Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31](=[O:48])(=[O:47])[N:32](CC4C=CC(OC)=CC=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)[CH:7]=1.N(OC(C)(C)C)=O.[N:56]([Si](C)(C)C)=[N+:57]=[N-].[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64]>C(#N)C>[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31]([NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:48])=[O:47])[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1)=[N+:56]=[N-:57]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)c(C2=CCNCC2)c1
Reaction time: 0.33 h
Yield: 25.7 %

Procedure:
To a solution of tert-butyl 4-(5-amino-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.105 g, 0.152 mmol) in dry acetonitrile (1.522 mL) at 0° C. was added tert-butyl nitrite (0.026 mL, 0.213 mmol) followed by dropwise addition of azidotrimethylsilane (0.024 mL, 0.183 mmol). The resulting mixture was stirred for 20 minutes, at which time no conversion to the desired was observed. Additional tert-butyl nitrite (0.052 mL) and azidotrimethylsilane (0.048 mL) were added at 0° C. and the reaction was once again stirred at RT for 1 h. Conversion was observed, but starting material was still the major reaction component, so the reaction was recooled to 0° C. and 0.156 mL of t-Bu nitrite was added, followed by dropwise addition of 0.144 mL of TMS-azide. After 20 minutes at RT, the reaction was complete and was concentrated under a vacuum. DCM (1.0 mL) was added, followed by TFA (0.235 mL, 3.04 mmol), and the reaction was stirred at RT for 1 h. The material was concentrated under a vacuum and purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min to provide 4-(4-azido-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide bis(2,2,2-trifluoroacetate) (0.028 g, 0.039 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30-2.44 (m, 2 H) 3.19 (m, J=5.20 Hz, 2 H) 3.47-3.56 (m, 2 H) 3.62-3.70 (m, 2 H) 4.29 (t, J=4.25 Hz, 2 H) 5.76-5.83 (m, 1 H) 6.29 (d, J=8.31 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.02 (d, J=2.74 Hz, 1 H) 7.08-7.15 (m, 2 H) 7.17 (dd, J=8.56, 2.69 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.38 (d, J=8.51 Hz, 1 H) 8.76 (br. s., 2 H) 12.53 (br. s., 1H); m/z (ESI) 496.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])[CH3:3].[N-:16]=[N+]=[N-].[Na+].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([O:4][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:15])[NH:16][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH3:3]
Reactant: CC(C)Oc1cccc2c1CCCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc2c1CCCC(=O)N2
Yield: 60.9 %

Procedure:
A mixture of 4.39 g of 5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one and 1.74 g of sodium azide in 70 ml of TFA is refluxed for 2 hours. The reaction medium is poured into 250 ml of water, brought to pH 7 by adding potassium carbonate and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and MeOH (100/0 to 90/10). 2.87 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:43]([CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:44])=[O:27])=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide (0.7 g, 1.69 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.35 mL, 2.5 mmol) was catalytic DMAP (20 mg) and cyclobutane carbonyl chloride (0.19 mL, 1.69 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The solution was washed with brine (5 mL), dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (6:4) afforded 0.63 g (75% yield) of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide. 1HNMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.67 (d, 2H), 7.41-7.08 (comp, 8H), 6.82-6.61 (comp, 3H), 3.79 (s, 3H), 2.41 (s, 2H), 3.09-3.02 (m, 1H), 2.41-2.23 (comp, 8H), 2.19-1.67 (comp, 6H); MS (M+1) 498.2.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CC(N(C)C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1cc(Cl)cnc1Cl
Yield: 87.7 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of dimethylacetamide is added dropwise at a temperature in the range from 0° to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at 55° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 21/2 hours at 55° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The crude product is purified by distillation, affording 36.4 g (87.8% of theory) of 2,5-dichloro-3 -fluoropyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1cnccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of pyrazine-2-carboxylic acid (1.26 g, 10 mmol) and 1,1′-carbonyldiimidazole (2.14 g, 13 mmol) in N,N-dimethylformamide (8 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3 g, mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.82 g, 45%) as a light yellow solid: LC/MS m/e calcd for C23H22N4O3 (M+H)+: 403.46, observed: 403.5.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1.CC([O-])(C)C.[K+]>CC#N.C1COCC1>[N:9]1[C:8]2[CH:7]=[C:6]3[N:14]([C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5]3
Reactant: Nc1cccnc1C#CCCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: c1cnc2cc3n(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 2-(6-chlorohex-1-ynyl)pyridin-3-amine (300 mg) in CH3CN (3 ml) was added a solution of KOtBu (387 mg) in THF (3.5 mL) at 0.0° C. The mixture was stirred at 0° C. for 30 min. The mixture was quenched with water at 0° C. and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (170 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].O.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O1CCCC1>[C:14]1([S:20]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([I:1])[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(I)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
5-Iodo-1H-pyrrolo[2,3-b]pyridine (24, 0.521 g, 2.13 mmol), tetra-N-butylammonium bromide (0.0689 g, 0.214 mmol), and 5.00 M sodium hydroxide in water (5.50 mL, 0.0275 mol) were combined in a round bottom flask. Benzenesulfonyl chloride (28, 0.327 mL, 2.56 mmol) in 5.0 mL of tetrahydrofuran was added dropwise at room temperature. The reaction was stirred at room temperature overnight and the two layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with 1M aqueous sodium bicarbonate followed by water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, then filtered and the filtrate concentrated. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (29, 0.702 g).
Reaction SMILES: C[C:2]([CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO.O1CCOCC1.O>[C:33]1([CH2:32][CH:2]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:4])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(Cc1cccc2ccccc12)(Cc1cccc2ccccc12)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: C[C@](Cc1c[nH]c2ccccc12)(NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
A solution of 4.24 g (7.6 mmol) of methyl bis-(1-naphthylmethyl)acetyl-(α-methyl-D-tryptophan) in 50 mL MeOH and 50 mL dioxane was treated with a solution of 1.0 g (25 mmol) of NaOH in 10 mL H2O and the solution left stirring at room temperature for 4 days. The solvent was removed under reduced pressure and the residue mixed with H2O and acidified to Congo red end point with dilute HCl. The crude product was collected and chromatographed on silica gel, eluting with CHCl3 : MeOH (95:5). There was obtained 2.37 g (57.8% yield) of the product as a solid foam. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCCCCC.C(O)C.C(O)C.O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
Ethyl 3-[{[4-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (18.23 g) obtained in Example A75(4) was dissolved in hexane-ethanol (1:1, volume ratio), subjected to HPLC using CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), and eluted with hexane-ethanol (1:1-1:4, volume ratio) as a mobile phase at room temperature and at a flow rate 60-50 mL/min. The resulting fraction containing an optically active form having a shorter retention time was concentrated to give an amorphous form (9.08 g, 99.9% ee). The obtained amorphous form (4.72 g) was dissolved in ethanol (19 mL) and tetrahydrofuran (19 mL), 1N aqueous sodium hydroxide solution (18.6 mL) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (40 mL) was added, and the mixture was neutralized with 1N hydrochloric acid (18.6 mL) under ice-cooling and stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (4.27 g, 96%, 99.9% ee) as a colorless amorphous form.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.[C:16]([C:20]1[CH:21]=[C:22]([NH2:25])[NH:23][N:24]=1)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O.C1(C)C=CC=CC=1>[C:16]([C:20]1[CH:21]=[C:22]([NH2:25])[N:23]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[CH:6]=2)[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cnn(CCOC3CCCCO3)c2)n1
Temperature: 150 °C
Yield: 81 %

Procedure:
To a mixture of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (for reference procedure see for example WO 2010/139731, which is incorporated herein by reference; 1.54 g, 4.81 mmol), 5-tert-butyl-2H-pyrazol-3-ylamine (668 mg, 4.81 mmol), copper (I) iodide (45 mg, 0.24 mmol) and K2CO3 (1.39 g, 10.1 mmol) was added a solution of toluene (5 mL), previously degassed by using a stream of argon. (R,R)-(−)-N,N′-Dimethyl-1,2-cyclohexanediamine (151 μL, 0.96 mmol) was then added and the reaction mixture was heated at 150° C. for 2.5 h under microwave irradiation. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to give the title compound (1.29 g, 81%). LCMS (Method 1): Rt 2.31 min, m/z 334 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH2:27])=[O:26])=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C@@:10]1([CH2:15][CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH2:27])=[O:26])=[N:23][CH:24]=3)[N:7]=2)[C:9]1=[O:17])#[N:14]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: NC(=O)c1ccc(N)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(N)=O)nc3)n2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 8, 5-aminopyridine-2-carboxamide (130 mg) obtained in Step A of Example 350, cesium carbonate (520 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (75 mg) in tetrahydrofuran (5.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (73 mg), and the mixture was stirred overnight at 80° C. under argon atmosphere. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethanol) to give the title compound (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16](O)=[O:17])[C:14]2([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16]([Cl:23])=[O:17])[C:14]2([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C(=O)O)C1c1ccc(OC(F)(F)F)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C(=O)Cl)C1c1ccc(OC(F)(F)F)c(Br)c1
Yield: 93.7 %

Procedure:
9.6 g (0.027 mol) of 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylic acid were dissolved in 100 ml of carbon tetrachloride, and 10 g of thionyl chloride were slowly added dropwise at 60° C., while stirring. The mixture was then heated under reflux for 4 hours. After the reaction period had ended, excess thionyl chloride, as well as carbon tetrachloride, were distilled off in the vacuum from a water jet. 9.4 g (93.7% of theory) of 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylic acid-chloride were obtained as a yellow liquid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7](=[C:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17](OC)=[O:18])[CH2:12][CH2:11]1)[CH2:8][CH3:9].O.Cl>C1COCC1>[CH:7](=[C:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCC=C1CCC(CC(=O)OC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCC=C1CCC(CCO)CC1

Procedure:
25.2 g of lithium aluminium hydride were introduced into 100 ml of THF, and a solution of 54.2 g of methyl (4-propylidenecyclohexyl)acetate in 200 ml of THF was then added dropwise with stirring at such a rate that the reaction boiled gently. The mixture was then refluxed for a further 3 h, cooled to RT and hydrolysed dropwise with 50 ml of water. 18% hydrochloric acid was then added until the precipitate formed had dissolved. Conventional work-up gave 2-(4-propylidenecyclohexyl)ethanol (boiling point 110° C. at 10 mmHg).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]([C:41]#[N:42])[C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[C@@H:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=3)[CH2:14][CH2:15][CH3:16])[C:8]=2[CH:40]=1.C(O)(=O)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:41]#[N:42])[C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[C@@H:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=3)[CH2:14][CH2:15][CH3:16])[C:8]=2[CH:40]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of LiOH (2.0 M in water, 4.5 mL, 9.0 mmol) was added to a solution of ethyl N-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate (0.100 g, 0.168 mmol) in THF (9.0 mL). The mixture was stirred at room temperature for four hours then acidified with acetic acid and extracted with ethyl acetate. The organics were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by reverse-phase HPLC eluting with 20-100% acetonitrile/water containing 0.1% TFA. Following lyophilization, the material was further purified by silica gel chromatography eluting with 5% MeOH in DCM containing 0.5% acetic acid to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.77 (br s, 1H); 7.60 (d, J=5 Hz, 2H); 7.52 (br s, 1H); 7.42 (br s, 1H); 7.31-7.35 (m, 4H); 7.25 (d, J=7 Hz, 2H); 6.78 (br s, 1H); 4.49 (d, J=11 Hz, 1H); 3.67 (br s, 2H); 3.44-3.47 (m, 1H); 2.66 (br, 2H); 1.45-1.53 (m, 2H); 0.98-1.05 (m, 2H); 0.73 (t, J=7 Hz, 3H). LC1: 3.97 min. (M+H)+ 565.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(N)(C)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:13][CH:5]([CH3:6])[CH3:4])=[C:15]([S:18]([CH3:21])(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Solvent: CC(C)N
Product: CC(C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Yield: 148.7 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile (0.323 g, 0.8 mmol) was stirred in isopropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) without chromatography gave 247 mg (74%) of the title compound. Mp 188.5-191° C. 1H NMR (200 MHz, CDCl3): δ=1.15 (d, 6H), 3.15 (s, 3H), 3.40 (m, 1H), 7.56 (s, 2H), 7.68 (s, 1H). Analysis: calc. for C15H15F6N3O2S: C, 43.38%; H, 3.64%; N, 10.12%. Found: C, 43.52%; H, 3.63%; N, 9.98%.