Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH:23]=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][Mg]Br>O1CCCC1>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH:23]([OH:24])[CH3:37])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C=O)c1OCc1cccc(C#N)c1
Solvent: C1CCOC1
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C(C)O)c1OCc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 5-(3-cyano-benzyloxy)-4-formyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (109) (1.4 g, 2.9 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added methyl magnesium bromide (4 mL, 1.0 M, 4.0 mmol) at −78° C. under nitrogen atmosphere and stirred for 30 minutes. The reaction mixture was quenched with a solution of saturated aqueous sodium bicarbonate, and the crude product extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 3:2) as an eluant to give [5-(3-cyano-benzyloxy)-4-(1-hydroxy-ethyl)-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (112) (1.04 g, 72% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:26])=[CH:21][CH:20]=1>>[CH2:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:38])=[O:26])=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CS(=O)(=NC(=O)NCc1ccccc1)c1ccc(N)cc1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)NCc3ccccc3)cc2)ncc1-c1cccs1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (175 mg, 0.65 mmol) with (RS)—S-(4-aminophenyl)-N-(benzylcarbamoyl)-S-methylsulphoximide (179 mg, 0.59 mmol) according to procedure 5c, the desired product is obtained in 26% yield (82 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Cl)[CH:2]=1.[CH:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(OCC)C>O1CCCC1>[CH3:9][C:1]1[CH:2]=[C:3]([C:21]2([OH:23])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:22]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
A 1.0 M solution of m-tolylmagnesium chloride in tetrahydrofuran (10 mL, 10 mmol) (Aldrich) was added dropwise to a solution of 9-fluorenone (1.8 g, 10 mmol) (Aldrich) in anhydrous tetrahydrofuran (5 mL) with stirring under argon at 0° C. The mixture was stirred at room temperature for 1 h, anhydrous diethyl ether (20 mL) was added and the formed precipitate was filtered and dissolved in chloroform (50 mL). The chloroform solution was washed with a saturated solution of ammonium chloride (10 mL), brine (10 mL), dried (MgSO4), the solvent evaporated and the residue recrystallized from diethyl ether/hexane to give the title compound as a white solid (2.42 g, 89%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[OH-].[Na+]>O>[NH2:1][CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CCN=[N+]=[N-])c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)cnc(Cn2nc3cc(CCN)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
A mixture composed of the above tert-butyl {8-(2-azidoethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}carbamate (31 mg), triphenylphosphine (23 mg), tetrahydrofuran (0.9 ml) and water (0.1 ml) was stirred at room temperature for five hours. A 0.2 N sodium hydroxide solution (2.5 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and then the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH silica used, ethyl acetate-chloroform) to obtain the title compound (17 mg) as an oil.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)[CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O>[C:28]1([C:24]2[N:23]=[C:22]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[OH:9])[N:21]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Hydrochloric acid (14.8 ml, 177.2 mmol) was added to pyridine (14.3 ml, 177.2 mmol), and the mixture was heated with removing water till an internal reaction temperature reach to 180° C. After the reaction mixture was cooled to 120° C., 6-(2-methoxyphenyl)-6′-phenyl-2,2′-bipyridine (3.0 g, 8.9 mmol) obtained by Example 13 was added to the reaction mixture and stirred for at 180° C. for 2 hours. After the reaction mixture was cooled, to which was then added an aqueous 1 mol/L sodium hydroxide solution, the mixture was extracted with dichloromethane, the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 2.7 g of 2-(6′-phenyl-2,2′-bipyridine-6-yl)phenol as yellow crystal. Yield: 93.9%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][O:22][CH3:23])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:23][O:22][CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCC1CNCCN1
Yield: 84.5 %

Procedure:
1,4-Dibenzyl-2-(methoxymethyl)piperazine (1.578 g, 5.08 mmol) and palladium (10% on carbon, 0.163 g, 1.53 mmol) in ethanol (50.8 ml) were stirred under an atmosphere of hydrogen at room temperature for 3 days. The reaction mixture was filtered through celite, washing with ethanol. The resulting mixture was evaporated to dryness to afford crude product. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford 2-(methoxymethyl)piperazine (0.559 g, 84%) as a yellow oil. This was used directly without further purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH2:22])[C:16]([C:23]([NH2:25])=[O:24])=[CH:15]2>CCCCCC>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[N:22]=[C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])[NH:25][C:23](=[O:24])[C:16]1=[CH:15]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2cc(F)ccc2nc1N
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3ccc(F)cc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
A mixture of diethyl oxalate (57.2 g., 0.392 mole) and 6-fluoro-2-aminoquinoline-3-carboxamide (5.34 g., 0.0261 mole) is heated for eighteen hours at 160° C. under a nitrogen atmosphere and then allowed to cool to room temperature. Hexane (300 ml.) is added, the mixture stirred and filtered to provide the desired product. It is washed with hexane and dried. Yield = 4.9 g. (71%); m.p. 272° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[Cl-].[NH4+].Br[CH2:20][CH:21]=[CH2:22]>C1COCC1.[Zn]>[CH2:22]([C:2]1([OH:1])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC1(O)CC[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (1 g, 4.58 mmol) in THF (10 mL) was added zinc powder (2.098 mL, 229 mmol), saturated aqueous ammonium chloride solution (20 mL) followed by 3-bromoprop-1-ene (1.663 g, 13.75 mmol) slowly at room temperature. The resulting mixture was heated to 80° C. for 3 hours, then allowed to stir at room temperature for additional 12 hours. The reaction mixture was filtered and the filtrate concentrated. To the residue was added ethyl acetate (20 mL) and the resulting mixture was washed with water (5 ml), brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield (1R)-benzyl 3-allyl-3-hydroxycyclopentanecarboxylate (580 mg, 2.228 mmol, 48.6% yield) as an oil. It was used as such for the next step without further purification. MS (ESI+) m/z 283 (M+Na)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=CC(S(Cl)(=O)=O)=C[CH:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])O.[Na+]>C(O)(C)(C)C>[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([O:23][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
P-toluenesulfonyl chloride (53.5 g) was added to a pyridine (100 ml)/tert-butanol (300 ml) solution of 2,6-dichloro-5-fluoronicotinic acid (24.5 g), and stirred overnight at room temperature. The reaction liquid was poured into aqueous 10% sodium hydrogencarbonate solution, stirred at room temperature for 2 hours, and then extracted with ethyl acetate. The extract was washed with saturated saline water, dried with anhydrous magnesium sulfate, the solvent was evaporated off, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (29.5 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27]([OH:29])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CCCCCCC.CCOC(C)=O>[C:16]([O:20][C:21](=[O:22])[NH:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:26]([C:27](=[O:29])[N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:25]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-tert-butoxycarbonylamino-5-trifluoromethyl-benzoic acid and using a gradient of n-heptane:EtOAc (100:0 to 0:60) for the chromatographic purification. Light brown solid (4%). MS (ESI): m/z=486.20 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:27]([F:33])([F:32])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.4 mg, 49.4%), MS (ISP) m/z=441.0 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([C:18](=[O:33])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:7]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[N:34]([C@@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@@H:8]([C:18](=[O:33])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:7]1)=[N+:35]=[N-:36]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
9.2 A mixture of 5.4 g (11.7 mmol) of tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate and 3.69 g (56.8 mmol) of sodium azide in 50 ml of dimethylformamide (DMF) is stirred at 60° C. for 12 hours. The insoluble matter is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure. The residue is then dissolved in 20 ml of water, and the aqueous solution is extracted twice with 10 ml of methylene chloride each time. The combined methylene chloride extracts are finally washed once with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Removal of the drying agent by filtration and stripping-off of the solvent gives 4.8 g (100%) of tert-butyl (2R,4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 431.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[Si:14]([O:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=c1[nH]cccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Reaction time: 8 h
Yield: 53.6 %

Procedure:
3-Hydroxypyridin-2(1H)-one (15 g, 135 mmol) and imidazole (23 g, 338 mmol) were suspended in dimethylformamide (200 mL) under inert atmosphere. A solution of tert-butyldimethylsilyl chloride (20.5 g, 136 mmol) in dimethylformamide (200 mL) is added dropwise at room temperature over 30 minutes. The reaction was then allowed to stir overnight. The resulting solution was then poured into water (300 mL) and the mixture extracted with tert-butyl methyl ether (3×500 mL). The combined organic layer was washed with water (300 mL), brine (300 mL) then dried over Na2SO4. The solvent is removed under reduced pressure and the crude product crystallized from heptanes to afford 16.3 g (53% yield) of the desired product. 1H NMR (250 MHz, CDCl3) δ ppm 12.98 (1H, m); 6.91 (1H, dd, J=1. Hz, J=6.8 Hz); 6.81 (1H, dd, J=1.8 Hz, J=7.2 Hz); 6.02-6.007 (1H, m); 0.90 (9H, s), and 0.17 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:16][C:14]([F:15])([F:17])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: CC1(O)CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCC(C)(O)CC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Yield: 14 %

Procedure:
The title compound was prepared from 1-[6-bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 4-methyl-piperidin-4-ol according to the procedure of example 25. Yield: 14%; MS: m/z=507 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([I:12])[CH:8]=1
Reactant: ClI
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Yield: 14.2 %

Procedure:
A solution of 4-chloro-2-nitroaniline (34.5 g) in acetic acid (500 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulphite and after column chromatography yielded 4-chloro-2-iodo-6-nitroaniline (8.5 g). δ (360 MHz, DMSO-d6) 7.13 (2H, bs, NH2), 8.08 (1H, d, 3-H) and 8.13 (1H, d, 5-H).
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].N[NH:10][C:11]([NH2:13])=[S:12].O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH2:2]([C:1]1[S:12][C:11]([NH2:13])=[N:10][N:8]=1)[CH2:3][CH2:4][CH2:5][C:6]1[S:12][C:11]([NH2:13])=[N:10][N:7]=1
Reactant: NNC(N)=S
Reactant: N#CCCCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCCCc2nnc(N)s2)s1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A mixture of adiponitrile (8.00 g, 73.98 mmol) and thiosemicarbazide (13.48 g, 147.96 mmol) in trifluoroacetic acid (TFA) (75 mL) was heated at 80° C. for 17 hours. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(butane-1,4-diyl)-bis(1,3,4-thiadiazol-2-amine) (1001, 13.07 g). 1H NMR (300 MHz, DMSO-d6) δ 7.00 (s, 4H), 2.84 (bs, 4H), 1.68 (bs, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]1=2.Cl.C([OH:32])(C)C>>[NH2:9][C:8]1[C:7]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:27])[CH3:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:32])=[N:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reactant: CC(C)O
Agent: Cl
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N

Procedure:
A solution of N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in isopropyl alcohol is treated with 25% hydrochloric acid at 0° C. to give a solution of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH:3]=[C:2]([O:1][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (10 g, 48.7 mmol) was dissolved in dry DMF (12.0 mL). Trimethylsilyl chloride (6.35 g, 7.39 mL, 58.4 mmol) and triethylamine (11.8 g, 16.2 mL, 117 mmol) were added under argon and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (1 drop Et3N was added during conditioning of the column) (silica gel, 100 g, 0% to 100% pentane in Et2O, 45 minutes). The title compound was obtained as a colorless liquid (13.2 g, 99%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.[I:13]C1C=CC(CC#N)=CC=1>>[OH:1][NH:2][C:3](=[NH:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:13])=[CH:7][CH:6]=1
Reactant: N#CCc1ccc(I)cc1
Reactant: N=C(Cc1cccc(I)c1)NO
Product: N=C(Cc1ccc(I)cc1)NO

Procedure:
The title compound is prepared essentially as described for N-hydroxy-2-(3-iodo-phenyl)-acetamidine, employing (4-iodo-phenyl)-acetonitrile. LC-MS (m/e): 277 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1([Cl:15])[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:5][C:6]1([Cl:15])[CH2:8][CH:7]1[C:9]1[CH:10]=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: ClC1(Cl)CC1c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2(Cl)Cl)cc1
Temperature: 4 °C

Procedure:
Nitric acid (25 g.) was added during three hours to a mixture of (2,2-dichlorocyclopropyl)benzene (45 g.), water (13 g.), acetic acid (40 g.) and concentrated sulfuric acid (177 g.) with cooling (to 3-5° C.). The resulting mixture was quenched in a mixture of ice (400 g.) and chloroform (200 g.). The layers were separated and the aqueous layer was washed with chloroform (100 g.). The chloroform layers were combined and washed with aqueous sodium carbonate (5%, 300 ml.). The sodium carbonate layer was backwashed with chloroform (75 g.). The combined chloroform extracts were dried, fitered and concentrated, affording p-(2,2-dichlorocyclopropyl)nitrobenzene mixed with the ortho isomer (57 g.).