Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][C@H:13]([CH3:18])[C:14]([O:16]C)=[O:15])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][C@H:13]([CH3:18])[C:14]([OH:16])=[O:15])[S:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)O
Yield: 33.7 %

Procedure:
The reaction was effected as described in Example 48, but using 1.74 g of methyl 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 70), 30 ml of methanol, 22 ml of tetrahydrofuran and 17.0 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0.56 g of the title compound as yellow crystals, melting at 131 to 134° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[O:8][N:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:25]=[S:26])=[CH:13][CH:12]=2)[O:8][N:7]=1
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 3-(2-furyl)-5-(4-aminophenyl)-1,2,4-oxadiazole (5.1 g, 0.02 mole) in 150 ml of dry tetrahydrofuran containing 3.1 ml of triethylamine, thiophosgene 2.53 g (0.02 mole) is added and the mixture is stirred at room temperature for 4 hours. After filtration, the solvent is evaporated in vacuo and the product is crystallized from petroleum ether to give 4.0 g (68%) of the title compound, m.p. 136°-137°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Yield: 43 %

Procedure:
6 ml (11.7 mmol) of a 2M solution of 4-fluorophenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by addition of a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 333 mg in the form of a white powder are obtained with a yield of 43%.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:40])([F:39])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH:50]1([C:53](Cl)=[O:54])[CH2:52][CH2:51]1>C1COCC1>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH:35][C:53]([CH:50]5[CH2:52][CH2:51]5)=[O:54])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:39])([F:40])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(N)ccc4OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CC5)ccc4OC(F)(F)F)cc3)cc2)CC1
Yield: 32.2 %

Procedure:
A stirred solution of 5′-amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenyl}-amide (50 mg) in dry THF (1 ml) was treated with N,N-diisopropylethylamine (60 μl) followed by cyclopropane carbonyl chloride (18 mg). After 16 h the mixture was evaporated and the residue purified by chromatography. Gradient elution with 0%-30% 20DCM:8EtOH:1NH3 in DCM over 35 mins gave the title compound as an off-white solid (18 mg).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:11][C:10]([NH:26][CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCC2CCCCC2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc([C@H]2NC(NCC3CCCCC3)=N[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 79 (0.23 g, 0.53 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue triturated with Et2O. The insoluble material is filtered to give 89 mg of the product 80. 1H NMR (DMSO-d6) δ 9.08 (m, 1 H), 8.54 (s, 1 H), 7.45 (m, 1 H), 7.15-6.90 (m, 6 H), 6.90-6.70 (m, 4 H), 5.18 (s, 2 H), 3.35-3.10 (m, 2 H), 1.90-1.65 (m, 5 H), 1.40-0.90 (m, 6 H); MS: m/z 334 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:14]#[N:15].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:13][C:4]1[C:3]([CH2:2][C:14]#[N:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1cccc(CC#N)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)-2-chlorobenzoate (748 mg, 2.84 mmol) in N,N-dimethylformamide (7 mL) was added sodium cyanide (412 mg, 8.41 mmol), and the mixture was stirred under a nitrogen stream at 80° C. for 1 hr. The reaction mixture was diluted with a mixed solvent of ethyl acetate and hexane (1:1). The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→80/20) and crystallized from ethyl acetate/hexane to give the title compound (470 mg, 79%) as white crystals.
Reaction SMILES: C(OC(=O)N[CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:12]2[C:13](=[O:14])[C:9](=[CH2:8])[N:10]([CH3:26])[C:11]2=[O:25])[CH:20]=[CH:19][C:18]=1[C:21]#[N:22]
Reactant: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C1C(=O)N(c2ccc(C#N)c(Cl)c2C)C(=O)N1C
Yield: 33.8 %

Procedure:
A solution of the N-Boc-protected amine 13B (300 mg, 0.763 mmol) in CH2Cl2 (3 mL) and TFA (3 mL) was stirred at rt for 1 h. The solution was then concentrated under reduced pressure and the residue azeotroped with a 1:1 solution of CH2Cl2/toluene (3×10 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 80:20 gradient) to afford the title compound (71 mg) as a white solid. 1H NMR (DMSO-d6) δ 2.21 (s, 3H), 3.12 (s, 3H), 5.16 (d, J=2.2 Hz, 1H), 5.39 (d, J=2.2 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H); 13C NMR (DMSO-d6) δ 15.70, 26.73, 95.59, 113.18, 115.83, 128.79, 132.09, 136.03, 136.37, 136.54, 136.68, 151.88, 160.56; HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.70 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.59 min retention time (98%).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:8]=2[CH2:7][CH2:6][C:5]1=[O:20])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:19][C:15]1[C:9]2[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][NH:4][C:5](=[O:20])[CH2:6][CH2:7][C:8]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCCC(=O)c2c(Cl)cccc2CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cccc(Cl)c2C(=O)CCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.60 g of 4-acetyl-9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione were dissolved in 240 ml of methanol and treated with a mixture of 36 ml of methanol and 4 ml of saturated potassium carbonate solution. The mixture was stirred at room temperature for 1 hour and thereafter the solvent was removed in vacuo. The residue was triturated in ethyl acetate. The crystallized-out 9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione was filtered off and exhibited a melting point of 211°-214°. The filtrate was chromatographed on 100 g of silica gel (particle size 0.2-0.5 mm). A further portion of 9-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione can be isolated from the ethyl acetate eluate.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36]([C:30]5([O:29][CH3:28])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COC1(C(=O)O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CCCCC1

Procedure:
The title compound, white solid (17.4 mg, 40.8%), MS (ISP) m/z=472.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 1-Methoxycyclohexane-1-carboxylic acid.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[SH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Reactant: Oc1ccc(S)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(OC)cc1
Yield: 82 %

Procedure:
Ethyl bromo(4-methoxyphenyl)acetate (16.5 g, 60.4 mmol) was added to a stirring solution of triethyl amine (10 ml), and 4-mercaptophenol (7.63 g, 60.4 mmol) in Chloroform (200 ml). The mixture was heated at reflux overnight before it was concentrated and the residue was extracted in ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The compound was isolated using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl[(4-hydroxyphenyl)sulfanyl](4-methoxyphenyl)acetate was isolated as a yellow oil (15.82 g). Yield 82%; MS: 317.2 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@@]1(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1CC[C@@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 94.1 %

Procedure:
A solution of (R)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (1.96 g, 8.18 mmol) in Pyridine (20 mL) was cooled to 0° C., then treated with the dropwise addition of ethyl chloroformate (0.942 mL, 9.81 mmol), causing a color change to orange. The mixture was allowed to come to room temperature and stirred over night. The reaction was concentrated in-vacuo, and the residue was taken up in ethyl acetate, washed 3× with 1M NaOH, 3× with 1M HCl, once with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (2.4 g, 7.70 mmol, 94% yield). The residue was used as-is in the next step. MS (ESI+)=334, (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2ccccc2)n1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(N(c2ccccc2)c2ccccn2)n1
Yield: 80.5 %

Procedure:
To a flask were added 18.4 g of 6-methyl-N-phenylpyridin-2-amine, 15.8 g of 2-bromopyridine, 11.5 g of sodium tert-butoxide, and 250 ml toluene. The mixture was purged thoroughly with nitrogen and 270 mg of 1,1′-bis(diphenylphosphino)ferrocene and 110 mg of palladium acetate were added. The reaction mixture was heated to 90 C for 6 hours, and then cooled to 22 C. After quenching with 100 ml water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 50 ml of 1M hydrochloric acid, and then basified with sodium hydroxide. The mixture was cooled to 5 C, and the crude product was filtered and washed with water. The product was dissolved in 100 ml hot 2-propanol and treated with 0.4 g activated carbon. After hot filtration through a bed of celite, 150 ml of water was added slowly and the mixture was seeded to induce crystallization. After cooling to 5 C, the product was filtered and washed with 50 ml of 33% 2-propanol in water. The product was dried resulting in 21 g of a light tan solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(N[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:23][C:22]([F:25])([F:24])[S:19]([O:11][C:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH:9]=1)(=[O:21])=[O:20]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
A −78° C. solution of 4-tert-butylcyclohexanone (1.54 g, 10 mmol) and N-phenyl(trifluoromethanesulfonamide) (3.75 g, 10.5 mmol) in THF (20 mmol) was treated with 1M NaHMDS in THF (11 mL), warmed to room temperature, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1Br.[CH2:50]([O:52][C:53]([Sn](CCCC)(CCCC)CCCC)=[CH2:54])[CH3:51]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1[C:50]([O:52][CH2:53][CH3:54])=[CH2:51]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(-c2ccc(C(=O)OC)cc2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
Compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (40 mg, 0.053 mmol) under Argon, was mixed with Pd(PPh3)4 (12 mg, 0.01 mmol, (1-ethoxyvinyl)tributylstannane (85 uL, 0.25 mmol) and dioxane (3 mL). The resulting mixture was heated at 100° C. and stirred over night. After cooled to room temperature, the mixture was filtered through 10% KF on silica gel and washed with EtOAc. After concentration, the crude product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate was used in the next step directly without further purification. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C41H53N5O5Si2 751.4, observed LCMS m/z 752.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cc2ccccc2F)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(Cc2ccccc2F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
5-(2-Fluoro-benzyl)-thiophene-2-carbaldehyde described in Preparation Example 123 (2.81 g, 12.7 mmol) was dissolved in ethanol (40 mL), sodium borohydride (964 mg, 25.4 mmol) was added at 0° C., and the solution was stirred at room temperature for 1 hour. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (2.10 g, 9.45 mmol, 74%) was obtained as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:34])[C:16]2[CH:21]=[N:20][C:19](S(C)(=O)=O)=[N:18][C:17]=2[N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:34])[C:16]2[CH:21]=[N:20][C:19]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:18][C:17]=2[N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCN1CCCC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-pyrrolidin-1-yl-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (25 mg, 0.07 mmol). 8-Cyclohexyl-5-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (18 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H31N5O3: 414.24 (M+H). Found: 414.3.
Reaction SMILES: BrC1C([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=CC(C)=CN=1.C([Mg]Cl)(C)C.ClC1C=CC=CC=1C=O>C1COCC1>[CH3:25][O:24][CH2:23][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=1)(=[O:11])=[O:10]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: O=Cc1ccccc1Cl
Solvent: C1CCOC1
Product: COCNS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (500 mg, 1.06 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added drop wise isopropylmagnesium chloride (2 M solution in THF, 1.27 mL, 2.54 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-chlorobenzaldehyde (271 pL, 2.01 mmol) at −30° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-chlorophenyl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (274 mg) as yellow foam in 48% yield. ESMS m/z (relative intensity): 535 (M+H)+ (100).
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7]#[N:8]>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7](=[N:1][OH:2])[NH2:8]
Reactant: NO
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Hydroxylamine (10 mL of a 50% solution in water) was added in one portion to a stirred suspension of 3,5-dibromo-4-hydroxybenzonitrile (30 g, 110 mmol) in ethanol (100 mL) at room temperature and the mixture was heated to reflux for 3 hours before cooling back down to room temperature. The solid was filtered, washed with cold ethanol and dried to yield the title compound (25.5 g, 75%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 5.92 (2 H, br s), 7.87 (2 H, s), 9.69 (1 H, br s), 10.19 (1 H, br s).
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][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[Cl:36][C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:38])=[O:26])=[O:37])[CH:35]=[CH:34][CH:33]=1
Reactant: CS(=O)(=NC(=O)Nc1cccc(Cl)c1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3cccc(Cl)c3)cc2)ncc1-c1cccs1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (115.5 mg, 0.43 mmol) with (RS)—S-(4-aminophenyl)-N-(3-chloro-phenylcarbamoyl)-S-methylsulphoximide (126 mg, 0.39 mmol) according to procedure 5c, the desired product is obtained in 26% yield (56 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).