Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:32])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (178 mg, 0.41 mmol) was dissolved in THF (5 mL). The mixture was added to methylmagnesium bromide (3 M in THF, 1.090 mL, 3.27 mmol) in THF (5 mL). The mixture was stirred at rt for 5 min. The mixture was cooled at 0° C. and ammonium chloride (aq) was added. The mixture was extracted by EtOAc, the organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound as a solid 107 mg (58%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14])(=[O:10])[CH3:9].OO>O.CC(C)=O>[C:8]([NH:11][C@@H:12]([CH2:13][S:14][S:4][CH2:3][C@H:2]([NH2:1])[C:5]([OH:7])=[O:6])[C:15]([OH:17])=[O:16])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: OO
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 10 %

Procedure:
L-cysteine (2.42 g, 20 mmol) and N-acetyl-L-cysteine (3.26 g, 20 mmol) were dissolved in 25 mL of water. The pH of this solution was 2.6 according to lithmus paper. Aqueous hydrogen peroxide (30%, 2.3 mL, 21 mmol) was added, and the reaction mixture was allowed to stand at room temperature overnight. A white precipitate stand at room temperature overnight. A white precipitate was filtered off (1.26 g). This material was shown to be L-cystine by comparison of spectral data with an authentic sample. The yellowish filtrate, containing the desired compound and the two symmetrical compounds (R,R)-N,N'-diacetylcystine and (minor amounts of) cystine was separated on a preparative HPLC using a Dynamax C1 8-column (8 μm, 60 Å, 21.4×250 mm) with a Dynamax C1 8-guard column (8 μm, 21.4×50 mm) and with Gilson dual solvent delivery system (305 pump, pumphead 100 SC acting as a solvent delivery pump, pumphead 5 SC acting as a sample injector, 806 manometric module, 811B dynamic mixer, 115 UV detector, 201 fraction collector, 201-202 fraction controller). The solvents used were A=10 mM HOAc/H2O and B=MeOH, with a 95:5 ratio of A:B. The solvent flow was 10 mL/min and the separation was recorded at 230 nm. After detection of each fraction on TLC (Merck 16483, plastic sheets silica gel 60 WF 254s, eluent nBuOH/HOAc/H2O 1:1:1, I2 as visualization agent), the fractions with acceptable purity were pooled and evaporated to give an oily residue. This residue was dissolved in acetone (pa) and the solution was evaporated to give the title product as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[CH:12]2)[NH:4][CH:3]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C=O)C>[Br:24][C:25]1[CH:32]=[C:31]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][C:9]([N:11]4[CH:15]=[C:14]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:13]=[CH:12]4)=[C:10]3[C:2]([CH3:1])=[CH:3]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cc1c[nH]c2nccc(-n3cnc(-c4ccccc4)c3)c12
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3cnc(-c4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Compound (97c) (0.140 g) was dissolved in DMF (1.7 mL), and sodium hydride (0.024 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 10 min. Then, 2-bromo-4-fluorobenzonitrile (0.112 g) was added to the reaction solution, followed by stirring at 50° C. for 30 min. Ice water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (97d) (0.160 g, 69%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[CH:11]=[CH:10][C:8]([NH2:9])=[N:7][C:5]2=[O:6])[CH2:3][CH2:2]1.[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20]([NH:9][C:8]2[CH:10]=[CH:11][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[N:7]=2)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccn(C2CC2)c(=O)n1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(C3CC3)c(=O)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 10.6 g. of 1-cyclopropylcytosine, 16.4 g. of N-acetylsulfanilyl chloride and 47 ml. of pyridine was stirred overnight after momentary cooling to maintain the reaction below 30°. The mixture was poured into 700 ml. of water, and after filtration by gravity, the solution was strongly acidified by addition of 6N hydrochloric acid. Gradual crystallization occurred overnight in a refrigerator before filtering the N4 -acetyl-N1 -(1-cyclopropyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-sulfanilamide; yield 10.7 g., m.p. 139°-143°.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1)([O-:10])=[O:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:3])[CH3:2])(=[O:32])=[O:31])=[O:21])=[CH:36][CH:37]=1)([O-:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
In a stream of nitrogen and at 0° C. 0.07 ml (0.80 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.70 mol) of 3-(4-nitrobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 5 and 171 mg (1.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 290 mg (yield: 89.8%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14]Cl)=[CH:4][N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:14][C:5]1[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[N+:17]=[N-:18]
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CNc1nc(Cl)ncc1CN=[N+]=[N-]
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.47 g (5.92 mmol) of (2-chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine and 0.46 g (7.1 mmol) NaN3 is dissolved in 6 ml of DMF and was stirred at 30° C. for 2.5 hours. Then the reaction mixture is cooled to rt., diluted with ethyl acetate and twice extracted with H2O. The organic layer is separated and dried over Na2SO4. Evaporation of the ethyl acetate yielded (5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as white crystalls.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[CH2:13][CH2:14]Br>>[CH3:10][O:11][CH:12]([O:16][CH3:17])[CH2:13][CH2:14][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CCBr)OC
Reactant: COC(=O)C1CCCC1
Product: COC(=O)C1(CCC(OC)OC)CCCC1
Yield: 72 %

Procedure:
Prepared according to a procedure identical to Stage A of Example 6, starting from methyl cyclopentanecarboxylate and 3-bromopropionaldehyde dimethyl acetal, with a 72% yield.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:31]([C:30]3[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=3)=[O:32])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=468.2.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.43 mmol) of the compound from Example 25A and 232 mg (1.58 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 398 mg (53% of theory)
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][O:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37].CC(C)([O-])C.[K+]>C1COCC1>[Cl:32][C:4]1[N:3]=[C:2]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[O:34][CH3:33])[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1
Reactant: COc1ccccc1N
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1Nc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37B, 100 mg, 0.217 mmol), 2-methoxyaniline (26.0 μl, 0.217 mmol), t-butyl X-Phos palladacycle (5.97 mg, 8.69 μmol) were combined in a 5 ml microwave vial. The vial was evacuated and backfilled (3×) with N2 gas before adding THF (2.2 ml) and potassium t-butoxide (326 μl, 0.326 mmol). The reaction was allowed to stir at 80° C. for 2 hours. Room temperature was attained and the mixture was filtered through a celite frit and concentrated in vacuo while loading onto silica gel. Purifcation by MPLC 0-20% EtOAc/DCM gave 6-chloro-3-methoxy-N-(2-methoxyphenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine (52B). MS: [M+H]+ m/z 547.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+].O>CO>[OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)c1ccc(CC2CCCCC2=NO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=NO)cc1
Reaction time: 8 h

Procedure:
Three grams of ethyl 2-[4-(2-hydroxyiminocyclohexan-1-ylmethyl)phenyl]propionate and 0.8 g of sodium hydroxide were dissolved in 50 ml of methanol and the solution was allowed to stand at room temperature overnight. To the reaction mixture was added 20 ml of water, methanol was removed by distillation and the residue was acidified with hydrochloric acid to precipitate crystals, which were collected by filtration and recrystallized from a mixture of ether and n-hexane affording 2.1 g of colorless crystals, m.p. 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:39])[CH2:33][C:34]#[C:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])[C:35]#[C:34][CH2:33][N:32]([CH3:39])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CN(C)CC#CC(=O)O
Product: CN(C)CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 12 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-(dimethylamino)but-2-ynoic acid (Intermediate 49), to afford the title compound (5.6 mg, 12%). Data: UPLC (C) Rt: 0.97 min; m/z 509.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[F:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1ccccc1F
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccc3F)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 2-fluorobenzoyl chloride.
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(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To an ice cold solution of ethyl isonipecotate (60 g, 0.382 mol) and triethylamine (38.65 g, 0.382 mol) in tetrahydrofuran (360 ml) was added dropwise benzoyl chloride (53.7 g, 0.382 mol) over a period of about 2 hours under nitrogen atmosphere. The reaction mixture was stirred for about 2 hours at the same temperature, and was filtered. The filtrate was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. Crystallization from isopropyl alcohol gave the titled compound (90.9 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:34][N:33]2[C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 7.5 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.087 g, 0.5 mmol) to give 0.013 g of product as a tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH:20]=[CH2:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:21][CH:20]([CH2:19][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C=CCP(=O)(OCC)OCC
Reactant: ON=Cc1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CC1CC(c2ccc(Cl)cc2)=NO1)OCC
Yield: 104.5 %

Procedure:
Preparation is carried out as in Example 1 from 23.34 g of 4-chlorobenzaldoxime, 22 g of N-chlorosuccinimide, 29.5 g of diethyl allylphosphonate and 22.9 ml of triethylamine in dichloromethane and provides 52 g of oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]#[N:13])=[CH:8][CH:9]=1
Reactant: N#CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: N#CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
3-(4-Nitrophenyl)propionitrile (740 mg, 4.2 mmol) was dissolved in methanol (100 mL), 10% Pd/C was added and the mixture was shaken under a hydrogen atmosphere (50 psi) at room temperature for 30 minutes. The mixture was filtered through Celite, and washed with 20 mL of methanol. The combined organic solvent was concentrated under reduced pressure to give crude materials which was further purified by flash column chromatography (Ethyl acetate:Hexanes 1:1) to yield 520 mg of 3-(4-Aminophenyl)propionitrile as a light yellow oil. 1H NMR (DMSO-d6): δ 6.91-6.88 (d, J=9.0 Hz, 2H), 6.49-6.46 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 2.66 (s, 4H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=2[CH3:35])=[CH:26][CH:27]=1)=[O:22].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:18][CH2:17][C:5]3[C:6]([C:9]4[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=4[Cl:15])=[N:7][O:8][C:4]=3[CH:1]3[CH2:3][CH2:2]3)=[CH:30][C:29]=2[CH3:35])=[CH:26][CH:27]=1)=[O:22]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2C)s1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2C)s1
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (0.188 g, 0.66 mmol), 5-(4-hydroxy-2-methyl-phenyl)-thiophene-2-carboxylic acid methyl ester (0.15 g, 0.60 mmol), and tri-N-butyl-phosphine (0.16 g, 0.79 mmol) in toluene (2 mL) is added a solution of ADDP (0.2 g, 0.79 mmol) in 1 mL of toluene. The reaction is stirred overnight. The reaction mixture is partitioned between ethyl acetate and water and the layers are separated. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude oil. The oil is chromatographed using a gradient of 10% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to yield the title compound (0.14 g, 41%). ES/MS m/e 514.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (10.95 g, 0.04) was dissolved in DCM (500 ml) and triethylamine (18.5 ml, 0.13 mol) was added. The mixture was cooled to 0° C. and methane sulphonyl chloride (7.4 ml, 0.048 mol) added. Allowed to reach ambient temperature and stirred overnight. The reaction mixture washed with water and the organic phase collected, dried over MgSO4, filtered and evaporated to dryness. The residual solid was crystallised from ethanol to yield 1-(methylsulfonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a white solid. Yield 12.3 g (78.5%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:11][CH:10]=1)C.[NH3:28]>CO>[C:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH2:28])=[CH:10][CH:11]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCCCC(N)=O)cc1
Temperature: 45 °C
Reaction time: 25 h
Yield: 56 %

Procedure:
4-[4-(4-tert-Butoxycarbonylaminobutyl)phenylamino]butyric acid ethyl ester 420 (0.44 g, 1.16 mmol) was added to 7N NH3 in methanol (40 mL). The reaction was stirred at 30° C. for 18 hours, at 45° C. for 25 hours, and finally at 50° C. for 84 hours. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20:1:0.1, chloroform/methanol/concentrated ammonium hydroxide, v/v) to provide 430 (0.23 g, 56%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m 2H), 2.37 (t, 2H), 2.50 (t, 2H), 3.11 (m, 4H), 6.52 (d, 2H), 6.97 (d, 2H). m/z (ESI) 350.