Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[N:53]=1>CN(C=O)C.O>[Cl:51][C:52]1[N:53]=[C:54]([O:58][CH:59]2[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:61][CH2:60]2)[CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1cccc(OC2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(Cl)n2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 18.27 %

Procedure:
DIPEA (271 mg, 2.1 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (162 mg, 0.7 mmol) in DMF (2 mL) followed by HOBt (94 mg, 0.7 mmol) and EDCI.HCl (134 mg, 0.7 mmol). After 2 minutes 2-chloro-6-(piperidin-4-yloxy)-pyridine hydrochloride (prepared according to the method used for the synthesis of Intermediate 15) (140 mg, 0.7 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 53 mg (18.27% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(6-chloro-pyridin-2-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 90%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (b, 1H), 7.8 (m, 3H), 7.4 (m, 3H), 7.1 (m, 1H), 6.8 (m, 1H), 5.2 (m, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.7 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH3:26][NH2:27]>CO>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:27][CH3:26])[S:8]1(=[O:25])=[O:24]
Reactant: CN
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CO
Product: CNCCOCCN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.66 g, 1.5 mmol) was treated with 8N methylamine in methanol to give 2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-methylethanamine which was treated with 1N hydrochloric acid in ether to afford its hydrochloride salt as a white solid (0.10 g, 16%). MS (ES) m/z 384.3 ([M+H]+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[CH2:36][C@H:33]5[CH2:34][CH2:35][C@H:30]([O:29][CH3:28])[CH2:31][CH2:32]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 88%), MS (ISP) m/z=485.5 [(M+H)+], mp 188.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and trans-2-(4-methoxy-cyclohexyl)-acetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:33])[N:5]=[CH:4][N:3]=1.[C:34](Cl)(=[O:39])[C:35](C)([CH3:37])[CH3:36].C(Cl)(=O)CC.CC(C)CC(Cl)=O.C(Cl)(=O)C(C)C.COCC(Cl)=O.C1(CC(Cl)=O)CCCC1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[CH3:33][C:6]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH2:15][N:14]([CH2:18][CH2:19][CH:20]([CH:21]4[CH2:22][CH2:23][N:24]([C:34](=[O:39])[CH:35]([CH3:37])[CH3:36])[CH2:25][CH2:26]4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:13][CH:12]3[CH2:11]2)=[O:9])=[C:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCNCC3)CC2C1
Reactant: CC(C)(C)C(=O)Cl
Agent: CC(C)C(=O)Cl
Agent: CC(C)CC(=O)Cl
Agent: CCC(=O)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)C(C)C)CC3)CC2C1

Procedure:
The following were prepared analogously from (4,6-dimethyl-pyrimidin-5-yl)-[5-(3-phenyl-3-piperidin-4-yl-propyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone using the acylating agent in parenthesis in place of pivaloyl chloride: V-13 (propionyl chloride), V-14 (3-methyl-butyryl chloride), V-19 (isobutyryl chloride), V-16 (methoxyacetyl chloride), V-17 (cyclopentylacetyl chloride) and V-22 (TFAA).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C)C=O>[CH2:23]([O:22][C:20]([C:19]([CH3:25])=[CH:1][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:21])[CH3:24]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 g (33.3 mmol) of 2-formylbenzoic acid and 14.5 g (40.0 mmol) of ethyl 2-(triphenylphosphanylidene)propionate in 100 cm3 of dimethylformamide is stirred at a temperature in the region of 20° C. for 1 hour. After removal of the solvent, the residue is dissolved in dichloromethane and then extracted twice with sodium bicarbonate solution. The aqueous phases are combined, washed with dichloromethane and then acidified with aqueous 6N hydrochloric acid solution to a pH of between 1 and 2. After extracting twice with dichloromethane, the organic phases are combined, dried over magnesium sulfate and then concentrated. 2-(2-Ethoxycarbonylpropen-1-yl)benzoic acid is thus obtained in the form of a yellow oil, which is used directly in the following step without further purification
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[F:32][C:33]([F:53])([F:52])[C:34]1[CH:35]=[C:36]([C@H:44]2[O:49][C:48](=[O:50])[NH:47][C@@H:46]([CH3:51])[CH2:45]2)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:53][C:33]([F:32])([F:52])[C:34]1[CH:35]=[C:36]([C@H:44]2[O:49][C:48](=[O:50])[N:47]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=3[C:13]3[CH:14]=[C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=4[CH3:31])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C@@H:46]([CH3:51])[CH2:45]2)[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@@H]3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (78.5 mg; 0.159 mmol) and (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (43.4 mg; 0-133 mmol) in DMF (1 mL) was added potassium tert-butoxide (14.9 mg; 0.133 mmol). The reaction was stirred at room temperature for 2 h, quenched with sat. NH4Cl, and partitioned between EtOAc (10 mL) and sat. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (4×25 mL) and the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford methyl 2″-({(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazinan-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate as a colorless glass. LCMS=740.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.89-7.82 (m, 3H), 7.71-7.66 (m, 2H), 7.59 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.41-7.38 (m, 1H), 7.30 (d, J=8 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.16 (d, J=8 Hz, 1H) 7.11-7.07 (m, 1H), 5.38 (d, J=15.6 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.30-3.25 (m, 1H), 2.34 (s, 3H), 2.17-2.12 (m, 1H), 1.73-1.65 (m, 1H), 1.08 (d, J=6.2 Hz, 3).
Reaction SMILES: O1C(N)CCOC2C=CC=CC1=2.ClC1N=C(N[C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])C(Cl)=CN=1>C(O)(C(F)(F)F)=O>[CH3:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: NC1CCOc2ccccc2O1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccccc1
Temperature: 115 °C
Yield: 204.9 %

Procedure:
A solution of 3,4-dihydro-2H-benz[b][1,4]dioxepin-ylamine (0.024 g, 0.00015 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (0.04 g, 0.00013 mol) in TFA (0.5 mL) was evaporated and then heated to 115° C. for 15 min. Purification by ISCO chromatography gave 2-[5-chloro-2-(3,4-dihydro-2H-benzo[b]1,4]dioxepin-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.036 g, 56%) vas a white solid. MP: 214-5° C.; 1H-NMR (DMSO-d6) δ 11.58 ((s, 1H), 9.36 (s, 1H), 8.74 (m, 2H), 8.20-1 (s, 1H), 7.74-6 (d, 1H), 7.50-2 (m, 1H), 7.42-8 (s, 1H), 7.14-6 (m, 2H), 6.86-8 (d, 1H), 4.05 (d, 2H), 4.09 (d, 2H), 2.81 (s, 3H), 2.07 (s, 2H); (LC/MS (ESI+): 426 (M+H).
Reaction SMILES: C([NH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=[O:8])[CH3:7])(=O)C.[ClH:16]>C(O)C>[ClH:16].[NH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)NC(Cc1ccccc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: CC(=O)C(N)Cc1ccccc1
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of 3-acetylamino-4-phenyl-2-butanone (12.5 g), 6N HCl (50 ml) and ethanol (50 ml) was stirred under refluxing conditions for 18 hours. The reaction mixture was concentrated under reduced pressure to yield 3-amino-4-phenyl-2-butanone hydrochloride (9.8 g, 81%).
Reaction SMILES: C([O:5][C:6]([C@@H:8]([NH:10][C:11]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([C@@H:8]([NH:10][C:11]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[CH3:9])([OH:7])=[O:5]
Reactant: COc1cc2c(N=C(Nc3c(C)cccc3C)N[C@@H](C)C(=O)OC(C)(C)C)ncnc2cc1OCCN1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(Nc3c(C)cccc3C)N[C@@H](C)C(=O)O)ncnc2cc1OCCN1CCCC1
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 4, N-[(S)-1-tert-butoxycarbonylethyl]-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(2-pyrrolidin-1ylethoxy)quinazolin-4-yl]guanidine was reacted with trifluoroacetic acid to give the title compound in 68% yield; NMR Spectrum: (DMSOd6, 100° C.) 1.47 (d, 3H), 1.75 (m, 4H), 2.33 (s, 6H), 2.67 (m, 4H), 2.93 (t, 2H), 3.88 (s, 3H), 4.28 (t, 2H), 4.58 (q, 1H), 7.13 (s, 1H), 7.19 (s, 3H), 7.75 (s, 1H), 8.48 (s, 1H),11.5 (br s, 1H); Mass Spectrum: M+H+ 505.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28](C)[C:27]1=[O:36].CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:23][CH2:24][CH2:25][N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]3=[O:36])[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21]
Reactant: Cn1c(=O)n(CCN)c2ccccc21
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(NCCn3c(=O)[nH]c4ccccc43)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.308 mmol), 1-(2-amino-ethyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one (140 mg, crude), and DIEA (85 mg, 0.66 mmol) in THF (3 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by preparative standard methods to afford the title compound (36.7 mg, 0.084 mmol, 24% yield over 2 steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.08-7.94 (m, 1H), 7.11-7.08 (m, 4H), 4.26-4.10 (m, 3H), 3.89-3.66 (m, 2H), 3.40-3.35 (m, 4H), 1.96-1.51 (m, 6H), 1.05-0.99 (m, 6H). MS (ESI) m/z 436.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23].[Cl-].[NH4+]>CN(C)C=O>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:23]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.2 g of 3,3-dimethylbutanoyl chloride was added, and the mixture was stirred for 6 hours. Thereafter, the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-(3,3-dimethylbutanoyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (12)).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:33][CH2:34]1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: CN1CCN(CCCl)CC1
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCN1CCN(C)CC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (100 mg, 0.290 mmol), 1-(2-chloro-ethyl)-4-methyl-piperazine dihydrochloride (82 mg, 0.348 mmol) and sodium hydride (60% dispersion in oil) (52 mg, 1.31 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88), except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in ethylacetate (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure and the title compound was purified by column chromatography eluting with dichloromethane/methanol (90/10).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N+:3]=1[O-]>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c2c1CCCC2
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)nc2c1CCCC2
Temperature: 100 °C
Yield: 36.6 %

Procedure:
A mixture of 2-bromo-4-nitro-5,6,7,8-tetrahydro-quinoline 1-oxide (example 7a) (7.9 g, 28.9 mmol), powdered iron (13.3 g, 238 mmol) and acetic acid (160 ml) was heated to 100° C. for 1 hr. After cooling the mixture was filtered and evaporated and the residue was partitioned (AcOEt/NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with CH2Cl2/MeOH=98/2) to provide 2.4 g (37%) of the title compound as a brown solid material. MS: m/e=226 (M+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(O)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (543 mg), 450 mg 6-hydroxy-2-oxindole, and 450 μL piperidine in 10 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give a brown solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>>[NH2:17][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(Cl)cn2COCCO
Temperature: 135 °C

Procedure:
4,5-Dichloro-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine (7b, 0.07 g) was covered with methanolic-ammonia (20 L) and heated in a sealed reaction vessel at 135° C. for 10 hours. The solvent was evaporated in vacuo to give a thick syrup. This syrup was subjected to column chromatography and elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3, which, after evaporation of the appropriate UV absorbing fractions, furnished colorless needles of 10, 0.04 g. (66.6%), mp 149°-150° C. 1H-NMR (DMSO-d6): δ8.14 (s, 1, C2--H), 7.56 (s, 1, C6--H), 6.92 (bs, 2, exchangeable with D2O, NH2), 5.49 (s, 1, N7--CH2) 4.64 (bs, 1, exchangeable with D2O, OH), 3.43 (m, 4, CH2): UVλmax nm (ε×104): (pH 7) 214 (2.5), 278 (1.3), (pH 1) 233 (2.8), 280 (1.3); (pH 11) 227 (1.4), 278 (1.3). Anal. Calcd. for C9H11N4O2Cl·1/4H2O: C, 43.73; H. 4.66; N, 22.67. Found: C, 43.87; H. 4.36; N. 22.23.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)C.[OH-].[Na+:30]>O1CCOCC1>[Na+:30].[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[CH:17][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([O-:28])=[O:3])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)[C:19]1=[O:27]
Reactant: CCOC(=O)COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C([O-])COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy] acetic acid ethyl ester (150 mg, 0.40 mmol) in dioxane (20 ml) was added 2N sodium hydroxide (2 ml) and the mixture was stirred for 1 h at room temperature. The resulting crystals were separated by filtration, washed with dioxane and dried. Thus pure title compound was obtained in 81.5% yield (120 mg).
Reaction SMILES: BrC1C(O)=C(C(CS(C2C=CC=C(Cl)C=2)(=O)=O)=CC=1)C(OC)=O.[Br:24][C:25]1[C:26]([O:46]C)=[C:27]([C:32]([CH2:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]>>[Br:24][C:25]1[C:26]([OH:46])=[C:27]([C:32]([CH2:35][S:36]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)(=[O:38])=[O:37])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 54, starting from methyl 3-bromo-6-(4-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 69).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=CC=C([O:43][C:44]([F:47])([F:46])[F:45])C=2N=1>>[NH:25]1[CH2:26][CH2:27][CH:22]([N:20]2[CH:21]=[C:17]([C:15]3[CH:16]=[C:11]([C:8]4[S:9][C:10]5[CH:2]=[CH:3][CH:4]=[C:5]([O:43][C:44]([F:47])([F:46])[F:45])[C:6]=5[N:7]=4)[C:12]([NH2:28])=[N:13][CH:14]=3)[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: FC(F)(F)Oc1cccc2sc(I)nc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(OC(F)(F)F)cccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-4-trifluoromethoxy-1,3-benzothiazole and conducting the Suzuki coupling at 50° C. for 12 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.12-9.03 (brm, 1H), 8.94-8.82 (brm, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.41 (brs, 2H), 8.34 (very brs, 2H), 8.26 (dd, J=2.2, 6.6 Hz, 1H), 8.07 (s, 1H), 7.66-7.60 (m, 2H), 4.57-4.48 (mc, 1H), 3.41 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.2 Hz, 2H), 2.30-2.12 (m, 4H). MS(ES+): m/z=461.06 (74) [MH+], 378.06 (100) [MH+-piperidine]. HPLC: tR=2.27 min (polar—5 min, ZQ2).