The mixture was carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.2 g of the product as a pale yellow oil. MS (m/z)=240 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH:4]([CH2:5]2)[N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Cl:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][N:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:18][C:19]1[CH:24]=[C:23]([N:7]2[CH:6]3[CH:4]([CH2:5]3)[N:3]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[C:2]2=[O:1])[CH:22]=[CH:21][N:20]=1
Reactant: Clc1cc(I)ccn1
Reactant: O=C1NC2CC2N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1C(=O)N(c2ccnc(Cl)c2)C2CC21
Yield: 74.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, benzyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.861 mmol) was reacted with 2-chloro-4-iodopyridine (227 mg, 0.947 mmol), xantphos (45 mg, 0.077 mmol), Pd2(dba)3 (24 mg, 0.025 mmol), cesium carbonate (421 mg, 1.29 mmol) and 1,4-dioxane (12 mL) at 100° C. for 3 hours. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 220 mg of the product (75% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][NH:19][C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][C:24]([F:31])=[C:25]([F:30])[CH:26]=3)[N:21]=2)=[O:11])[CH:5]=1.[OH-].[Na+]>CO.O>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[F:31])[N:21]=[C:20]([NH:19][CH2:18][C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][N:12]1[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:32])=[O:2])=[O:11])[CH:29]=[N:28]2
Reactant: COC(=O)c1cccc(C(=O)N2CCCC[C@H]2CNc2cnc3cc(F)c(F)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(C(=O)N2CCCC[C@H]2CNc2cnc3cc(F)c(F)cc3n2)c1
Reaction time: 12 h
Yield: 95.6 %

Procedure:
3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoic acid methyl ester (0.5 g) was dissolved in methanol (15 ml) and treated with 1M sodium hydroxide (1.7 ml). The reaction mixture was stirred for 12 h, additional 1M sodium hydroxide (1.7 ml) added and stirring continued for a further 24 h The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate (×3). the combined organic phase was dried (MgSO4), fioltered and solvent removed at reduced pressure to give the title compound (0.463 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[N:30]=[CH:29][C:28]([N:31]([CH2:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])[CH2:36][CH2:35]3)[CH3:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH2:46]=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:20])[CH3:21])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[CH2:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([N:40]4[CH2:41][C:42](=[O:43])[N:44]([CH3:46])[CH2:45]4)[CH2:38][CH2:39]3)=[CH:29][N:30]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CNC(=O)CN[C@H]1CC[C@H](CN(C)c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)nc2)CC1
Solvent: CCO
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(N(C)C[C@H]3CC[C@H](N4CC(=O)N(C)C4)CC3)cn1)C(=O)C2

Procedure:
The mixture of Example 122 (38 mg, 0.061 mmol) and formaldehyde (0.046 ml, 37% solution, 10 eq, 0.612 mmol) was heated for 15 h in EtOH (1 mL) at 80° C. The reaction mixture was concentrated to dryness and the residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH 9: 1] 1:0→0:1) yielding the title compound as a colorless solid (31 mg, 0.048 mmol, 79%). HPLC: FtRet=1.236; LC-MS: m/z 646.4 [M+H]+.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 20 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([C:43]2[C:44](C)=[C:45](OS(C)(=O)=O)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:6][N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(OS(C)(=O)=O)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 80.9 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.9%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH:16]1([NH:19][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Yield: 51.1 %

Procedure:
A suspension of 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 3.60 g; 15.22 mmol; 1.0 eq.), cyclopropylamine (5.27 mL; 76.1 mmol; 5.0 eq.), and N-ethyldiisopropylamine (26.22 mL; 152.2 mmol; 10.0 eq.) was heated at 80° C. in 1-butanol (36.0 mL) for 23 h., then 15 h. at 100° C. The reaction mixture was then concentrated under vacuum till dryness. Diethyl ether was added and the solid was filtered, washed with water and dried. The product was then purified by chromatography on silicagel (from 5% to 95% EtOAc in c-Hex), to give the title compound as a white solid (2.0 g; 51.1%). HPLC, Rt: 2.54 min. (purity 100%). LC/MS, M+(ESI): 258.0, M−(ESI): 256.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:10]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[NH:8][N:7]=1)(=[O:3])[CH3:2].[H-].[Na+].F[C:19]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[C:13]([O:12][CH2:11][C:9]1[CH:10]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:7]([C:19]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=2[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[N:8]=1)(=[O:15])[CH3:14]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)OCc1cc(COC(C)=O)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(COC(C)=O)n(-c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 4.2 g. (20 mmol) of 3,5-diacetoxymethylpyrazole in 15 ml. of DMF was added dropwise to a suspension of 960 mg. (20 mmol) of NaH (50% in mineral oil) in 25 ml. of DMF stirred at 0° and under argon. After the evolution of H2 had ceased, 4.9 g. (20 mmol) of 2-fluoro-5-nitrobenzophenone was added in one portion. After stirring at 0° for 4 hours, the mixture was poured into ice-water and extracted with EtOAc. The organic phase was washed with dil. brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel using benzene/EtOAc (1:1) as eluent. Removal of the solvents gave crude end product as a gum which was not purified further. The nmr (CDCl3) had signals at: δ2.00 (3H, s, CH3), 2.07 (3H, s, CH3), 4.82 (2H, s, CH2), 5.10 (2 H, s, CH2) 6.33 (1H, s, C=CH), and 7.30-8.67 (8H, m, C6H5 +C6H3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/O)=[CH:9]/[C:10]([CH:12]2[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=O)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[N:31]=[C:10]([CH:12]3[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1NN
Reactant: CC1(C)CC(C(=O)/C=C(\O)c2ccc(Cl)cc2)CCO1
Agent: Cl
Product: COc1ccccc1-n1nc(C2CCOC(C)(C)C2)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from (Z)-3-(4-chlorophenyl)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-hydroxyprop-2-en-1-one and (2-methoxyphenyl)hydrazine hydrochloride according to the procedure in Example 50, step B.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1.[Cl-].[NH4+]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:30]([C:27]1[S:26][C:25]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)#[N:31]
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: N#Cc1ccc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3ccc(C#N)s3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 20.4 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.22 g, 0.7 mmol) and 2-bromo-5-cyanothiophene (0.13 g, 0.7 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.034 g, 4%) and copper(I) iodide (0.007 g, 6%), and the mixture was heated at 85°-90° C. for 2 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.06 g, 18%). This was combined with product (0.017 g) obtained in a second, similar reaction and was triturated from dichloromethane-hexanes to provide a white solid, mp 106°-107° C. Anal. (C25H25NO3S.0.5 H2O) calcd: C, 70.07; H, 6.11; N, 3.27; found: C, 70.15; H, 5.84; N, 3.32.