Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8].ClC1C=CC=CC=1C(C)CN([CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[CH2:6][N:5]([CH2:46][CH2:47][CH2:48][O:49][C:50]2[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=2)[CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:23])([F:21])[F:22])[C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(Cl)cc2)C1
Yield: 33 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propylamine in 33% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 568 (MH+).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]([CH2:30][CH:31]=[CH2:32])[CH2:12][O:13][SiH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22]C(C)(O)CC(C)C)=[CH:17][CH:16]=1)[CH:9]=[CH2:10].[OH-].[Na+]>C(Cl)Cl>[CH2:30]([CH:11]([CH2:8][CH:9]=[CH2:10])[CH2:12][O:13][SiH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH:31]=[CH2:32]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(C#CC(C)(O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#Cc1ccc([SiH2]OCC(CC=C)CC=C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Firstly, dist. toluene (5 mL) was added to and dissolved in 1-(diallylethoxysilyl)-4-(3,5-dimethyl-3-hydroxy-hexynyl)benzene (125 mg, 0.35 mmol) obtained in Synthesis example 10. The resultant mixture was added with NaOH (9.9 mg, 0.25 mmol), and then was stirred under a nitrogen atmosphere at 80° C. for 16 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with CH2Cl2, and an organic layer was washed with dist. H2O and sat. NaCl. The organic layer thus collected was dried with MgSO4, and the dried organic layer was filtered and concentrated to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 1-(diallylethoxysilyl)-4-ethynylbenzene (5 mg, 6% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[S:6]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH3:1][N:2]([CH2:11][C:8]1[CH:9]=[CH:10][S:6][CH:7]=1)[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: O=Cc1ccsc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCO)Cc1ccsc1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
2-(Methylamino)-ethanol (0.047 mol, 3.5 g) and 3-thiophenecarboxaldehyde (0.047 mol, 5.3 g) were dissolved in 50 mL of MeOH and 10 mL of AcOH. NaCNBH3 (0.023 mol, 1.5 g) was added portionwise, and the resulting mixture was stirred for 18 h. The solvent was removed in vacuo, and the residue was taken up in 1N KOH and extracted with EtOAc. The organics were dried and concentrated to give an oil which was filtered through a six inch silica gel plug using 1:1 hexanes:ethyl acetate to give 7.6 g of product. 1H NMR (300 MHz) CDCl3: 7.3 (m, 1H), 7.12 (s, 1H), 7.05 (d, 1H), 3.6 (m, 4H), 2.57 (t, 2H), 2.25 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:27]=[CH:26][C:9]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[C:4]([CH2:6][O:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH3:35])[CH:27]=[CH:26][C:9]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1)([OH:5])=[O:3]
Reactant: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
To a solution of 4.30 g of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone in 43 ml of ethanol was added a solution of 6.2 g of potassium carbonate in 11 ml of water, and the mixture was stirred at 50° C. for 5 hours. After completion of the reaction, the mixture was neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethyl acetate-n-hexane to give 3.13 g of 2'-carboxymethoxy-4-n-hexyl-4'-(3-methyl-2-butenyloxy)chalcone.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.[CH2:17]=[O:18]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:17][OH:18]
Reactant: C=O
Reactant: C#CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCC#CCCOC1CCCCO1
Temperature: -23 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 8.0 mL (51 mmol) of 2-(3-butynyloxy)tetrahydro-2H-pyran in 150 mL of THF under nitrogen atmosphere at −23° C. was added dropwise a solution of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the temperature at −23° C. The resulting solution was stirred at 0° C. for 2 h, recooled to −23° C. and 2.4 g (76.5 mmol) of paraformaldehyde was added in several portions. The mixture was stirred at −23° C. for 1 h and let warm to room temperature and stirred for 18 h. The reaction mixture was poured into a large excess of ice water and extracted with ether. The organics were washed with brine until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was kugelrohr distilled to provide 7.26 g (77%) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless liquid. El Mass Spec: 185.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@H:6]([NH:20][C:21]([NH2:23])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCO>[CH2:31]([O:30][C:28]([C:27]1[N:23]=[C:21]([NH:20][C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[O:22][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(N)=O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)Nc1nc(C(=O)OCC)co1
Temperature: 25 °C

Procedure:
To a suspension of (R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is warmed up slowly to room temperature and stirred at reflux overnight. The reaction is concentrated and the residue is taken up in EtOAc and H2O. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-((R)-1-biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carboxylic acid ethyl ester. HPLC retention time=1.42 minutes (condition B); MS (m+1)=423.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>ClCCl>[C:18]([O:21][CH2:22][C:23]([N:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:1]([CH3:3])[CH3:2])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(C(C)C)C1CCCCC1
Yield: 99.5 %

Procedure:
To a solution of 5.0 g of N-isopropylcyclohexylamine and 4.3 g of triethylamine in 100 ml of dry dichloromethane was added dropwise 5.8 g of acetoxyacetyl chloride with stirring under ice-cooling, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was successively washed with an aqueous sodium bicarbonate solution and water, dried under reduced pressure to obtain 8.5 g of 2-acetoxy-N-cyclohexyl-N-isopropylacetamide in an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[NH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[OH:24])[CH2:17]1.[BH4-].[Na+]>CO.ClCCl>[OH:24][CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([CH2:15][NH:14][CH2:12][C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)[CH2:17]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1ccc2nccc(C(O)CN3CCC[C@@H](CN)C3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc(C(O)CN3CCC[C@@H](CNCc4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Molecular sieve, type 3A, (1.082 g) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.095 g, 0.54 mmol) were added to a solution of (3S)-2-(3-aminomethyl-piperidin-1-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.171 g, 0.54 mmol) in MeOH (1.6 ml) and dichloromethane (3.8 ml). The reaction mixture was stirred at room temperature for 16 hours and sodium borohydride (0.054 g, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15](C)=[CH:14][C:13]=1[Cl:20].[H-].[CH2:24]([Al+]CC(C)C)C(C)C.CO>C1COCC1>[Cl:18][C:17]1[C:16]([CH3:24])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:21]
Reactant: CON(C)C(=O)c1ccccc1Nc1c(Cl)cc(C)cc1Cl
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a magnetically stirred 0° C. solution in dry THF (25 mL) of N-methoxy-N-methyl-2-[(2,6-dichloro-4-methylphenyl)amino]benzamide (3.8 g, 11.2 mmol), prepared as in step 1, was added dropwise diisobutylaluminum hydride (1.0M in THF, 24.6 mL) and the reaction mixture was stirred at ambient temperature for 16 hours. Methanol (5 mL) was added dropwise and the mixture was stirred for 15 minutes until a white precipitate had formed. The reaction mixture was concentrated, the residue was taken up in methanol (10 mL), the insoluble white solid was filtered, and the filtrate was evaporated in vacuo and then purified by chromatography on silica gel (5:1 hexane/CH2Cl2) to provide 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (1.98 g; 63%) and over reduced alcohol side product (0.70 g; 22%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:21][C@@H:22]1[C@H:27]([NH:28][C:29]([C:31]2[NH:32][C:33]([CH2:37][CH3:38])=[C:34]([Cl:36])[N:35]=2)=[O:30])[CH2:26][CH2:25][N:24]([C:39]2[S:40][C:41]3[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH2:23]1.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Cl:36][C:34]1[N:35]=[C:31]([C:29]([NH:28][C@@H:27]2[CH2:26][CH2:25][N:24]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:23][C@@H:22]2[NH:21][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:30])[NH:32][C:33]=1[CH2:37][CH3:38]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](N)C3)sc12
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(CC)CC)C3)sc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.5 %

Procedure:
3-Pentanone (68.9 μL, 0.65 mmol) and sodium triacetoxyborohydride (165 mg, 0.78 mmol) were added four times every two hours to a mixed solution of ethyl 2-[(3S,4R)-3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl]-1,3-benzothiazole-7-carboxylate obtained in Example (202e) (62.0 mg, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluate: hexane:ethyl acetate=1:1 v/v) to obtain 48 mg of the title compound (68%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Yield: 85.2 %

Procedure:
A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (712 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in isopropyl alcohol (7.1 mL) was stirred at 80° C. for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (1.12 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:11][CH2:12][CH2:13][OH:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[O:9]
Reactant: NCCO
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(NCCO)c1cncc(Br)c1
Reaction time: 72 h

Procedure:
5-Bromonicotinic acid (0.020 g, 0.10 mmol), 2-aminoethanol (9.16 mg, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol), and dioxane (2 mL) were added to a 20 mL vial. The vial was sealed and placed on a heater/shaker for 3 days at 40° C. The reaction mixture, containing the title compound, was used without purification.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([Cl:17])=[O:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncn(-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.00 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid in 20 mL DCM was added 10.0 mL (137 mmol) thionyl chloride and 1 drop of DMF. The reaction mixture was stirred at 40° C. for 1 h. The solvent was removed by distillation. Yield: 2.20 g (100%); ESI-MS: m/z=204 (M+H)+ (methyl ester); Rt(HPLC): 1.04 min (method 8) (methyl ester)
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15](O)=[O:16])=O)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]3[CH2:13][CH2:14][C:15](=[O:16])[NH:21][N:22]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)C2CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)C3CC3)cc2)=NN1
Yield: 68.1 %

Procedure:
2.0 g (7.7 millimoles) of 3-(p-cyclopropylcarbonylaminobenzoyl)-propionic acid, 0.45 g (9.0 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 6 hours. The product is filtered off at 10° C. and recrystallized from dimethylformamide/water, giving 1.35 g (68% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-3(2H)-pyridazinone, as colorless crystals, identical with the compound from Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([S:32][CH3:31])[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide (475 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with solid sodium thiomethoxide (355 mg, 5 mmol) and the mixture heated at 70° C. for 16 h. The solvent was concentrated to about 2 mL and added to 5 mL cold 1M HCl. The light yellow solid precipitate was collected by filtration and product was purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H), 7.28 (d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd,1H, J=8.8 Hz, 2.4 Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H, J=5.2 Hz), 10.13 (s, 1H). MS: m/z476.1 (M++1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[N:12]=[CH:11][N:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2ccnc2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.65g, 55% dispersion in oil, pre-washed with petrol) in dry DMF (5ml) at 10-15° C under nitrogen, was added a solution of imidazole (1.02g, 15 mmol) over five minutes. The reaction mixture effervesced and an exotherm took place. After stirring for 11/2hours at room temperature, the cloudy solution was added drop-wise over one hour to a solution of 4,6-dichloropyrimidine in dry DMF (10ml) at 0° C. for one hour, added to water and then extracted with ether (×3). The combined ether extracts were washed with dilute sodium hydroxide solution and water (×3) and then dried. Concentration under reduced pressure gave 4-chloro-6-(imidazol-1-yl)pyrimidine as a pale yellow solid (1.00g); m.p. 122-4° C., which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](Cl)=[O:17].O>C(#N)C>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](=[O:17])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: COCCOC(=O)Cl
Solvent: CC#N
Solvent: O
Product: COCCOC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 130 °C
Yield: 82.1 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (2.00 g) and chloroformic acid 2-methoxyethyl ester (1.52 g) were dissolved in acetonitrile (25 mL) and heated to 130° C. for 15 minutes in a sealed microwave process vial. Water (25 mL) was added to the reaction mixture, and the product was collected by filtration and washed with water (25 mL) and heptane (25 mL) to furnish 2.48 g (82% yield) of the title compound as a white solid. LC-MS (m/z) 304 (MH+); tR=2.93, (UV, ELSD) 96%, 97%. 1H NMR (500 MHz, CDCl3): 2.36 (m, 6H), 3.40 (m, 3H), 3.60 (m, 2H), 4.35 (m, 2H), 6.55 (broad s, 1H), 7.45 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:41]3[CH2:42][CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:40]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: c1ccc2c(c1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCc3ccccc3C2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (97 mg), 1,2,3,4-tetrahydroisoquinoline (67 μl), HOBt (19 mg) and triethylamine (104 μl) were dissolved in 1,2-dichloroethane (5 ml), WSC.HCl (107 mg) was added, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (102 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([C:21]([CH3:29])([C:23]2[NH:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[CH3:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH:39]=O)=[CH:32][CH:31]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:39][CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:15][C:14]([C:21]([CH3:29])([C:23]2[NH:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[CH3:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=CCCCc1ccncc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCN)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCNCCCCc2ccncc2)c1

Procedure:
Prepared essentially as described in EXAMPLE 3.2D starting from 2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl}ethylamine (97 mg) and using 4-pyridin-4-yl butyraldehyde to give the title compound (73 mg). m/e=520 (M+1)