Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([C:21]3[CH:29]=[C:28]4[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]4[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])=[CH:23][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cccc(OCc4ccccc4)c3)ccc12
Yield: 78.5 %

Procedure:
930 mg of 3-benzyloxyphenylboronic acid, 1.24 g of caesium fluoride, 31.5 mg of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)diphenyl and 13.5 mg of palladium acetate are successively added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy)methyl]-1H-indazol-3-yl)butanamide, prepared in Example 25, and the mixture is refluxed for 18 hours. The reaction medium is filtered through a sinter funnel packed with Celite and 75 cm3 of ethyl acetate are added to the filtrate. The organic phase is washed with 25 cm3 of saturated sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate gradient (90/10 to 75/25 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1.1 g of N-[6-[3-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy)methyl]-1H-indazol-3-yl]butanamide are obtained in the form of an oil in a purity of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[N:10]=2)=[N:7][CH:8]=1.[H][H]>O1CCOCC1>[CH2:35]([O:34][C:32](=[O:33])[N:25]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)[N:5]=1)[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1)[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)N(c1ccncc1)c1nc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)ncc1OC
Reactant: [H][H]
Solvent: C1COCCO1
Product: C=CCOC(=O)N(c1ccncc1)c1nc(-c2n[nH]c3ccccc23)ncc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.22 g of tert-butyl 3-(5-methoxy-4-{[(prop-2-en-1-yloxy)carbonyl](pyridin-4-yl)amino}pyrimidin-2-yl)-1H-indazole-1-carboxylate (1-9-1, 2.43 mmol, 1 eq.) was suspended in 1,4-dioxane. 2.43 ml of hydrogen acid 4M in 1,4-dioxane (9.711 mmol, 4 eq.) were added dropwise. The reaction mixture was stirred for 24 hours at room temperature. 2.43 ml of hydrogen acid 4M in 1,4-dioxane (9.711 mmol, 4 eq.) were added dropwise again and stirred for further two hours. The reaction mixture was concentrated under vacuo. The residue was extracted with saturated aq. sodium hydrogen carbonate-solution and ethyl acetate. The aqueous layer was reextracted twice by ethyl acetate. The combined organic layers were dried over a silicone filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/methanol 0-25%) provided 877 mg (1.96 mmol, 80.8%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(OC(=O)C)(=O)C>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:1][C:2]2[N:3]=[N:4][C:5]([CH:8]=[CH:18][C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Cc1ccc(C)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)nn2)cc1
Yield: 44.4 %

Procedure:
24 g of 3,6-dimethylpyridazine and 60 g of p-nitrobenzenealdehyde are dissolved in one liter of acetic acid anhydride, which is heated and refluxed to obtain 33 g of 3,6-di(p-nitrostyryl)pyridazine (K').
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[C:4]([F:18])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CCCC1CCC(O)(c2ccc(Br)cc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CC=C(c2ccc(Br)cc2F)CC1
Yield: 99 %

Procedure:
A Dean-Stark condenser was attached, and a mixture of compound (68) (42.0 g, 133.2 mmol) and PTSA (0.42 g, 1 wt %) was refluxed in a toluene (300 mL) solvent for 3 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and dried over magnesium sulfate. Toluene was distilled off by an evaporator, and thus 4′-bromo-2′-fluoro-4-propyl-2,3,4,5-tetrahydro-1,1′-biphenyl (69) (39.2 g, yield 99.0%) was obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:7]=2[N:8]=1)#[N:2].[N:19]([Sn](C)(C)C)=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[NH:19]1[C:1]([C:3]2[N:4]=[CH:5][C:6]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:7]=3[N:8]=2)=[N:2][N:21]=[N:20]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C#N)nc2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2cnc(-c3nnn[nH]3)nc2C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 2-cyano-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Intermediate 9, Step D) (71 mg, 0.29 mmol) in toluene was added azidotrimethyltin (596 mg, 2.9 mmol). The resulting mixture was heated at 110° C. overnight. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase silica gel chromatography (gradient 5-50% acetonitrile in water containing 0.1% TFA) to yield tert-butyl 2-(1H-tetrazol-5-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. The product was treated as described for Intermediate 9, Step E, to yield the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.C[O-].[Na+].Br[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2.C(Cl)Cl>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH2:3][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cnc2ccccc2c1
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(prop-2-en-1-yl)piperidine (from Procedure 5, Step B) (260 mg, 1.15 mmol) in THF (3 mL) under argon was treated with 0.5M 9-BBN solution in THF (2.30 mL, 1.15 mmol). The resulting mixture was stirred at rt for 2 h, then treated with sodium methoxide (68 mg, 1.25 mmol). The resulting mixture was stirred until it was homogeneous (˜15 min) and then was treated with 3-(bromo) quinoline (0.155 mL, 1.15 mmol) and [1,1′-bis(triphenylphosphino)ferrocene)dichloropalladium.methylene chloride (41 mg, 0.05 mmol). The resulting mixture was heated at reflux for 30 min, cooled and quenched with 1N NaOH (20 mL). The quenched reaction was extracted with 2×50 mL of ether; the extracts were dried over magnesium sulfate, combined and concentrated. FC (15 g of silica gel, 4:1 v/v hexanes/ethyl acetate) afforded the title compound (240 mg).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:20](=O)[C:19]4[C:14](=[CH:15][C:16]([OH:24])=[C:17]([CH2:22][CH3:23])[CH:18]=4)[O:13][C:12]=3[CH3:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O.[NH2:27][NH2:28]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:20]([C:19]4[CH:18]=[C:17]([CH2:22][CH3:23])[C:16]([OH:24])=[CH:15][C:14]=4[OH:13])=[N:27][NH:28][C:12]=3[CH3:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1cc2c(=O)c(-c3ccc4c(c3)OCCO4)c(C)oc2cc1O
Reactant: NN
Solvent: O
Product: CCc1cc(-c2n[nH]c(C)c2-c2ccc3c(c2)OCCO3)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-6-ethyl-7-hydroxy-2-methyl-chromen-4-one (0.6 g, 1.77 mmol), hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-methyl-1H-pyrazol-3-yl]-6-ethyl-benzene-1,3-diol as a clear oil which solidified over a period of 1 month (0.38 g, 60.9%); Rf 0.4 cf SM 0.6 Hexane/Ethyl acetate/MeOH (8/4/1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nn(Cc2ccccc2)c2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nn(Cc2ccccc2)c2ccccc12

Procedure:
1-benzyl-1H-indazol-3-carbaldehyde (2.36 g, 10 mmol, 1 eq.) and toluene (12 mL) were placed in a thoroughly dried 100 mL flask fitted with a magnetic stirrer and inerted with nitrogen. A 70% solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.8 mL, 10 mmol, 2 eq.) was then slowly added to the solution at room temperature. Once the reaction was complete (after approximately 15 minutes), 2 M HCl (10 mL), H2O (10 mL) and toluene (15 mL) were added. The phases were separated and the aqueous phase was extracted twice with toluene. The pooled organic phases were washed with water and concentrated. The product was then precipitated out by adding n-hexane, filtered and dried. Yield: 1.95 g of white solid (82.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]([C:16]1[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)NCc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 18.5 %

Procedure:
Ethyl 2-chlorobenzylcarbamate (809.9 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (932.3 mg) were dissolved in tetrahydrofuran (20 ml), and to the solution was added sodium hydride (151.6 mg) under ice-cooling. The reaction mixture was heated at reflux for 5 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (100 g, hexane:ethyl acetate=5:1) to give the title compound (0.286 g, 19%).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH3:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=3)[N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:17]=2)[CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:16]([C:13]4[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH:12]=4)=[CH:17][N:18]3[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:22]=2)[C:5]([CH3:6])=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3cc(N)ccc23)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2c(C3=CCN(C)CC3)cn(S(=O)(=O)c3ccccc3)c2c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 33.8 %

Procedure:
Hexane-2,5-dione (930 mg, 8.16 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-6-amine (1.66 g, 1.13 mmol) in toluene (80 mL). Para-toluenesulfonic acid (30 mg, 0.17 mmol) was then added, and the resulting solution was stirred for 4 hours at 130° C. After filtration, the filtrate was concentrated and the residue was purified by column chromatography using a 30:1 dichloromethane/methanol solvent system. The product was washed with petroleum ether to afford 170 mg (32%) of 6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole as a yellow solid. 1H NMR (DMSO) δ 8.3 (s, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 8.0 (s, 1H), 7.8 (s, 1H), 7.6 (s, 1H), 7.4 (s, 1H), 7.4 (s, 1H), 7.1 (s, 1H), 6.3 (s, 1H), 5.8 (s, 1H), 5.8 (s, 1H), 3.0 (s, 2H), 2.27 (s, 3H), 2.6 (d, 2H), 2.6 (d, 2H), 1.8 (d, 3H), 1.8 (d, 3H). LC/MS (EI) tR 2.48, m/z 446.0 (M++1)
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCCN1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((R)-3-tert-butoxycarbonylaminopiperidin-1-yl)ethyl ester (2.86 g, 8.72 mmol) in DCM (100 mL) was added TFA (25 mL) and the mixture stirred at RT for 3 h. Toluene was added and volatiles were removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 1M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless oil (1.678 g, 84%). 1H NMR (CDCl3, 300 MHz): 4.18 (2H, t, J=6.0 Hz), 2.89-2.77 (2H, m), 2.68-2.59 & 2.62 (3H, m & t, J=6.0 Hz), 2.19-2.11 (1H, m), 2.00-1.94 (1H, m), 1.84-1.65 (2H, m), 1.60-1.46 (1H, m), 1.23 (2H, bs), 1.20 (9H, s), 1.15-1.03 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]1([CH3:25])[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH3:25][C@:12]1([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@](C)(NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]1(NC(=O)OCc2ccccc2)CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (S)-tert-butyl 3-(benzyloxycarbonylamino)-3-methylpiperidine-1-carboxylate (3.5 g, 10.04 mmol) in dioxane (14 mL) was added 4N HCl in dioxane (15 mL, 60 mmol) drop wise at 0° C. The resultant clear solution was stirred at room temperature for 2 h. The reaction mixture was concentrated, the pale yellow foam was dissolved in water (50 mL), washed with ethyl acetate (2×30 mL), the aqueous layer was basified with saturated NaHCO3 (until reach pH ˜9) at 0° C. The resultant aqueous layer was extracted with CHCl3 (3×50 mL), the combined organic extracts was washed with water (50 mL), brine (10 mL), dried (Na2SO4), concentrated and dried in high vacuum to get the product (S)-benzyl (3-methylpiperidin-3-yl)carbamate (2.45 g, 9.85 mmol, 98% yield) as a light yellow solid. Anal. Calcd. for C14H20N2O2 m/z 248.3, found: 249.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.42-7.26 (m, 5 H), 5.13-4.97 (m, 2 H), 3.20 (d, J=13.2 Hz, 1 H), 2.93-2.82 (m, 1 H), 2.60-2.50 (m, 2 H), 2.13 (d, J=13.0 Hz, 1 H), 1.69-1.56 (m, 1 H), 1.54-1.37 (m, 2 H), 1.27 (s, 3 H).
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
A mixture of 65 mg (0.15 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 45 mg (0.225 mmol, 1.5 equiv) of 4-(methanesulfonyl)phenylboronic acid, 6 mg (0.0075 mmol, 5 mol %) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 45 mg (0.225 mmol, 1.5 equiv) of 4-(methanesulfonyl)phenylboronic acid, 12 mg (0.015 mmol, 10 mol %) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 10% ethyl acetate in dichloromethane) to afford 42 mg (62% yield) of desired 7-cyclohexyl-6-(4′-methanesulfonyl-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H NMR; LC-MS—calcd for C26H24N4O2S [M++H]+: 457.16, found: 457.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:31][CH2:32]1)[CH3:19]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=428.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+].Cl.C#N>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1Cl
Reactant: [C-]#N
Agent: C#N
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid [Aromatic Intermediate 11, step a] (13.2 g) in DMF (150 mL) was treated with a solution of potassium cyanide (7.23 g) in water (50 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted with ethyl acetate (3×250 mL). The combined organic phases were washed with water (3×250 mL) and brine (250 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled, compound as a white solid. Yield 10.3 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][O:44][CH2:45][C:46]([NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22])=[O:47]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A mixture of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 266) (300 mg, 0.639 mmol), N-ethyldiisopropylamine (0.22 ml, 1.278 mmol) and methoxyacetyl chloride (0.067 ml, 0.639 mmol) in dichloromethane (3 ml) was stirred at 23° C. for 16 h. Diluted with dichloromethane, washed with water, dried the organic layer over MgSO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc, followed by trituration with diethyl ether to give the title compound (46 mg, 13%) as a white solid. MS (ISP) 542.7 [(M+H)+]; mp 188° C.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:19]=[N:20]\[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[Br-].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][Zn+].[Cl-].[NH4+]>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[Br:1][C:2]1[C:3]([C@@H:19]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:32][C:31]2[CH:30]=[C:29]([F:28])[CH:36]=[C:35]([F:37])[CH:34]=2)=[N:4][CH:5]=[C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:7]=1
Reactant: CC(C)(C)[S@](=O)/N=C\c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Reactant: Fc1cc(F)cc(C[Zn+])c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S,Z)—N-((3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (30C, 3.7 G, 8.5 mmol) and Cu(OTf)2 (154 mg, 0.4 mmol) in methylene chloride (30 ml) at 0° C. was added (3,5-difluorobenzyl)zinc bromide (0.5 M in THF, 25.5 ml, 12.8 mmol) dropwise. The reaction stirred at room temperature for one hour. Ammonium chloride (aq, 100 ml) was added to the reaction and the mixture was extracted with methylene chloride (2×100 ml). The organic layer was dried over Na2SO4 filtered and concentrated (about 1:3 ratio of two diastereomers). The crude was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title compound as a single diastereomer. MS (m/z) 563.83 [M+H]+.