Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:7])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of L-cysteine ethyl ester hydrochloride (18.6 g, 0.1 mole) in 200 mL TFA was added triphenylmethanol (52 g, 0.2 mole). The resulting dark brown solution was allowed to stir for 2 h at room temperature under nitrogen. The solvent was removed in vacuo and ethanol (100 mL) added to the residue. A 1M solution of sodium ethoxide (50 mL) was added to the ethanolic solution and stirred for 90 min. during which time the solution turned cloudy. The mixture was filtered, the filtered was concentrated in vacuo to give an oily residue. Flash column chromatography using ethyl acetate:hexane (1:3) and ethyl acetate gave the desired product (containing some ethyl acetate which is difficult to remove) which was stored under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.ClCCl.C(O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1F
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 500 mg, 1.64 mmol), tetrabutylammonium iodide (605 mg, 1.64 mmol) and 2,4-difluorobenzyl bromide (840 μL, 6.54 mmol) in dimethylformamide (10 mL) was heated at 100° C. overnight. Dichloromethane (250 mL) was added and the solution was washed with water (3×100 mL), aqueous sodium thiosulfate (100 mL), and brine (100 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 45-50% ethyl acetate/petroleum ether. Fractions homogeneous for the product were concentrated to give an oil which was co-evaporated with ethanol and then held under high vacuum to give (4S,7R)-1-(2,4-difluoro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (508 mg, 71%). APCI(+)-MS (M+H) 431.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]=[N+]=[N-])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2′-Azidomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.784 g, 2.07 mmol) and 10% palladium on carbon (440 g) were combined in MeOH (8 mL) and stirred under a balloon of H2 at room temperature for 1 hour. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC. The desired fractions were combined, concentrated, and the isolated material was diluted with EtOAc and neutralized with saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, decanted, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22]>CC(C)=O.O>[CH3:20][N:21]([CH2:23][CH2:24][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Yield: 69.9 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (5.0 g, 0.029 mole) and potassium carbonate (8.3 g, 0.060 mole) in acetone (200 ml) and water (60 ml) was treated with N,N-dimethylaminoethyl chloride hydrochloride (8.64 g, 0.060 mole) and heated under reflux for 10 h. The mixture was concentrated under vacuum to approx. 80 ml volume, then acidified with 2M HCl acid (150 ml) and washed with ethyl acetate (2×80 ml). The acid solution was basified with K2CO3 and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2 SO4) and concentrated under vacuum to afford the title compound as a yellow solid (4.87 g, 70%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:9]([NH:8][CH2:7][C:5]1[S:6][C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:22]=2)=[CH:3][CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CNCc1ccc(Br)s1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1

Procedure:
In analogy to example 1, step 3, (5-bromo-thiophen-2-ylmethyl)-isobutyl-amine was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine as a light yellow oil. MS: 324.3 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Combine 4-Hydroxybenzaldehyde (8.0 g, 65.5 mmol), 6-Chloronicotinonitrile (9.07 g, 65.5 mmol), powdered K2CO3 (13.6 g, 98.3 mmol), and DMA/Toluene (80/240 mL) in a 500 mL RB flask equipped with a stir, reflux condenser and a Dean Stark Trap. Reflux the reaction mixture for several hours under a Nitrogen atmosphere then cool to room temperature and quench with sat NH4Cl (aq). Add Ethyl acetate to extract the product and wash several times with water and then brine. Dry the organic layer over Na2SO4. Concentrate and flash chromatograph using 2:1 Hexanes:Ethyl acetate to give 13.2 g (88% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 7.1 (1H, d), 7.3-7.4 (2H, m), 7.9-8.0 (3H, m), 8.5 (1H, d), 10.0 (1H, s); MS m/z 225 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1>[Pd].C(O)C>[F:21][C:18]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH2:15])[CH:9]=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cncc(C(F)(F)F)c1
Reaction time: 6 h
Yield: 99.4 %

Procedure:
A Parr hydrogenation flask was charged with 10% Palladium on carbon, 50% wet (0.050 g, 0.023 mmol) and ethanol (10 mL). Triethylamine (1.0 ml, 3.09 mmol), 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (0.70 g, 3.09 mmol) and an additional 10 mL of ethanol were added. The flask was purged of air, charged with 48 psi of hydrogen, and shaken for 6 h. The reaction mixture was purged of hydrogen in vacuo and filtered through Celite®, washing with EtOAc (20 mL) and EtOH (20 mL). The filtrate was concentrated in vacuo and the product partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with sat aq NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo to provide 5-(trifluoromethyl)pyridin-3-amine (498 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.14 (m, 1 H), 8.00 (s, 1 H), 7.13 (m, 1 H), 5.84 (s, 2 H); MS (ESI) m/z 163.0 (M+H+).
Reaction SMILES: [CH:1]1([N:6]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([OH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>N1C(C)=CC(C)=CC=1C>[CH:16]1([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)=[CH:10][CH:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Reactant: COc1ccc(O)cc1OC
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-cyclopentyl-N-cyclohexyl amide (2.350 g, 6.71 mmol), 3,4-dimethoxy phenol (1.051 g, 6.81mmol) and cuprous oxide (478 mg, 3.34 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 153.96° C. (DSC).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:40]6[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]6)=[CH:25][CH:26]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-(3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde (2.1 g) was suspended in anhydrous dichloromethane (15 mL), treated with tert-butyl piperazine-1-carboxylate (1.6 g), and stirred for one hour. To the resulting mixture was added sodium triacetoxy borohydride 1.36 g in three portions. The reaction was stirred for 3 hours, diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over MgSO4, and purified by MPLC silica gel chromatography (30-60% EtOAc in hexane) to yield 2.62 g of the title compound (M+H 662).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1C
Temperature: 25 °C
Yield: 71.1 %

Procedure:
MeOH (220 mL) was added to a flask containing 4-(1-phenethylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (7.0 g, 23.1 mmol). NaOMe solution (5.3 mL, 23.1 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.93 g, 27.7 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl (200 mL) and CH2Cl2 (200 mL). The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-40% EtOAc/hexanes) to give 5.75 g of the title compound as a pale yellow solid. MS: (+) m/z 372.14, 374.16 (M+Na, 79/81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: NCc1ccc(F)cc1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(F)cc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (2,4-difluorophenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 525 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(SC)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Yield: 29.7 %

Procedure:
According to the procedure described in Example 4a) 2 g of 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 0.81 g ethanesulfonylchloride to give 0.7 g 4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=5.85 min, [M+1]+=611.31.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32](I)=[CH:31]2)[CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[N:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)=[CH:31]2)[CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Reactant: CC1(C)OB(c2ccc3cnc(-c4ccccc4)nc3c2)OC1(C)C
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+]
Product: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Temperature: 80 °C

Procedure:
A flask equipped with a reflux condenser was charged with 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (67 mg, 0.20 mmol), 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.20 mmol) and Na2CO3 (56 mg, 0.51 mmol). The reaction setup was evacuated and refilled with Ar (3×). Pd(PPh3)4 (24 mg, 0.021 mmol) was added swiftly minimizing exposure to air and the system was evacuated and refilled with Ar (3×) again. Degassed solvent mixture H2O-DMF (1:5 v/v, 5 mL) was added and the reaction mixture was heated at 80° C. for 42 h. The resulting orange-light brown solution was partitioned between DCM (˜80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (3×). Combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure (125 mg). Purification by flash chromatography (silica gel, 25 g, 0-2% MeOH in DCM) provided the title compound as a pale yellow solid; The material was also later triturated (hexane 2×, Et2O 1×); 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=0.8 Hz, 1H), 8.65-8.58 (m, 2H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.75 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.39 (s, 1H), 5.44 (br, 2H), 5.33 (quintet, J=8.2 Hz, 1H), 2.67-2.40 (m, 4H), 2.17-1.89 (m, 2H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.91 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([C:38]#[N:39])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(Cl)ccc34)nc(N)c21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(C#N)ccc34)nc(N)c21
Temperature: 130 °C
Reaction time: 15 h

Procedure:
A DMF (4 mL) solution containing 4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 176, (149 mg, 0.273 mmol), zinc cyanide (19.3 mg, 0.164 mmol), 1,1′-bis(diphenylphosphino)ferrocene (15.16 mg, 0.027 mmol), and tris(dibenzylideneacetone)dipalladium (0) (12.52 mg, 0.014 mmol) was degassed for 1 hour at rt. The reaction mixture was then stirred for 15 hours at 130° C. The reaction mixture was then cooled and ethyl acetate (30 mL) and water (10 mL) were added. The water layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to afford the indicated product. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1NMR (500 MHz, CD3COCD3): δ 0.56 (m, 2H); 0.71 (M, 2H); 1.73 (s, 3H); 2.77 (m, 1H); 3.06 (m, 2H); 5.02 (t, J=7.0 Hz, 2H); 7.00 (br, 2H); 7.52 (br, 1H); 7.84 (d, J=8.2 Hz, 1H); 9.28 (d, J=8.2 Hz, 1H). m/z=536.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CC(C)C)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.5 %

Procedure:
To 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 23C, 0.3 g, 0.755 mmol) in THF (2 mL) was sequentially added N-methylmorpholine N-oxide (50% in water) (0.35 mL, 0.755 mmol) and osmium tetroxide (4% in water) (0.118 mL, 0.015 mmol) at room temperature. The reaction mixture was stirred at room temperature for 60 h. Next, sodium periodate (0.242 g, 1.132 mmol) dissolved in 1.5 mL of water was added at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 30 min. and the reaction mixture was partitioned between ethyl acetate (10 mL) and brine (5 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.3 g, 0.751 mmol, 100% yield) as an off-white solid. LC/MS M+1=400.2.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[Cl:12].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][OH:2])=[C:6]([Cl:12])[CH:7]=1
Reactant: COC(=O)Cc1ccc(Br)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: OCCc1ccc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
4-Bromo-2-chlorophenylacetic acid methyl ester (259 g) of Reference Example 16 was dissolved in ethanol (1400 mL) and water (355 mL), calcium chloride (107 g) was added at 7° C., and the mixture was stirred for 30 min. To the reaction mixture was added sodium borohydride (73 g) by portions so that the inside temperature would not exceed 15° C. After stirring at 7° C. for 1 hr, the mixture was stirred at room temperature for 1 hr. 0.1M Hydrochloric acid (4257 mL) was added dropwise to the reaction mixture, and the reaction solvent was evaporated under reduced pressure. 0.1M Hydrochloric acid (4257 mL) was added dropwise to the residue, and 1M hydrochloric acid (3000 mL) was further added dropwise. After partitioning and extraction with ethyl acetate, the organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (229 g) as a brown oil.
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][CH3:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH2:11]([C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:12]
Reactant: CCOC(=O)Cn1ccnc1CC
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CCc1nccn1CC(=O)NN
Yield: 94 %

Procedure:
As described for example 112a, (2-ethyl-imidazol-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 6 h. Evaporation of all volatiles and crystallization from methanol/diisopropylether afforded the title compound as a white solid (yield: 94%). MS: m/e=169.3 [M+H]+.