Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([NH:27][CH3:26])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(N)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
1-(3-Amino-4-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and an aqueous solution (about 40%; 500 mg) of methylamine were added to pyridine (1,200 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (210 mg) as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H-].[Na+].[CH3:17]N(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:17])[C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]c3cnccc3c2c1
Agent: [H-]
Agent: [Na+]
Product: Cn1c2ccc(Br)cc2c2ccncc21
Reaction time: 1 h

Procedure:
A solution of 6-bromo-β-carboline (1.0 g, 4.05 mmol) in 12 mL of DMF was stirred in an ice bath and 186 mg (4.65 mmol, 1.15 equiv.) of 60% sodium hydride in mineral oil dispersion was added. Gas evolution was observed and stirring was continued for 1 h at ambient temperature. The homogenous reaction was partitioned between EtOAc and H2O. The organic layer was washed again with H2O followed by brine. After drying (MgSO4), evaporation gave a pale yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([S:34]([C:36]([F:39])([F:37])[F:38])=[O:35])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 108 mg (0.50 mmol) 4-(4-Imidazol-1-yl-butyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued overnight. After addition of 10 ml water the resulting precipitate was washed with water, 10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) to yield 167 mg colorless powder that was further purified by HPLC-MS to give 75 mg (29%) colorless powder.
Reaction SMILES: [C:1]([C:9]12OC1[O:13][C:12]([C:16]([O:18]CC)=[O:17])=[CH:11][C:10]2=[O:21])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>O1CCOCC1>[Cl:22][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[O:13][C:1]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Reactant: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)c(Cl)c(-c2ccccc2)o1

Procedure:
A solution of ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo[4.1.0]hept-3-ene-3-carboxylate (2.9 g) prepared as in Example 44, in dioxan (30 ml) and concentrated hydrochloric acid (10 mol) was heated under reflux for 2 hours. The solution was evaporated under vacuum and the solid residue was crystallised from ethyl acetate-petroleum ether 60°-80° C. and then from dioxan-water to give the title product (mp 216°-218° C. with decomposition).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O>C(O)C.[Pd]>[NH2:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(C(F)(F)F)cc1N

Procedure:
A solution of 1.1 g (5.0 mmol) 4-methylamino-3-nitrobenzotrifluoride in 200 ml ethanol was hydrogenated at atm. pressure by using 5% Pd-C (0.15 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give 3-amino-4-methylaminobenzotrifluoride as crystals.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([NH:11][CH:12]=[N:13]2)=[C:9](Cl)[N:8]=1>C(O)(=O)C>[CH2:2]([O:5][C:9]1[N:8]=[C:7]([Cl:6])[N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[CH:3]=[CH2:4]
Reactant: C=CCO
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [Na]
Solvent: CC(=O)O
Product: C=CCOc1nc(Cl)nc2nc[nH]c12
Yield: 94 %

Procedure:
Sodium (0.37 g, 15.9 mmol) was reacted with allyl alcohol (20 ml) under nitrogen with cooling in an ice bath. 2,6-Dichloropurine (1.00 g, 5.29 mmol) was added and the reaction was refluxed for 2 h, after which time the reaction mixture was allowed to cool. The mixture was neutralised with glacial acetic acid and the solvent was removed. The residue was triturated with cold water to yield the title compound as a white solid (1.05 g, 94%), m.p. 208-209° C.; νmax (cm−1) 3422,3017, 2782, 2685, 2595 (NH, C—H); δH (200 MHz, d6-DMSO) 8.454 (1H, s, C(8)H), 6.230-6.036 (1H, m, CH2CH═CH2), 5.478 (1H, dd, J=1.6 Hz, J=17.2 Hz, CH2CH═CH2), 5.327 (1H, dd, J=1.6 Hz, J=10.4 Hz, CN2CH═CH2), 5.054 (2H, d, J=5.5 Hz, CH2CH═CH2); m/z 210 (M+, 68%), 195 (64), 183 (12), 175 ([M—Cl]+, 98%), 154 ([MH—OCH2CH═CH2]+, 21%), 135 ([MH—Cl—CH2CH═CH2]+, 50%), 119 ([MH—Cl—OCH2CH═CH2]+, 33%), 92 (12), 53 (18), 41 ([CH2CH═CH2]+, 100%), 32 (53).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:26])[CH3:25]>C(O)C>[CH2:24]([NH:26][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH3:25]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CCN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 9 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and 33% ethylamine in ethanol (20 ml) yielded the title compound, 0.29 g, m.p. 181°-182° C. (recrystallised from ethanol/water and then from ethanol).
Reaction SMILES: C(OC1C=CC(OC(CO)CO)=NC=1)C1C=CC=CC=1.C(OC(OCC)CCCNC(=O)C)C.[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][C@H:50]2[CH2:55][O:54][C@@H:53]([CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:52][CH2:51]2)=[N:47][CH:48]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC1C=CC(O[C@@H]2CO[C@@H](CCCNC(=O)C)OC2)=NC=1)C1C=CC=CC=1>>[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH:50]2[CH2:55][O:54][CH:53]([CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:52][CH2:51]2)=[N:47][CH:48]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(OCc3ccccc3)cn2)CO1
Agent: CC(=O)NCCC[C@H]1OC[C@H](Oc2ccc(OCc3ccccc3)cn2)CO1
Agent: CCOC(CCCNC(C)=O)OCC
Agent: OCC(CO)Oc1ccc(OCc2ccccc2)cn1
Product: CC(=O)NCCCC1OCC(Oc2ccc(OCc3ccccc3)cn2)CO1

Procedure:
2-(5-Benzyloxypyridin-2-yloxy)propane-1,3-diol (216 mg, 784 μmol) was reacted with N-(4,4-diethoxybutyl)acetamide in analogy to example 3d. Yield: cis-N-{3-[5-(5-benzyloxypyridin-2-yloxy)-[1,3]dioxan-2-yl]propyl}acetamide (example 16), 21 mg (7%), M+H+: 387.22 and trans-N-{3-[5-(5-benzyloxypyridin-2-yloxy)-[1,3]dioxan-2-yl]propyl}acetamide (example 17), 6 mg (2%), M+H+: 387.23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:24]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)ccc3F)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 2-fluoro-5-methylbenzoic acid are converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCO>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH2:28][NH:27][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:30]=[CH:31][C:32]=2[Cl:38])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide and 5-(tert.butoxycarbonylamino)methyl-2-chloro benzoic acid with TBTU and TEA. Yield: (85%). MS [m+H]+=588 (Br/Cl-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1>C(N)C1C=CC=CC=1>[C:15]1([CH2:10][NH:9][C:3]2[N:13]3[C:14]4[N:9]([C:10]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=5)=[CH:11][CH2:12]3)[N:8]=[CH:7][C:6]=4[C:5](=[O:25])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Solvent: NCc1ccccc1
Product: O=c1nc(NCc2ccccc2)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Temperature: 25 °C

Procedure:
A 200 mg amount of 5-(methylthio)-8-[3-trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 9) was suspended in 10.0 ml of benzylamine. The reaction mixture was cooled to room temperature and filtered. The solid on the filter was washed with ether and air dried to give 189 mg of the product of the example as a white solid, m.p. 220°-224° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[N:30]=[N:31][C:32]([CH:34]=O)=[CH:33][C:26]=2[NH:25]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[N:31]=[N:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[CH:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1cc2c(nn1)SCC(=O)N2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CSc2nnc(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)cc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carbaldehyde (for a synthesis see WO2004058144, Example 58) (65 mg, 0.33 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (210 mg; 1.0 mmol) was added and the mixture was stirred at room temperature for 4 h. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give 42 mg of the title compound as an oil which solidified to an off-white powder upon standing.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[C-]#N.[K+]>CO.C(OCC)(=O)C.O.CCOC(C)=O.CCCCCC>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:5]#[N:6])([N:2]([CH3:3])[CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
500 ml (10 equiv.) of dimethylamine solution and 109.9 g (5 equiv.) of dimethylamine hydrochloride were added to a solution of 50 g (1 equiv.) of tert-butyloxycarbonyl-4-oxopiperidine in 100 ml of methanol, and the mixture was cooled to 5° C. 5 ml (0.1 equiv.) of hydrochloric acid were then added dropwise, over a period of 10 minutes, to the reaction mixture, and stirring was carried out for 60 minutes at room temperature. 48.9 g (3 equiv.) of potassium cyanide were added in portions to the reaction mixture, and stirring was carried out for 24 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (50% EtOAc/hexane). When the reaction was complete, 150 ml of water were added to the reaction mixture, and extraction was carried out 3× with 100 ml of ethyl acetate. The combined organic phases were dried with Na2SO4. After removal of the solvent under reduced pressure, crude product was obtained and was recrystallized from hexane. 57 g (90%) of product were obtained in the form of a colourless solid.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:17]/[N:18]=[C:19]2\[NH:20][C:21](=[O:37])[C:22]3[NH:23][C:24]([C:33]([F:36])([F:35])[F:34])=[N:25][C:26]=3[N:27]\2[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]2[N:20]3[C:21](=[O:37])[C:22]4[NH:23][C:24]([C:33]([F:35])([F:36])[F:34])=[N:25][C:26]=4[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:19]3=[N:18][N:17]=2)[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCn1/c(=N/NC(=O)CCc2nc(Cc3ccccc3)no2)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2c(CCc3nc(Cc4ccccc4)no3)nnc12
Yield: 17.9 %

Procedure:
The mixture of 3-(3-benzyl-1,2,4-oxadiazol-5-yl)-N′-[(2E)-6-oxo-3-pentyl-8-(trifluoromethyl)-1,3,6,7-tetrahydro-2H-purin-2-ylidene]propanohydrazide (220.1 mg, 0.424 mmole) in toluene (20 ml) was refluxed for 5 hours. After evaporation of solvent, the residue was purified by preparative LCMS to yield the desired product (37.9 mg, 17.8%) as white solid. LCMS calculated for C23H24F3N8O2 (M+H): 501.2. found 501.1.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:14]([O:15][C:16]([F:19])([F:18])[F:17])=[C:13]([F:20])[C:12]([F:21])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7].Cl>C(O)C>[F:3][C:4]1[C:14]([O:15][C:16]([F:17])([F:18])[F:19])=[C:13]([F:20])[C:12]([F:21])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC(F)(F)F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)c(F)c(OC(F)(F)F)c1F
Reaction time: 2 h
Yield: 87.4 %

Procedure:
19.3 ml (0.0193 moles) of a 1N aqueous solution of sodium hydroxide were added to a solution of 5.05 g (0.0175 moles) of ethyl 2,4,5-trifluoro-3-trifluoromethoxybenzoate [(XXVIII), X=X'=F, R16 =C2H5O] [prepared as described in step (b) above] in 100 ml of ethanol, and the mixture was allowed to stand at room temperature for 2 hours. At the end of this time, 19.3 ml of 1N aqueous hydrochloric acid were added, and then the reaction mixture was concentrated by evaporation under reduced pressure. The residue was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, to give 3.98 g of 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.3 %

Procedure:
A solution of ethyl isonipecotate (25 g; 0.165 mol) in dichloromethane (250 ml) and triethylamine (50 ml) was cooled in a water bath and triphenylmethyl chloride (48.7 g; 0.175 mol) was added portionwise. Shortly after the addition was completed a precipitate was formed. The mixture was stirred at room temperature for 24 h and the mixture was then washed with water, dried over sodium sulfate and evaporated to dryness to give a yellow oil (74.0 g). This oil was triturated with methanol to give the product as cream coloured crystals in 97% yield (61.9 g); m.p. 164° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[NH2:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.52 mmol, 271 mg) and Et3N (3.05 mmol, 0.42 mL) were added sequentially to a solution of 3-chloro-4-(3-chlorophenoxy)aniline (1.02 mmol, 258 mg) in DCM (6 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-chloro-4-(3-chlorophenoxy)phenyl)picolinamide (0.52 mmol, 187 mg, 51%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]1[O:17][C@H:16]1[CH2:18][OH:19]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][C@@H:16]([OH:17])[CH2:18][OH:19])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@@H](O)CO)n1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 3.00 g, 26.55 mmol) in N,N-dimethylformamide (15 mL) was treated with solid potassium carbonate (5.50 g, 39.82 mmol) and (S)-(−)-glycidol (3.93 g, 53.10 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the N,N-dimethylformamide was removed in vacuo. Purification by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) afforded (R)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (3.17 g, 64%) as a yellow oil: LR-ES-MS m/z calculated for C6H9N3O4 [M]+ 187, observed [M+H]+ 188.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][C:25](O)=[O:26].COC1C2N=C(NC(=O)CC3CCOCC3)SC=2C(C2CCOCC2)=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:25](=[O:26])[CH2:24][CH:20]3[CH2:21][CH2:22][CH2:23][O:19]3)[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)CC1CCCO1
Agent: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCCO3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (tetrahydro-furan-2-yl)-acetic acid, the title compound was prepared in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as white solid (50% yield). Mp 170-174° C., MS: m/e=377(M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[C:5]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: OCCCNc1nc(Cl)ccc1C(F)(F)F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of 3-{[6-chloro-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 302) (0.63 g, 2.45 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.45 g, 2.05 mmol) in THF (6.80 mL) was added triphenylphosphine (0.70 g, 2.66 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.68 g, 2.66 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.58 g, 62%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.02 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 6.60 (d, 1H), 6.48 (b, 1H), 4.15 (q, 2H), 4.04 (t, 2H), 3.65 (q, 2H), 3.46 (qt, 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 2.08 (qt, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=[N:20]O)[CH2:15]2)[CH2:10][CH2:9]1>C1COCC1>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH2:15]2)[CH2:12][CH2:13]1
Reactant: CN1CCN(C2CCCC(=NO)C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C2CCCC(N)C2)CC1
Temperature: 25 °C
Yield: 67 %

Procedure:
LAH (13015 g, 355.45 mmol, 2.5 eq.) was taken up in THF (600 ml), and 3-(4-methylpiperazin-1-yl)cyclohexanone oxime (30.0 g, 142.18 mmol, 1.0 eq.) was added in portions at 0° C. The reaction mixture was then heated to RT and refluxed for 14 hours. Then it was cooled to 0° C. again, hydrolyzed with 15% NaOH solution (15 ml), filtered off and washed with 10% MeOH in DCM (500 ml). The filtrate was concentrated under reduced pressure and used in the next stage without being purified further. Yield: 67% (19.0 g, 96.44 mmol)