Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[NH:11][CH:8]3[N:9]=2)=[C:5]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[N:4]=[CH:3]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH2:39]1)(=O)=O>O>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:37][CH:38]4[CH2:42][CH2:41][N:40]([C:43]5[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=5)[CH2:39]4)[CH:8]3[N:9]=2)=[C:5]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[N:4]=[CH:3]1
Reactant: COc1ccc(N2CCC(COS(C)(=O)=O)C2)cc1
Reactant: CN1C(=O)NC2N=C3C(=C(c4ccco4)N=CN3N)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(CN3C(=O)N(C)N4C5=C(c6ccco6)N=CN(N)C5=NC34)C2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 7.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-1-methyl-3H-[1,2,4]triazolo[5,1-f]purin-2-one (0.1 g, 0.368 mmol), DMF (3 ml), potassium carbonate (0.76 g, 0.553 mmol) and [1-(4-methoxyphenyl)pyrrolidin-3-yl]methyl methanesulfonate (0.115 g, 0.405 mmol) stirred at 60° C. for 48 hours. Reaction mixture was cooled to 0° C. Water was added and solid obtained was filtered off. The crude product was purified by HPLC/MS to obtain 5-amino-8-(2-furyl)-3-[[1-(4-methoxyphenyl)pyrrolidin-3-yl]methyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (0.012 g, 7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:34](I)[CH3:35]>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([O:22][CH2:34][CH3:35])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c2cccc(OCc3ccccc3)c2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred mixture of 8-benzyloxy-4-carboxy-2-methylquinoline (700 mg), potassium carbonate (659 mg) and N,N-dimethylformamide (0.3 ml) was dropwise added ethyl iodide (409 mg) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at ambient temperature. To the mixture was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, dried over magnesium sulfate. The solvent was removed, and the residue was crystallized from diisopropyl ether to give 8-benzyloxy-4-ethoxycarbonyl-2-methylquinoline (686 mg) as solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cccc(CCl)c1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Product: COc1cccc(CN2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]piperazine and 3-methoxybenzyl chloride by the method described in example 15 to give the product (67%, mp: 93°-96° C.). Calc'd for C25H32N2O3 : C, 73.50%; H, 7.90%; N, 6.86%. Found: C, 73.23%; H, 7.92%; N, 6.99%.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH2:23])[CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH:23][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])[CH3:22]
Reactant: CC(N)CN(C)C
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(NC(C)CN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.500 g, 2.08 mmol), N1,N1-dimethyl-1,2-propanediamine (0.636 g, 6.24 mmol), DIPEA (2.2 mL, 12.5 mmol) and DMF (12 mL) was stirred 4 hours at room temperature. The reaction was then concentrated in vacuo, the residue was dissolved in 2 N NaOH (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with brine (10 mL) dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (100% CH2Cl2 to 5% MeOH/CH2Cl2) to provide the title compound (0.621 g, 93%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.33 (d, J=6.4 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 3.79 (heptet, J=7.2 Hz, 1H), 3.45 (br d, J=5.2 Hz, 4H), 2.55 (dd, J=12.0 Hz, J=7.6 Hz, 1H), 2.39 (dd, J=12.4 Hz, J=5.8 Hz, 1H), 2.29 (s, 6H), 1.69 (br s, 1H), 1.31 (d, J=6.8 Hz, 2H), 1.22 (t, J=7.4 Hz, 6H). MS (ESI) (M+H)+=323.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[C:1]([NH:5][C:26]([C:15]1[N:16]([CH3:25])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)[N:14]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NC(C)(C)C)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using t-butylamine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[CH2:29][N:30]2[C@@H:34]([CH3:35])[C@@H:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][C:31]2=[O:42])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=1.[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:35][C@H:34]1[C@@H:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C:31](=[O:42])[N:30]1[CH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[C:7]1[C:8]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:43])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: OB(O)c1ccccc1
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+]
Solvent: COCCOC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1-c1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
[2′-((4S,5R)-4-Methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-6-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.100 g, 0.16 mmol), phenylboronic acid (0.029 g, 0.24 mmol), potassium carbonate (0.055 g, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.018 g, 0.02 mmol) were combined in DME (2 mL) and H2O (1 mL), and the mixture was purged with N2 for 10 minutes. The reaction was stirred at 90° C. for 5 hours, until no starting material was seen by analytical LCMS. The pH was adjusted to pH 7 with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography to give the title compound. M+H is 546.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[CH:18][CH:19]=2)=[CH:3][CH:2]=1
Reactant: NCc1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CNCc2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Yield: 51 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step a) using 1-(4-dibenzo[b,d]furan-4-ylphenyl)methanamine and 4-(trifluoromethyl)benzaldehyde gave the title compound (51%). M+(LC/MS(ESI)): 432.4
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:14][NH2:15])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(C2CCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-cyclobutylpyridazine (22.5 g, 0.11 mol) and hydrazine hydrate (34 ml, 0.66 mol) were heated at reflux in dioxane (280 ml) for 24 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (13.3 g, 64%). 1H NMR (250 MHz , d6-DMSO) 1.68-1.86 (1H, m), 2.00-2.11 (3H, m), 2.29-2.38 (2H, m), 3.52-3.61 (1H, m), 4.35 (2H, br), 6.99 (1H, s), 8.06 (1H, br); MS (ES+) m/e 198 [MH]+, 200 [MH]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)NC(C)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[(3-methoxyphenyl)sulfonyl]acetamide (0.4 g, 1.75 mmol) in DCM at 0° C. was added BBr3 and the reaction was stirred at rt for 2 h. The reaction was quenched with pH=4 buffer and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated to afford the title compound. LC-MS: m/e 216 (M+H)+ (0.5 min).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-2-imidazolone (300 mg, 0.88 mmol) prepared in Preparation 3 was suspended in 10 ml of dichloromethane. Then, pyridine (85 μl, 1.05 mmol) and 4-nitrobenzoyl chloride (163 mg, 0.88 mmol) were added thereto one after another. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 hours while the reaction being monitored by TLC. After the reaction was completed, the whole mixture was diluted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, concentrated, and finally purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]2[C:33]([NH2:34])=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:22][CH:21]=1.P(Cl)(Cl)(Cl)=O>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][C:28]2[C:33]([NH:34][C:16](=[O:18])[CH2:15][CH:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:14][CH2:13]3)=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:24][CH:25]=1
Reactant: Nc1cncnc1NCc1ccc(F)cc1
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CC1CCN(Cc2ccccc2)CC1)Nc1cncnc1NCc1ccc(F)cc1
Yield: 61 %

Procedure:
A mixture of 52.4 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride, 38.7 parts of N4 -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine and 765 parts of phosphoryl chloride was stirred and refluxed for 30 minutes. The reaction mixture was evaporated. The residue was decomposed with ice water. The product was extracted with dichloromethane after treatment with sodium hydroxide. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 37 parts (61%) of N-[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]-1-(phenylmethyl)-4-piperidineacetamide; mp. 157.3° C. (interm. 45).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=2)[C:3]=1[Cl:23].[NH:24]1C(=O)CC[C@H:25]1C(O)=O.Cl>>[Cl:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]#[N:24])=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(-c3ccc(OC)c(F)c3)c(Cl)c(Br)c2c1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: Cl
Product: N#Cc1c(Cl)c(-c2ccc(O)c(F)c2)nc2ccc(O)cc12
Yield: 41 %

Procedure:
This compound was prepared from 34b according to method F and method G (using Pyr./HCl). Yellow solid; Yield: 41% (for two steps); mp 325–328° C. (dec.); 1H-NMR (300 MHz, DMSO-d6) δ 7.10 (dd, J=8.8, 8.7 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.43 (dd, J=8.4, 1.4 Hz, 1H), 7.49 (dd, J=9.2, 2.5 Hz, 1H), 7.55 (dd, J=12.2, 2.0 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 10.37 (s, 1H), 10.97 (s, 1H); MS (ESI) m/z 313 ([M−H]−), 315 ([M+H]+); Anal. Calcd for C16H8ClFN2O2: C: 61.07, H: 2.56, N: 8.90. Found: C: 60.80, H: 2.57, N: 8.55.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[CH2:20]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:27])=[CH:29][CH:30]=1)[CH2:19][CH2:18][CH3:17]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)CC1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)CC3)cc2)cc1

Procedure:
([1-(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4-4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 395.55 (C24H33N3O2); MS (ESI): 396 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].[CH2:9]([CH:11]1[O:13][CH2:12]1)[Cl:10]>O>[Cl:10][CH2:9][CH:11]([CH2:12][NH:4][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:2][OH:1])[OH:13]
Reactant: ClCC1CO1
Reactant: NC(CO)(CO)CO
Solvent: O
Product: OCC(CO)(CO)NCC(O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 Grams (0.1 mol) of tris(hydroxymethyl)methylamine (from Aldrich Chemical Co.) is dissolved in 125 ml of water. To this solution is slowly added about 0.12 mole (a 20% excess) of epichlorhydrin (Aldrich Chemical). After stirring for one hour at ambient temperature, the solution is extracted twice using 50 ml of methylene chloride to remove the unreacted epichlorhydrin. The aqueous phase containing the reactive Cl-compound is used immediately.
Reaction SMILES: Br[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:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)c1
Yield: 71.9 %

Procedure:
Following general procedure D, (6-bromo-4-(3-((dimethylamino)methyl)phenylamino)quinoline-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (81 mg, 72%) as a yellow-green solid. NMR (300 MHz, MeOD+TFA-d) δ 9.44 (s, 1H), 8.25 (dd, J=8.9, 1.9 Hz, 1H), 8.09-7.95 (m, 2H), 7.79-7.54 (m, 4H), 7.19 (dd, J=11.5, 2.3 Hz, 1H), 7.06 (s, 1H), 4.38 (s, 2H), 2.91-2.82 (m, 1H), 2.83 (s, 6H), 1.23-1.14 (m, 4H); ESI MS m/z 490 [C29H25ClFN3O2+H]+; HPLC 97.3% (AUC), tR=11.07 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH3:9][S:10][C:11](SC)=[C:12]([C:16](=O)[CH3:17])[C:13](=[O:15])[CH3:14].C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:17][C:16]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[C:11]([S:10][CH3:9])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CSC(SC)=C(C(C)=O)C(C)=O
Reactant: NNc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nn(-c2ccccn2)c(C)c1C(C)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of pyridin-2-yl-hydrazine (1.0 equivalent) and 3-(bis-methylsulfanyl-methylene)-pentane-2,4-dione (1.0 equivalent) was stirred at 60° C. overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was washed by brine twice, dried over magensium sulfate, and filtered. The organic solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: C([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=[O:25])[CH2:8][CH2:7]1)=O)C.Cl[C:27](OCC)=O.C(OC(=O)C)(=O)C>>[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=[O:25])[CH2:8][CH2:7]1)(=[O:3])[CH3:27]
Reactant: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1

Procedure:
3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared as described for 4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester in Example 8 but substituting ethyl chloroformate with with acetic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C@H:45]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[CH:62]=2)=[CH:57][CH:56]=1)[CH2:46][C@:47]([CH2:52][OH:53])([CH3:51])[C:48]([OH:50])=[O:49]>CN(C=O)C>[Cl:67][C:63]1[CH:62]=[C:61]([C:58]2[CH:57]=[CH:56][C:55]([CH2:54][C@@H:45]([NH:44][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:46][C@:47]([CH2:52][OH:53])([CH3:51])[C:48]([OH:50])=[O:49])=[CH:60][CH:59]=2)[CH:66]=[CH:65][CH:64]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@](C)(CO)C(=O)O)on1
Reaction time: 0.08 h
Yield: 14.5 %

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (9 mg, 32 μmol) was combined with HATU (12 mg, 32 μmol) and DMF (0.2 mL) and the resulting mixture was stirred for 5 minutes. DIPEA (17 μL, 96 μmol) and (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (79 mg, 38 μmol) pre-dissolved in DMF were added and the resulting mixture was stirred for 15 minutes then concentrated. The residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (2.2 mg). MS m/z [M+H]+ calc'd for C24H25ClN2O6, 473.14. found 473.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:28]=[C:27]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=1)([O-])=O.CCCCCC>ClC1C=CC=CC=1Cl>[CH:36]1[C:37]2[NH:20][C:23]3[C:24](=[CH:25][CH:26]=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=3)[C:32]=2[CH:33]=[CH:34][C:35]=1[C:38](=[O:40])[CH3:39]
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1ccc2c(c1)[nH]c1cc(C(C)=O)ccc12
Temperature: 180 °C

Procedure:
The mixture of triphenylphosphine (3.47 g, 13.24 mmol) and 1,1′-(2-nitro-[1,1′-biphenyl]-4,4′-diyl)diethanone (1.5 g, 5.30 mmol) in 1,2-dichlorobenzene (o-DCB) (15.90 mL) was heated at 180° C. under microwave irradiation for 1 h. The reaction mixture was cooled and poured in to the hexane (50 mL). Most of the impurities were removed by precipitation from hexane. The compound was further purified on silica gel ((0-100% EtOAc/Hexane). Fractions were concentrated to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C

Procedure:
To 0.102 g (0.428 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.134 g (0.429 mmol) of the above prepared 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridine, dissolved in 2.5 ml of abs. acetonitrile, was added 0.168 g of Cs2CO3 (0.516 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=88/12) yielded 0.221 g of pure title compound as colorless oil.