Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccc(F)cc3)nc(N3CCCC3)c2)cc1
Yield: 22.6 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 77 mg (0.55 mmole) 4-fluorophenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 45 mg (22%) pure 4-[2-(4-fluoro-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a white solid mp.: 245-246° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][CH:42]=O)[C:34](=[O:44])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][CH2:42][N:14]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15][CH2:16][CH3:17])[C:34](=[O:44])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCC=O)C(=O)C1
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine hydrochloride prepared as described in Example 1 (500 mg, 2 mmol, 1 eq) and triethylamine (0.3 mL, 2.2 mmol, 1.1 eq.) in 1,2-dichlororethane (20 mL) under inert atmosphere was added the 3-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (550 mg, 2 mmol, 1 eq.) in a single portion followed by the sodium triacetoxyborohydride (650 mg, 3 mmol, 1.5 eq.). The reaction was stirred at room temperature for 20 hr, concentrated in-vacuo and then partitioned between 10% KOH (40 mL) and ethyl acetate (75 mL), the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by chromatography provided 858 mg of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:15][CH2:14][O:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Yield: 143.3 %

Procedure:
Methyl iodide (9.38 ml, 150 mmol) was added to a suspension of 4-(tert-butoxycarbonyl)-2-morpholinecarboxylic acid (14.5 g, 62.6 mmol) and dry potassium carbonate (17.3 g, 125 mmol) in dry dimethylformamide (DMF) (360 ml). The mixture was stirred over night, filtered through Celite and concentrated. The residue was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulfate and concentrated to give 22 g of crude product.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][N:26]([C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:17])[CH3:27])[CH3:22]
Reactant: CCOC(=O)CNC
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1ccc2c(CC)nn(C3CCCC3)c2c1
Yield: 56 %

Procedure:
This compound was prepared according to the method of Example 35, using 284 mg (1.10 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 169 mg (1.10 mmol, 1.0 equiv) sarcosine ethyl ester hydrochloride as starting materials, to give 220 mg (56%) of a clear oil: Anal. calcd for C20H27N3O3: C, 67.21; H, 7.61; N, 11.76. Found: C, 66.93; H, 7.73; N, 11.77.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)C=C4)[CH2:12][CH2:11]2)C)OC1.C(=O)([O-])O.[Na+].ClC1C=CC=[C:40]([C:44]([O:46]O)=O)C=1>C(Cl)Cl>[O:29]1[C:20]2=[C:21]3[C@:22]([CH3:23])([CH2:17][CH2:18][C:19]2=[O:30])[C@@H:24]2[C@H:14]([C@H:13]4[C@:27]([CH3:28])([CH2:26][CH2:25]2)[C@@H:10]([CH2:8][CH3:5])[CH2:11][CH2:12]4)[C@@H:40]2[O:46][C@:44]123
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Yield: 79 %

Procedure:
To a solution of 0.43 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one in 10 ml of methylene chloride was added 3 ml of 0.5M-aqueous sodium hydrogen carbonate solution under stirring and cooling in an ice-water bath, followed by gradual addition of 0.34 g (2.0 mmoles) of m-chloroperbenzoic acid. The mixture was stirred at room temperature for 2 days. The reaction mixture thus obtained was subjected to phase separation and the aqueous layer was extracted twice with 10 ml portions of methylene chloride. The extract was combined with the organic layer obtained above and the mixture was washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 0.35 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one (yield: 79%). The 1H-MNR and IR spectra of this product were in agreement with those of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one obtained in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: C#CC1CC1
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Product: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]

Procedure:
5-Bromo-3-nitrothiophene-2-carboxylic acid methyl ester was reacted with ethynylcyclopropane by method Q. The product with the molecular weight of 251.26 (C11H9NO4S) was obtained in this way; MS (ESI): 252 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:16][C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1Nc2ccccc2C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2[nH]c3ccccc3c2-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
3-Phenyloxindole (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and heated to 80° C. with stirring in a preheated oil bath. After 20 minutes, 5 ml of acetone and 1 ml of water are then added and the mixture is heated for a further 30 minutes. The hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.59 g of product in an HPLC purity of 98% (29% of theory). A structural elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.67 g of product in an HPLC purity of 40% can be isolated from the filtrate (13% of theory).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[CH:23]1([NH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=2[N+:40]([O-:42])=[O:41])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.O1CCOCC1.C(OCC)(=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:31]([N+:40]([O-:42])=[O:41])[CH:32]=3)(=[O:38])=[O:37])=[O:17])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(C2CCC(C(C)(C)C)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CCC(c2ccc(C(=O)NS(=O)(=O)c3ccc(NC4CCCCC4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 3 h

Procedure:
A mixture of Example 5C (55 mg, 0.20 mmol) and 1M LiOH (0.3 mL) in THF (2 mL) was heated to 50° C., stirred for 3 hours, concentrated, dissolved in DMF (0.5 mL), and treated with a mixture of Example 3A (60 mg, 0.20 mmol), EDCI (96 mg, 0.50 mmol), and DMAP (10 mg) in dioxane (2.0 mL). The mixture was stirred for 16 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel, with 50% ethyl acetate/hexanes to provide a ˜2:1 mixture of diastereomers. MS (ESI(−)) m/e 540 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (2d, 1H total), 8.33 (2d, 1H total), 7.95 (m, 1H), 7.82 and 7.78 (2d, 2H total), 7.45 (m, 1H), 7.30 (m, 2H), 3.71 (m, 1H), 2.28-0.95 (m, 20H), 0.86 and 0.75 (2s, 9H total).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=O)(C)(C)C.O1CC(=O)N=N1.C(OC(=O)CCNC(=O)C1C=CC(C2[NH:38][O:39][C:40](=[O:42])N=2)=CC=1)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:39]1[C:40](=[O:42])[N:14]=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:16][CH:15]=2)[NH:38]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Agent: O=C1CON=N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2nc(=O)o[nH]2)cc1

Procedure:
Compound 14 (3.25 g, 14.9 mmol) was converted into oxadiazolone 15 as described earlier for the preparation of compound 3. The resulting crude light orange solid was stirred for 5 h in a mixture of DCM (15 mL) and TFA (8 mL). Concentration under reduced pressure and evaporation with toluene (2×10 mL) gave a brown solid which was purified by silica gel (40 g) column chromatography (eluent: EtOAc) to yield compound 16 (1.81 g, 69% over the three steps). Rf 0.5 (EtOAc).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>CC(O)(C)C.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc2ccc(N3CCOCC3)cc2[nH]1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of 1H-indol-6-amine (3.14 g, 23.76 mmol), 1-chloro-2-(2-chloroethoxy)ethane (4.18 mL, 35.6 mmol), and sodium carbonate (10.07 g, 95 mmol) in t-BuOH (90 mL) was heated at 100° C. in a pressure tube for 3.5 days. On cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through CELITE®. The filtrate was concentrated under vacuum to dryness. To the residue was added water (50 mL). The mixture was adjusted to pH 11 with saturated NaHCO3 solution and extracted with CH2Cl2 (4×80 mL). The combined extract was washed with brine (50 mL) and dried over anhydrous MgSO4. The desired product (3.96 g, 19.58 mmol, 82% yield) was isolated as a beige solid with ISCO (300 g silica gel, solid loading, 20-50% ethyl acetate/hexane).
Reaction SMILES: [O-2:1].[O-2].[O-2].[U+6:4].[N+:5]([O-])([O-])=[O:6].[NH4+:9]>>[NH4+:5].[NH4+:9].[O-2:6].[O-2:1].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[U:4].[U:4]
Reactant: [U+6]
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Agent: [O-2]
Product: [U]

Procedure:
reacting solid uranium trioxide with aqueous ammonium nitrate to form an insoluble ammonium uranate
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[CH3:16])=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.[CH2:17]([O:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18]>>[CH2:17]([O:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)\[CH3:16])=[CH:31][CH:32]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18]
Reactant: C/C(=C\CO)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 78 %

Procedure:
The title compound (678 mg, 77%) was prepared from (E)-3-(4-furan-2-yl-phenyl)-but-2-en-1-ol (430 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (526 mg, 2.21 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)=[O:15])[CH2:10][C@H:9]2[CH3:24])=[C:4]2[CH:25]=[N:26][CH:27]=[CH:28][C:3]=12.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C1(P(C2CCCCC2)C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:22][C:19]1([F:23])[CH2:20][CH2:21][CH:16]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=4)=[C:3]4[CH:28]=[CH:27][N:26]=[CH:25][C:4]=34)[C@H:9]([CH3:24])[CH2:10]2)=[O:15])[CH2:17][CH2:18]1
Reactant: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(Cl)c2ccncc12
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(-c2ccc(C#N)cc2)c2ccncc12
Temperature: 100 °C

Procedure:
A 15 ml Schlenk tube was charged with (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 (123 mg, 300 μmol), 4-cyanophenylboronic acid (66 mg, 450 μmol), tris(dibenzylideneacetone)-dipalladium (o) (5.5 mg, 6.0 μmol), dicyclohexyl(2,6-dimethoxyphenyl)phosphine (4.0 mg, 12 μmol), and potassium phosphate tribasic (127 mg, 600 μmol). The tube was evacuated and backfilled with argon 5 times and previously degassed n-butanol (1 ml) was added. The reaction was heated at 100° C. for 21 hours, then cooled and added to 30 ml aqueous K2CO3. This was extracted three times with dichloromethane (30 ml) and the combined extracts were dried (MgSO4) and evaporated to give an orange oil. The residue was chromatographed over silica with a gradient of hexane with 2.5% triethylamine and 0-100% ethyl acetate with 2.5% triethylamine to give (R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile 65 as a yellow solid. LC/MS m/z=477 (M+H+).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:19])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>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.C(O)C>[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31]([C:2]2[NH:3][C:4](=[O:19])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=2)=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Temperature: 150 °C
Yield: 65 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (53.7 mg, 179 mop and ethanol (850 μL) (650 μL+200 μL rinse). The resulting mixture was treated with a 2M aqueous sodium carbonate solution (270 μL, 540 μmol), 4-(trifluoromethyl)phenylboronic acid (42.1 mg, 222 μmol), and tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 11.4 μmol). The vial was tightly sealed and heated in a microwave at 150° C. for 8 min. At this time, the reaction was filtered through a pad of Celite®, rinsing copiously with methanol, and the filtrate was concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 10-40% ethyl acetate/hexanes) afforded 2-(4-(trifluoromethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as a light yellow solid (47.7 mg, 65.0%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.13 (s, 9H) 0.85 (t, J=8.10 Hz, 2H) 3.56 (t, J=8.10 Hz, 2H) 5.58 (s, 2H) 6.59 (d, J=3.39 Hz, 1H) 7.34 (d, J=3.39 Hz, 1H) 7.90 (d, J=7.91 Hz, 2H) 8.36 (d, J=8.29 Hz, 2H) 12.45 (s, 1H). LC-MS calcd. for C19H23F3N3O2Si [(M+H)4] 410, obsd. 410.1.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[CH2:6]1[CH:1]2[CH:2]([C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:7]2=[O:9])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1=CCCCC1
Reactant: C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=C1C2=C(CCCC2)C2CCCCC12
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 43 %

Procedure:
In a 250 ml three neck round bottom flask, equipped with a mechanical stirrer, a thermometer and a reflux condenser 16.276 g of polyphosphoric acid was charged and heated to a temperature of 70° C. 16.276 g of 1-cyclohexenecarboxylic acid and 10.592 g of cyclohexane were added dropwise maintaining a temperature of the reaction mass below 100° C. The mixture was stirred at 78° C. for additional 4.5 hours. The dark brown reaction mass was was poured onto 237 g of ice and neutralised with 89 g aqueous ammonium sulphate solution in 474 g of water. The resulting mixture was then extracted 4 times with 300 ml of petroleum ether and 300 ml of diethyl ether. All organic layers were combined, washed successively with 5% aqueous ammonium hydroxide, brine dried over magnesium sulphate and concentrated in vacuum. Fractional distillation (b.p. 130° C. at 3.0 mmHg) of this crude product yielded 10.294 g of 1,2,3,4,4a,5,6,7,8,9a-decahydro-9H-fluoren-9-one. 1H-NMR (CDCl3): δ2.73 (q, J=7 Hz, 1H), 2.2-0.5 (m, 17H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([F:25])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)cc1F
Yield: 1.9 %

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluoro-4-methylbenzyl bromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.43 (m, 4H), 7.19 (t, J=7.9 Hz, 1H), 6.88-6.80 (m, 2H), 5.34 (s, 2H), 3.88 (s, 2H), 3.16-3.13 (m, 2H), 2.87-2.85 (m, 2H), 2.23 (d, J=1.5 Hz, 3H), 1.81-1.78 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C@@H:18]([C:33]#[C:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@:19]([NH2:32])([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([O:22]C)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.COC1C=CC(B(O)O)=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C@@H:18]([C:33]#[C:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@:19]([NH2:32])([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@](N)(OCc1ccccc1)[C@H](C#Cc1ccccc1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)[C@@H](C#Cc3ccccc3)[C@](N)(OCc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl (2R)-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-(3S)-benzyl-oxy-5-phenyl-pent-4-ynoate: The starting sulfonamide 65e (927 mg, 1.75 mmol) and 4-methoxyphenylboronic acid (400 mg, 2.63 mmol) are taken up in 25 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water in the presence of Pd(PPh3)4 (61 mg, 0.05 mmol) and 371 mg of Na2CO3 and brought to reflux for 4 hr. The mixture is cooled to room temperature, poured into water, and extracted with methylene chloride. The organic layer is dried over MgSO4, filtered and evaporated. The crude product is purified by silica gel chromatography using 9:1 hexane:EtOAc to give the desired product as a colorless oil.