Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:30])([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]([CH3:30])([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)(C)S(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)(C)S(N)(=O)=O
Reaction time: 14 h
Yield: 34.2 %

Procedure:
Dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.26 g, 0.53 mmol) and pyridine-3-boronic acid (0.78 g, 0.63 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at 100° C. for 31 hours, at which time additional palladium acetate (0.002 equivalent) was added. Heating was resumed for 14 hours, and then additional pyridine-3-boronic acid (0.3 equivalent) was added. The reaction was heated for another 22 hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with ethyl acetate and isolated by filtration. The product was finally recrystallized from isopropanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.090 g of dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 159-160° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(O)[CH2:31][CH2:32][OH:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:29][Si:2]([CH3:1])([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:31][CH2:32][OH:33])=[O:23])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1

Procedure:
A mixture of 2.2 g. of methyl 4-[14-(trimethylsilyl)tetradecylamino]benzoate, 280 mg. of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22].C(OCC)(=O)C>C(#N)C.O>[CH2:11]([O:10][C:8]([C:7]1[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4][N:5]([CH2:21][CH3:22])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC)nc1C(F)(F)F

Procedure:
Ethyl 3-trifluoromethylpyrazole-4-carboxylate (5 g), potassium carbonate (3.48 g) and ethyl iodide (2.3 ml) in acetonitrile were heated at reflux overnight. After cooling, ethyl acetate and water were added and the organic phase separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to give a yellow oil which was purified by crystallisation in hexane to produce 4-ethoxycarbonyl-1-ethyl-3-trifluoromethylpyrazole as white crystals (3.65 g), 1H NMR (CDCl3) δ1.25(3H,t), 1.45(3H,t), 4.10(2H,q), 4.20(2H,q) 7.90(1H,s) ppm.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:9]1([CH:8]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:15]#[N:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cccnc1
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1cccnc1

Procedure:
The compound was prepared substantially in accordance with the procedure in Example 12A, using 3-chloropyridine (9.5 ml, 100 mmol), benzyl cyanide (11.6 ml, 100 mmol) and potassium t-butoxide (22.4 g, 200 mmol) in 200 ml of DMF.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH2:11])[CH:7]=[CH:8]2)=[N:3]1.C[Al](C)C.C1(C)C=CC=CC=1.C[O:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([NH:43][CH3:44])=[O:42])[CH:35]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCCl>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:25](=[O:24])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][C:27]=3[NH:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([NH:43][CH3:44])=[O:42])[CH:35]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(N)cc2n1
Reactant: CNC(=O)Nc1cc(CNc2ncccc2C(=O)OC)ccn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CNC(=O)Nc1cc(CNc2ncccc2C(=O)Nc2ccc3cn(C)nc3c2)ccn1
Temperature: 85 °C
Yield: 52.9 %

Procedure:
A suspension of 2-methyl-2H-indazol-6-ylamine [Davies J. Chem. Soc.; 1955; 2412-2419] (809 mg, 5.5 mmol) in DCE (13.5 mL) was treated at 0° C. consecutively with, trimethylaluminium (2 M) in toluene (4.23 mL, 8.46 mmol), 2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methyl ester (1.34 g, 4.23 mmol) and DCE (20 mL). The reaction mixture was placed under a nitrogen atmosphere and heated for 10 hours at 85° C. (bath temperature). On cooling the reaction was poured into aqueous sodium-potassium tartrate solution (150 mL) and partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (Gradient elution: 100% CH2Cl2 to 90% CH2Cl2/10% MeOH) to give N-(2-methyl-2H-indazol-6-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide (964 mg, 53%) as a solid; Mp. 205-207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (505 mg, 2.348 mmol) and cesium carbonate (1339 mg, 4.11 mmol) in DMF (5 ml) was added benzyl bromide (0.351 ml, 2.94 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed 2 times with water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 709 mg of 1-[2-(benzyloxy)-5-bromophenyl]ethanone, 703 mg (2.304 mmol) of which were combined with BISPIN (731 mg, 2.88 mmol), PdCl2(dppf) (202 mg, 0.276 mmol), and potassium acetate (452 mg, 4.61 mmol) in 1,4-dioxane (2 ml)/DMSO (10 ml). The mixture was heated at 80° C. overnight. The solids were filtered through a silica plug washing with EtOAc. Water was added and the filtrate was extracted 3 times with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 634 mg of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone. A mixture of 64 mg (0.182 mmol) of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone, 63 mg (0.105 mmol) of (4S,5R)-3-{[6-azetidin-1-yl-3-(5-chloro-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 27), potassium carbonate (1M aqueous) (0.400 ml, 0.400 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (15 mg, 0.023 mmol) in 1,4-dioxane (1.5 ml) was heated at 120° C. with microwaves for 4 hours, then transferred to an oil bath at 120° C. overnight. The mixture was filtered through a silica plug, washing with EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. Mass spectrum (ESI) 790.6 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[CH:2].[Br:13][C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:17](I)=[CH:16][N:15]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[N:15]=[CH:16][C:17]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:11])([F:12])[F:10])[CH:7]=3)[N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]=2[CH:19]=1
Reactant: C#Cc1cnn(CC(F)(F)F)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(-c2cnn(CC(F)(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 148, 326 mg 1.87 mmole) was dissolved in DMF (4.9 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 565 mg 1.50 mmole) was added. To the solution was added triethylamine (0.91 mL, 655 mg 6.5 mmole) and copper(I) iodide (10 mg 0.052 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37 mg 0.052 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 110 minutes. The reaction was cooled and added to water (50 ml). The reaction were extracted with ethyl acetate thrice (3×20 ml). The combined organic extracts were washed with water (3×20 mL) and brine, dried and concentrated in vacuo. The residue was purified using column chromatography eluting with 100% dichloromethane, 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to afford the title compound (300 mg, 47%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.80 (q, J=8.20 Hz, 2H), 6.76 (d, J=0.95 Hz, 1H), 7.84 (d, J=0.63 Hz, 1H), 7.94 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3, 470.385 MHz): −71.56.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10].[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([OH:34])[C:32]4[C:27](=[CH:28][C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([O:34][C:12]([NH:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[C:32]4[C:27](=[CH:28][C:29]([C:35]([F:37])([F:38])[F:36])=[CH:30][CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CCCCN=C=O
Reactant: O=C1c2cc(C(F)(F)F)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCNC(=O)OC1c2ccc(C(F)(F)F)cc2C(=O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Pyridine (10 cc.) and butyl isocyanate (11.2 cc.) are added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-6-trifluoromethyl-isoindolin-1-one (3.8 g.) in acetonitrile (380 cc.). The mixture is heated to the reflux temperature and triethylamine (0.5 cc.) is added. Refluxing is continued for 50 minutes until dissolution. After cooling the solution, the precipitate formed is filtered off and washed with water (30 cc.). After drying, a first crop of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-n-butylaminocarbonyloxy-6-trifluoromethyl-isoindolin-1-one (2.8 g.) is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17](Cl)[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CCCl
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)CCN1CCN(c2ccc(C(C)(C)C)cc2)CC1

Procedure:
5 g (22.9 millimoles) of N-(4-tert-butylphenyl)-piperazine, 8.3 g (68.7 millimoles) of neohexyl chloride, 3.2 g (22.9 millimoles) of potassium carbonate and 3.8 g (22.9 millimoles) of potassium iodide are stirred for 16 hours at 140° C. The mixture is taken up in dichloromethane and dilute sodium hydroxide solution. The organic phase is washed, dried over sodium sulfate and evaporated down under reduced pressure, and the residue is chromatographed over silica gel using 1:1 methyl tert-butyl ether/hexane to give 1.5 g (22% of theory) of a colourless oil (for IR data, see Table 1a).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and benzoyl chloride (53 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 30 mg of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamideas a brown oil (Yield: 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.O.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:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]=2[F:33])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccccc4)cc23)c1F
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To 5-bromo-3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (32, 55.0 mg, 0.10 mmol) in tetrahydrofuran (10 mL) were added 1.0 M potassium carbonate in water (3.5 mL), phenylboronic acid (18.8 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) under an atmosphere of nitrogen. The reaction was stirred at 65° C. for 3 hours, and then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude compound 33 that was used in the next step.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2[CH2:16]O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:16][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Cc1ccccc1-c1noc(C2CC2)c1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccccc1-c1noc(C2CC2)c1CBr

Procedure:
Into a 100 mL round bottom flask was placed (5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methanol (1.86 g, 8.11 mmol), triphenylphosphine (3.50 g, 12.2 mmol, 1.5 equiv) and dichloromethane (50 mL). The mixture was stirred until completely dissolved, and then slowly cannulated dropwise into a stirring solution of carbon tetrabromide (4.00 g, 12.2 mmol, 1.5 eq) in dichloromethane (20 mL). The solution was stirred for one hour and the solvent was then evaporated in vacuo. The crude residue was purified by silica gel chromatography using a 0-50% gradient of ethyl acetate/hexanes. The desired product was obtained as a yellow oil. MS m/z 292.0/294.0 (M+1, Br79/Br81 isotope pattern).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:39]=[O:40])[S:37][CH:38]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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:39]([C:36]1[S:37][CH:38]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:22])[CH2:16][CH2:15]2)[CH:35]=1)=[O:40]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)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: [Cs+]
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Yield: 85.9 %

Procedure:
A solution of 5-bromo-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (428 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (960 mg, 4 mmol), Cs2CO3 (800 mg, 2.46 mmol), and Pd(PPh3)4 (100 mg, 0.0865 mmol) were heated in a Smith microwave at 160° C. for 20 min. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was washed with MeOH (1×5 mL) to give the title compound (395 mg, 86%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:21]=[N:20][N:19]=4)[S:11][C:10]=3[C:9]=2[CH:31]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:22]1[CH:21]=[N:20][N:19]=[C:18]1[C:12]1[S:11][C:10]2[C:9]3[CH:31]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: COC(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (210 mg) in THF (4 mL) and ethanol (2 mL) was added sodium hydroxide solution (38 mg in 2 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=[C:15]2[C:14]=1Cl)(=[O:12])[NH2:11].[CH3:28][C@:29]1([NH2:37])[CH2:33][CH2:32][C@@H:31]([NH2:34])[C:30]1([CH3:36])[CH3:35]>CN(C)C=O>[NH2:37][C@@:29]1([CH3:28])[CH2:33][CH2:32][C@@H:31]([NH:34][C:14]2[C:15]3[N:16]([CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=3)[N:17]=[CH:18][C:13]=2[C:10](=[O:12])[NH2:11])[C:30]1([CH3:36])[CH3:35]
Reactant: CC1(C)[C@H](N)CC[C@]1(C)N
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
N,N-Diisopropylethylamine (7.18 mL, 41.1 mmol) was added to a mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (3.67 g, 13.71 mmol, from Preparation 4), (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (2.93 g, 20.57 mmol, prepared according to conditions described in Tetrahedron Asymmetry 2001, 12, 1579 and Eur. J. Inorg. Chem. 2006, 839) and N,N-dimethylformamide (50 mL). The mixture was stirred in a 90° C. oil bath for 1 h, quenched with saturated sodium bicarbonate (250 mL) and extracted with ethyl acetate (4×200 mL). The combined extracts were dried (MgSO4), filtered, concentrated and pumped under vacuum. The solid residue was treated with ethyl acetate (60 mL) and sonicated for 10 min. Vacuum filtration gave the first batch of the title compound (2.292 g). The filtrate was concentrated to dryness. The solid residue was treated with dichloromethane (5 mL), ethyl acetate (4 mL) and hexanes (16 mL). The mixture was sonicated for 15 min and filtered. The solid was washed with 20% ethyl acetate in hexanes to give second batch of the title compound (2.146 g). The combined amount of the title compound was 4.438 g (87% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 8.19 (1 H, s), 8.00 (1 H, d, J=1.66 Hz), 7.33 (1 H, d, J=1.66 Hz), 4.47 (1 H, t, J=8.18 Hz), 4.35 (2 H, q, J=7.03 Hz), 2.21-2.49 (1 H, m), 1.77-1.93 (2 H, m), 1.63-1.75 (1 H, m), 1.38 (3 H, t, J=7.21 Hz), 1.21 (3 H, s), 1.07 (3 H, s), 0.96 (3 H, s); MS (ES+) m/z: 374.2 (M+H); HPLC retention time: 2.975 min (analytical HPLC Method F).
Reaction SMILES: C(OC(C(OC(C(C(F)(F)F)(F)F)(F)F)(C(F)(F)F)[F:8])=O)(C)C.[CH:24]([O:33][C:34]([C:36]([O:42][C:43]([C:46]([C:49]([F:52])([F:51])[F:50])([F:48])[F:47])([F:45])[F:44])([C:38]([F:41])([F:40])[F:39])[F:37])=[O:35])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]>C1C=CC=CC=1>[C:24]([O:33][C:34]([C:36]([O:42][C:43]([C:46]([C:49]([F:50])([F:51])[F:52])([F:48])[F:47])([F:44])[F:45])([C:38]([F:40])([F:39])[F:41])[F:37])=[O:35])([C:29]([F:32])([F:31])[F:30])([C:25]([F:28])([F:27])[F:26])[F:8]
Reactant: CC(C)OC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: c1ccccc1
Product: O=C(OC(F)(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h

Procedure:
Further, the same operation was repeated once. The total amount of benzene injected was 0.219 g, and the total amount of R-113 injected was 21 ml. Further, nitrogen was supplied for 1.5 hours. The product was quantified by 19F-NMR, whereby the yield of the above identified compound to (CH3)2CHOCOCF(CF3)OCF2CF2CF3, was 48.1%, and the yield of (CF3)2CHOCOCF(CF3)OCF2CF2CF3 to (CH3)2CHOCOCF(CF3)OCF2CF2CF3, was 19.1%.