Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[SH:9][CH2:10][C:11](O)=[O:12]>Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:11](=[O:12])[CH2:10][SH:9])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)CS
Agent: Cl
Product: O=C(CS)Nc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-aminophenol (4.0 g, 36.7 mmol) and mercaptoacetic acid (2.93 g, 38.5 mmol) under an atmosphere of carbon dioxide was heated to reflux (oil bath temperature ˜120° C.) for 4 hours. The mixture was cooled and diluted with 2 N hydrochloric acid (˜100 mL). A purple solid, 1.3 g, was collected by filtration and washed with water. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give a colorless solid, 1.03 g (15%). MS m/z 184 (MH+). 1H NMR (DMSO-d6) δ 2.08 (t, 1H), 3.24 (s, 2H), 6.70 (d, 2H), 7.35 (d, 2H), 9.21 (br s, 1H) and 9.83 (s, 1 H). Anal. calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64. Found: C, 52.57; H, 4.95; N, 7.40.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH2:39][CH3:40])[N:17]=[C:16]2[CH3:41])=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[CH2:37]([C:18]1[N:17]=[C:16]([CH3:41])[N:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][N:11]=2)[C:20](=[O:21])[C:19]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][CH:28]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nc(C)n(-c2ncc(OCc3ccccc3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the methanol (10 mL) solution of 4′-{[1-[5-(benzyloxy)pyrimidin-2-yl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (235 mg, 0.434 mmol), 10% Pd—C (containing 50% moisture, 120 mg) was added for hydrogenation. After stirring at room temperature for 1 hr, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was distilled off and the resulting residues were subjected to silica gel column chromatography (chloroform:methanol=10:1) to obtain 4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].I[C:16]1C=CC(N)=C(C)C=1>>[F:14][C:2]([F:1])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH3:16])=[O:4]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: Cc1cc(I)ccc1N
Product: Cc1cc(I)ccc1NC(=O)C(F)(F)F

Procedure:
Title compound was synthesized in a manner analogous to Intermediate 32 using 4-iodo-2-methylaniline as a substrate. ES/MS calcd. for C9H7F3INO 328.95. Found m/z=330 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11].FC(F)(F)S(O[C:18]1[C:19]2[CH2:40][N:39]([CH3:41])[CH2:38][CH2:37][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])=[CH:27][CH:26]=2)[N:23]=1)(=O)=O>CS(C)=O>[CH3:41][N:39]1[CH2:38][CH2:37][C:20]2[N:21]=[C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH3:36])=[CH:29][CH:30]=3)[N:23]=[C:18]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[CH2:10][OH:11])[C:19]=2[CH2:40]1
Reactant: OC[C@@H]1Cc2ccccc2N1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CN(C)CC3)cc1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
(S)-Indolin-2-ylmethanol (25.5 mg, 0.17 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (80 mg, 0.17 mmol, Example 9a) in DMSO (1 mL). The reaction was heated to 80° C. for 2 h. The solution was allowed to cool down, filtered and the product was purified on preparative HPLC to give (S)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)indolin-2-yl)methanol (22.00 mg, 27.6%). MS (ESI+)/(ESI−) m/z 468/466
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CN(C)c1ccc(CBr)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Product: CN(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
Similarly, N-cyclopropyl-N-[1-(4-dimethylaminobenzyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide and 1-bromomethyl-4-dimethylaminobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 82.9 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.640 mmol) was reacted with tert-butyl cis-4-aminocyclohexylcarbamate (164 mg, 0.767 mmol) to afford the desired product (259 mg, 83%) as a brown solid: ESI MS m/z 489 [C24H30BrN3O3+H]+.
Reaction SMILES: [C:1]([C:3]([CH3:9])([CH3:8])[C:4]([NH:6][NH2:7])=O)#[N:2].Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])OC)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[N:19]=[C:4]([C:3]([CH3:9])([CH3:8])[C:1]#[N:2])[NH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: COC(=N)c1ccc(F)cc1
Reactant: CC(C)(C#N)C(=O)NN
Agent: Cl
Product: CC(C)(C#N)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 70 %

Procedure:
This compound was synthesized from 2-cyano-2-methylpropanehydrazide and methyl 4-fluorobenzimidate hydrochloride as described in example 64 step 3 (300 mg, yield 70%). 1H NMR (300 MHz, MeOD) δ 8.03-7.98 (m, 2H), 7.29-7.23 (m, 2H), 1.81 (s, 6H). MS (ESI) m/z: Calculated for C12H11FN4: 230.10. found: 231.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13]C)=[O:12])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[N:3]1
Reactant: COC(=O)c1cccc2cnn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1ncc2cccc(C(=O)O)c21
Temperature: 80 °C
Yield: 96.4 %

Procedure:
Methyl 1-methylindazole-7-carboxylate (1 g, 5.3 mmol) was suspended in a mixture of sodium hydroxide (12 mL of 1.0 M, 12 mmol) and 1,4-dioxane (8.7 mL). The reaction mixture was heated at 80° C. for 30 minutes. The dioxane was evaporated off and the aqueous layer was extracted with ethyl acetate three times and the extracts were discarded. The aqueous layer was then acidified with 4M hydrochloric acid and then filtered and washed with 1M hydrochloric acid to yield 1-methylindazole-7-carboxylic acid (0.9 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 8.20 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 4.18 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[CH2:24][CH2:23]3)[CH3:19])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[ClH:1].[ClH:1].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[CH2:26][CH2:27]2)[CH3:19])=[CH:6][CH:5]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccccc2F)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])O
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(Oc2ccccc2F)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of 17.8 g (33.4 mol) of 1-{2-{N-{3-[(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(2-fluorophenoxy)piperidine dihydrochloride, 260 ml methanol and 110 ml 3N HCl was heated at reflux for 3 hours under nitrogen and cooled to room temperature. The solution was neutralized with saturated sodium bicarbonate and the methanol evaporated. The residue was made basic with sodium carbonate, extracted twice with ether, washed with saturated sodium chloride and dried over potassium carbonate. Evaporation of the solvent provided an oil. The yield of the dihydrochloride was 14.9 g (30.4 mmol). Recrystallization from ethanol provided 12.25 g (75%) of the desired ketone.
Reaction SMILES: C(OC([N:8]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([Cl:42])[CH:40]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:11]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:9]1=[O:43])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:40]=[C:41]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:36]2=[CH:37][CH:38]=1
Reactant: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C1c1ccccc1C
Yield: 68 %

Procedure:
In a manner similar to the method described in example 24d, racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.37 g, 0.59 mmol) prepared in example 29a was reacted with trifluoroacetic acid (20 mL) in dichlormethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.21 g, 67%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([N:51]=C=O)[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>C(Cl)Cl>[F:39][C:40]([F:54])([F:55])[C:41]1[CH:42]=[C:43]([NH:51][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=3)[CH2:12][CH2:13]2)=[O:5])[CH:44]=[C:45]([C:47]([F:48])([F:50])[F:49])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2OCc2ccncc2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(OCc2ccncc2)c(N2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)nc1C#N
Reaction time: 2 h

Procedure:
A mixture of 5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (100 mg) and 30% TFA in DCM (11 ml) was stirred for 2 hours. The mixture was concentrated in vacuo to dryness. To the residue was added DCM (5 ml), TEA (0.31 mmol, 51 ul), and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.15 mmol, 26 ul). The resulting mixture was stirred at room temperature for 3 hours. After concentrated in vacuo, the crude product was purified by column on silica using 70% EtOAc/Hexanes to give the product N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide. 1H NMR (CD3OD) 8.594 (s, 2H), 8.073 (s, 2H), 7.555-7.534 (m, 3H), 5.584 (s, 2H), 4.043-4.029 (m, 4H), 3.739-3.713 (m, 4H) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:29]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=4[O:27][CH3:26])(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,5-dimethoxybenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:30])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[BH4-].[Na+].C(=O)(O)[O-].[Na+].[ClH:38]>CO.C(O)(=O)C>[ClH:38].[OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]([OH:30])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(C(O)CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The methyl 2-hydroxy-5-[4-(2-oxo-1-benzimidazolinyl)piperidinoacetyl]benzoate is dissolved in one liter of methanol and cooled in an ice-methanol bath. Sodium borohydride (7.44 g) is added in portions over a period of 25 minutes. The mixture is stirred for approximately 30 minutes and poured onto one liter of ice-water. The mixture is acidified with 500 ml of a 10% acetic acid solution made basic by the addition of sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with water, dried over MgSO4 which is removed by filtration, and the filtrate evaporated in vacuo leaving a residue of 11.3 g, having a m.pt. of 211°-13° C. (dec.). The residue is dissolved in one equivalent of methanolic hydrogen chloride and precipitated from solution with diethyl ether. Recrystallization of the precipitate from methanol yields methyl 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)piperidino]ethyl]benzoate hydrochloride having a m.pt. of 229°-30° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)[Cl:25]>>[Cl:25][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc2ccccc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: ClCc1ccc2ccccc2n1

Procedure:
2-Methylquinoline (5.0 g) was dissolved in carbon tetrachloride (25 mL), imide N-bromosuccinate (6.2 g) and 2,2′-azobisisobutyronitrile (AIBN) (57 mg) were added thereto, and the mixture was refluxed for 4 hr. After ice-cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (3.7 g) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Cl-].[Na+]>ClCCl.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH2:16][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:33])[CH3:32])[CH3:29])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1CCCCC1C=C(C)C(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCCCC1C=C(C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of 1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)piperidine (9.9 g), (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (17.0 g) and triethylamine (16.5 ml) in dichloromethane (100 ml) was added trimethylsilyl trifluoromethanesulfonate (28.6 ml at -15° C. After stirring at 0° C. for 2 hours, the reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (200 ml). The mixture was stirred for 2 hours at ambient temperature. After addition of sodium chloride (40 g), the organic layer was separated, washed with saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1-7:3, V/V) to give (3S,4R)-4-[4-(1-allyloxycarbonylpiperidin-2-yl)-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (13.48 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cn1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 6-methylpyridine-3-boronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=394.1 ([M+H]+).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C.CCOCC>C(O)C>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]([NH:14][C:8]3([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:16])[CH2:22][CH2:21]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCN(Cc2ccccc2)CC1
Yield: 42 %

Procedure:
600 ml of 1N aqueous sodium hydroxide solution was added to a solution of 7.62 g (20 mmol) of 1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid ethyl ester in 300 ml of ethanol, and the mixture was heated under reflux for 2 hours. Ater ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.90 g (42%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:13][CH2:14][CH2:15]Br)(=[O:12])[C:9]([CH3:11])=O>C(O)C>[N:1]1[C:9]([C:8]([O:13][CH2:14][CH3:15])=[O:12])=[CH:11][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]=12
Reactant: Nc1ncccn1
Reactant: CC(=O)C(=O)OCCBr
Solvent: CCO
Product: CCOC(=O)c1cn2cccnc2n1
Temperature: 75 °C
Yield: 29.8 %

Procedure:
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90%, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75° C. for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2×) and the aq layers were extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30%) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2-carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60%) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (2 g, 20%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[C:28](=[O:47])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1CN(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][C:28]5=[O:47])=[CH:37][CH:36]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)C1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: CN(C)Cc1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N5CCN(C)CC5=O)cc4)cc23)CC1
Temperature: 160 °C
Yield: 7.6 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.048 mmol) was added 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-piperazinone (31 mg, 0.097 mmol) in dioxane (3.0 mL) and H2O (1.0 mL), potassium carbonate (13 mg, 0.097 mmol) and chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (10 mg, 0.016 mmol). The reaction mixture was reacted in a microwave at 160° C. for 10 min. The reaction mixture was heated in a microwave at 160° C. for 10 min. The reaction mixture was concentrated under Nitrogen and purified by Gilson Preparatory HPLC. The desired fraction in CH3CN and H2O was treated with saturated potassium carbonate to neutralize salts and then concentrated to give 1.9 mg the title compound (8%).
Reaction SMILES: O[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[SH:14][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nc2ccccc2nc1O
Solvent: c1ccncc1
Product: Cc1nc2ccccc2nc1S

Procedure:
2-Hydroxy-3-methylquinoxaline (2 g) and phosphorus pentasulphide (3.05 g) were stirred together in 40 ml of pyridine and the reaction mixture heated to reflux.