Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:22][C:23]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:22][C:23]1([F:29])[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25][CH2:24]1
Reactant: Nc1nnc(Cl)c(-c2ccccc2)n1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nnc(N2CCC(F)(F)CC2)c(-c2ccccc2)n1
Yield: 13.9 %

Procedure:
6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 14%) was prepared from 6-chloro-5-phenyl-1,2,4-triazin-3-amine (0.20 g, 0.96 mmol), K2CO3 (0.23 g, 1.67 mmol) and 4,4-difluoropiperidine hydrochloride (0.22 g, 1.45 mmol) according to the general procedure of Example 2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8]C=1F)(=[O:3])[NH2:2].[NH2:26]C1C=CN=C(C(N)=O)C=1.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][N:26]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1cc(N)ccn1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2ccnc(C(N)=O)c2)C(=O)O)cc1OC
Yield: 63 %

Procedure:
99C was prepared in a procedure similar to that of 13A using 99B, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 63%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.83 (s, 3H) 3.84 (s, 3H) 5.45 (s, 1H) 6.95-7.01 (m, 2H) 7.05-7.11 (m, 3H) 8.11 (d, J=6.59 Hz, 1H); LCMS: 331 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].O.[OH-].[Li+].Cl[CH2:58][C:59]1[O:60][C:61](=[O:65])[O:62]C=1C>>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][C:16]2[O:65][C:61](=[O:62])[O:60][C:59]=2[CH3:58])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: Cc1oc(=O)oc1CCl
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 48.8 %

Procedure:
Following a procedure similar to that described in Example 78(a), but using 2.25 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 68(a)] and using 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.95 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% purity) for esterification, 1.23 g of the title compound was obtained as crystals, melting at 145° C.
Reaction SMILES: BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1.C([O:21][C:22](=[O:39])[C:23]([S:35]([CH3:38])(=[O:37])=[O:36])([CH3:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[CH3:33])C.[OH-].[Li+]>O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][C:23]([CH3:34])([S:35]([CH3:38])(=[O:37])=[O:36])[C:22]([OH:39])=[O:21])=[C:27]([CH3:33])[CH:28]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cc1C)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Br)ccc1CCC(C)(C(=O)O)S(C)(=O)=O

Procedure:
The title compound was synthesized according to the general procedure of Preparation Number 2, Step 3, for the preparation of (II) except that 4-(4-bromo-2-methyl-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester was used instead of (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate and that the lithium hydroxide was dissolve in water prior to addition. Yield: 3.259 (81.2%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2cccc(Cl)c2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(Cl)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (71 mg, 0.40 mmol) was reacted with the product from Example 144a (143 mg, 0.41 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (122 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.16 (s, 2 H) 6.25 (d, J=6.98 Hz, 1 H) 6.66 (d, J=8.83 Hz, 2 H) 7.07-7.25 (m, J=8.46 Hz, 5 H) 7.38-7.53 (m, 3 H) 7.80 (d, J=8.45 Hz, 1 H) 8.40 (d, J=6.99 Hz, 1 H) 8.99 (d, J=8.83 HZ, 1 H) 9.79 (s, 1 H) 11.02 (br s,1H) 14.38 (br s,1 H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with o-toluidine to yield 2-[(2-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C@H:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][CH:23]=1)[CH3:18].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[C:28](=[O:29])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([O:19][CH2:17][CH3:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of N-butyl-N-[4-(trifluoromethyl)benzyl]amine (0.486 g, 2.10 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (80 mL) and the organic phase was washed with 5% HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.355 g (35%) of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:18]1([CH:24]=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])(=O)C.[NH2+]1CCCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:18]1(/[CH:24]=[C:9](\[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)OC(=O)/C(=C/C1CCCCC1)C(=O)c1ccccc1O
Temperature: 22 °C
Reaction time: 192 h
Yield: 49.9 %

Procedure:
Prepared according to general procedure B using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (236 mg, 1.0 mmol), cyclohexanecarboxaldehyde (120 μL, 1.0 mmol) 7.0 mL benzene, piperidinium acetate (2.0 mL, 0.025M in toluene) and sodium sulfate (2.1 g), stirred at 22° C. for 8 d. Purified via column chromatography with 5% EtOAc/hexanes, yielding 165 mg (50%) of a white solid. Rf=0.59 (10% ether/hexanes); mp=62-65° C.; IR (film) 2929.2; 1716.6; 1631.9; 1257.5; 1153.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.92 (s, 1H); 7.51-7.46 (m, 2H); 7.02 (d, J=8.2 Hz, 1H); 6.90-6.86 (m, 2H); 2.11 (m, 1H); 1.68-1.60 (m, 5H); 1.35 (s, 9H); 1.20-1.15 (m, 5H). 13C NMR (125 MHz, CDCl3) δ 200.8, 163.7, 162.6, 152.2, 136.9, 132.3, 124.6, 120.5, 119.2, 118.4, 82.3, 31.9, 28.5, 28.0, 25.8, 25.1; LRMS (electrospray): Mass calculated for C20H26O4 [M]+, 330.18. Found [M+23]+, 353.6.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20](OCC)=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:35][NH2:36])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([NH:36][NH:35][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 41 (0.5 mmols, 0.20 g); octanoyl hydrazine (0.62 mmols, 0.100 g). Yield: 0.196 g (74%), white solid, m.p.=182° C.-183° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[CH3:42][S:43]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(C)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 38.7 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.230 g, 0.498 mmol) was dissolved in dichloromethane (4.6 mL), and the solution was added with triethylamine (0.139 mL, 0.997 mmol) and methanesulfonyl chloride (0.0460 mL, 0.598 mmol), followed by stirring under ice-cooling for 1.5 hours. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-methanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.104 g, yield 61%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([C:28]4[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=4[Cl:33])=[O:27])[C@@H:21]([O:36][CH3:37])[CH2:20]3)[S:12][C:13]=2[C:14]([O:16]CC)=[O:15])=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[C:1]([C:3]1([NH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([C:28]4[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=4[Cl:33])=[O:27])[C@@H:21]([O:36][CH3:37])[CH2:20]3)[S:12][C:13]=2[C:14]([OH:16])=[O:15])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1C(=O)NC1(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CO[C@H]1CN(c2nc(C(=O)NC3(C#N)CC3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl

Procedure:
To a solution of ethyl 4-{[(1-cyanocyclopropyl)amino]carbonyl}-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate (0.09 g, 0.16 mmol, Example 230) in methanol (2 mL) was added potassium carbonate (0.022 g, 0.16 mmol) and water (0.5 mL). After heating in the microwave for 30 min at 80°, reaction was complete by LCMS analysis. The reaction mixture was diluted with water and acidified with 1N HCl. After concentrating to remove methanol, the resulting white precipitate was filtered, washed with water and dried (0.071 g). MS (ES) M+H+: 541 for C21H22Cl2N6O5S; NMR: 1.33-1.41 (m, 2 H) 1.64 (s, 2 H) 1.75 (s, 2 H) 2.19 (s, 3 H) 3.37 (s, 3H) 3.43 (s, 1 H) 3.57 (s, 1 H) 4.08 (s, 1 H) 4.27 (d, 2 H) 4.40 (s, 1 H) 7.16 (d, 1 H) 9.87 (s, 1 H) 12.17 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:3]1
Reactant: CC1CCN(Cc2cccc(OCCCCN)c2)C1
Reactant: Nc1nnc(Br)s1
Product: CC1CCN(Cc2cccc(OCCCCNc3nnc(N)s3)c2)C1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-[(3-methylpyrrolidin-1-yl) methyl]-phenoxy]-butanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccc(F)c(F)c1
Product: N#Cc1cccnc1-c1ccc(F)c(F)c1
Yield: 77 %

Procedure:
Prepared in 77% yield from 2-chloro-3-cyanopyridine and 3,4-difluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (DMSO-d6) δ 7.62-7.71 (m, 2H), 7.74-7.79 (m, 1H), 7.95 (ddd, J=11.7, 7.8, 2.2 Hz, 1H), 8.46 (dd, J=7.8, 1.7 Hz, 1H) 8.94 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:22](=[O:23])[NH:21][CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CC(O)=O>[N:11]1([C:14]2[N:15]=[CH:16][C:17]3[C:22](=[O:23])[NH:21][CH2:20][C:18]=3[N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C1NCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCc2nc(N3CCNCC3)ncc21
Temperature: 60 °C

Procedure:
While heating at 60° C. 1.6 g (5.18 mmol, Referential Example 42) of 2-(4-benzylpiperazino)-5-oxo-5,6-dihydro(7H)pyrrolo[3,4-d]pyrimidine, 0.16 g of 10% Pd-C and 30 ml of AcOH, H2 was bubbled. One hour later, Pd-C was filtered off and then the solvent was distilled off. The residue was suspended in a 10% aqueous NaHCO3 solution.
Reaction SMILES: [OH-].[K+].[Br:3][C:4](=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])[CH2:5][CH3:6].[C:14]([CH:20](Cl)[C:21]([NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:52])[CH:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:38][C:37]=2[C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH2:33][CH3:34])[CH:27]=[CH:26][C:25]=1[Cl:53])=[O:22])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].O>CO.CN(C)C=O>[C:14]([CH:20]([N:9]1[C:8](=[O:13])[C:7](=[C:4]([Br:3])[CH2:5][CH3:6])[NH:11][C:10]1=[O:12])[C:21]([NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:52])[CH:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH2:45][CH3:46])([CH3:43])[CH3:44])=[CH:38][C:37]=2[C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH2:33][CH3:34])[CH:27]=[CH:26][C:25]=1[Cl:53])=[O:22])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CCC(Br)=C1NC(=O)NC1=O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCC(Br)=C1NC(=O)N(C(C(=O)Nc2cc(NC(=O)C(CC)Oc3ccc(C(C)(C)CC)cc3C(C)(C)CC)ccc2Cl)C(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing 4 g of potassium hydroxide dissolved in 15 ml of methanol, was added a solution containing 17 g of 5-α-bromo-n-propylidenehydantoin dissolved in 50 ml of dimethylformamide, and further was added dropwise a solution containing 25 g of α-pivaloyl-α-chloro-2'-chloro-5'-[α-(2,4-di-tert-amylphenoxy)butyramido]acetanilide dissolved in 250 ml of dimethylformamide. After being stirred for 2 hours at room temperature, the reaction mixture was poured into 2 liters of water, and extracted with 1 liter of ethyl acetate. The ethyl acetate layer was separated, washed with a dilute hydrochloric acid solution, washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of n-hexane and ethyl acetate, yielding 18 g of the coupler. The melting point was 129° to 131° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:30]([C:34]1[CH:35]=[CH:36][C:37]([C:40]#[C:41][C:2]2[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:10])=[CH:6][CH:7]=2)=[CH:38][CH:39]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 58.5 %

Procedure:
To a solution of methyl 5-{[[(4-bromophenyl)sulfonyl](hexyl)amino]methyl}-2-fluorobenzoate (96 mg; 0.20 mmol) in DMF (5 mL) were added (Aldrich, p-butylphenylacetylene (31 mg; 0.20 mmol), bis(triphenylphosphine) palladium (II) chloride (6.9 mg; 0.01 mmol), copper(I) iodide (1.9 mg; 0.01 mmol), triphenylphosphine (10.4 mg; 0.04 mmol) and TEA (0.08 mL; 0.59 mmol). The mixture was stirred for 1500 s at 150° C. under MW. The mixture was diluted with Et2O (50 mL) and the precipitate obtained filtrated off. Filtrate was washed with HCl 1N and with brine (75 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography using silicagel (c-Hex:EtOAc, 9:1 then 1:1) gave 66 mg (63.3%) of the title compound as a white solid. HPLC: Rt=6.12 min (purity=99.6%). LC/MS: M+(ESI): 564.4. 1H NMR (CDCl3) δ: 7.79 (d, J=8.3 Hz, 3H) 7.64 (d, J=8.7 Hz, 2H), 7.56 (m, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 7.15 (s, 1H), 4.33 (s, 2H), 3.92 (s, 3H), 3.11 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (t, J=7.7 Hz, 2H), 1.35 (m, 5H), 1.15 (m, 5H), 0.93 (t, J=7.3 Hz, 3H), 0.81 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]>[Cr].[Ni]>[CH:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]
Reactant: CC1=NCCN1C(C)C
Agent: [Cr]
Agent: [Ni]
Product: Cc1nccn1C(C)C
Yield: 98 %

Procedure:
The procedure of Example 1 was followed except that 50.0 g of 1-isopropyl-2-methylimidazoline and about 5 g of Raney Nickel-chromium catalyst was charged. GLC analysis showed that 98% yield of 1-isopropyl-2-methylimidazole was obtained with >99% conversion of imidazoline.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:23])[CH:16]=3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CC2CCCCC2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(CC2CCCCC2)s1)c1ccc(O)c(O)c1
Yield: 60.5 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-cyclohexylmethyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,4-dimethoxy-benzamide prepared in Example 48 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with ethyl acetate to obtain a product as a white solid in a yield of 60.5%, mp: 133-134 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.75˜0.90 (2H, m), 0.95˜1.18 (3H, m), 1.15˜1.17 (6H, m), 2.65 (2H, d, J=7.0 Hz), 6.75 (1H, d, J=8.0 Hz, ArH), 6.76 (2H, d, J=8.4 Hz, ArH), 7.32 (2H, d, J=8.4 Hz, ArH), 7.41 (1H, d, J=2.4 Hz, ArH), 7.46 (1H, dd, J=8.4, 2.4 Hz, ArH), 9.52 (1H, br, OH), 12.15 (1H, br, CONH); EI-MS m/e (%): 424.1 (M+, 21), 288.1 (36), 205.1 (100); HREI-MS Calcd. for C23H24N2O4S: 424.1457. found: 424.1458.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[CH:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24]>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:29]1[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=1)[CH:23]=[O:24])[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: O=Cc1cccc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3cccc(C=O)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol 1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.