Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C@@H:16]2[C:26]3([CH2:28][CH2:27]3)[C@H:25]3[C@@H:18]([O:19][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:23][CH2:24]3)[C@@H:17]2[F:41])[C:10]1=[O:42])(=O)C1C=CC=CC=1>CO.N.C(O)(C(F)(F)F)=O.O>[F:41][C@H:17]1[C@H:18]([OH:19])[C@@H:25]([CH2:24][OH:23])[C:26]2([CH2:27][CH2:28]2)[C@H:16]1[N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:42]
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@H](n1ccc(=O)n(C(=O)c3ccccc3)c1=O)C21CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=c1ccn([C@H]2[C@@H](F)[C@H](O)[C@@H](CO)C23CC3)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 28 (0.2 g, 0.32 mmol) was dissolved in saturated MeOH with NH3 (20 mL) and stirred for 8 h at room temperature. The solvent was evaporated under vacuum and the residue was purified by silica gel vacuum column (35% EtOAc/hexane) to give the debenzolated compound. Debenzoylated compound was dissolved in 10 mL of CF3COOH/H2O (2:1, v/v) and heated to 50° C. for 3 h. The solvent was removed under vacuum and the residue was co-evaporated with ethanol (3×10 mL) under vacuum. The residue was purified by combiflash chromatography (7% MeOH/CH2Cl2) to give 29 in 60 mg (68%) as white foam. [α]24D 5.4° (c 0.67, MeOH); 1H NMR (500 MHz, DMSO-d6) δ 11.17 (bs, 1H), 7.68 (d, J=15.6, 1 H), 5.80 (d, J=19.7, 1H), 5.67 (d, J=14.5 Hz, 1 H), 4.74-4.78 (bs, 2H, —OH), 4.70 (m, 1H), 4.10-4.13 (bm, 1 H, —OH), 3.32-3.43 (m, 2 H), 2.1-2.08 (m, 1 H), 0.69-0.74 (m, 1 H), 0.49-0.56 (m, 2 H), 0.43 (m, 1 H); 13C NMR (500 MHz, MeOH-d4) δ 164.9, 161.4, 152.3, 140.2, 109.6, 76.0, 74.0, 60.2, 51.4, 21.1, 14.7, 11.0, 7.3; HR-MS Cald. For (C12H15FN2O4+H)+ 270.16. found 270.1226.
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The hydrolysis of lactose requires the incorporation of equal moles of water and lactose to yield one mole each of glucose and galactose. Neutral lactase enzyme (2600-4000 units per liter (MaxiLact)) is injected into the milk concentrate to hydrolyze the lactose sugar into glucose and galactose. Preferably, a minimum of 70% of the lactose must be hydrolyzed and the desired level is in the 98% range. This process reduces water activity by decreasing the amount of water and by increasing the number of moles of sugar dissolved in the concentrate. Since lactose solubility is about 21.6%, a 4× concentration of milk is the practical limit of concentration using conventional technology. Further concentration results in graininess, crystallization and viscosity increases. Furthermore, the insoluble lactose must be subtracted from the water activity equation since it is no longer dissolved.
Reaction SMILES: [Li+].[OH-:2].O.OO.C([C@@H]1COC(=O)N1[C:19](=[O:41])[C@@H:20]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH2:21][N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1>C1COCC1>[C:25]([O:24][C:23]([N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:21][C@H:20]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:19]([OH:41])=[O:2])=[O:29])([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1

Procedure:
LiOH (1.41 g, 33.5 mmol) was added to a flask containing THF (360 mL) and H2O (120 mL), which was stirred until dissolved. At this point, the reaction was cooled to 0° C. with ice, and hydrogen peroxide (35 wt. %, 6.52 g) was added. This solution was stirred for 10 minutes, at which point tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (8.6 g, 16.8 mmol) was added as a solution in THF (20 mL). The reaction was stirred overnight with warming. The reaction was quenched by the addition of 10% aqueous Na2SO3 (1 mL) and saturated aqueous NaHCO3 (1 mL) and stirred for 10 minutes. The reaction was concentrated to remove THF and the aqueous layer extracted with ether (3×). The aqueous layer was diluted with EtOAc and acidified with 1N HCl. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried with MgSO4 and concentrated to give the crude product, (S)-3-( tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid as a clear oil (LCMS (APCI+) [M-Boc+H]+ 254.1; Rt: 3.03 min).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[OH:15]S(O)(=O)=O.N([O-])=O.[Na+]>Cl.O>[OH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c2ccccc12
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Stir a slurry of 1-amino-4-nitroisoquinoline H2SO4 (120 g, 418 mmol) in aqueous HCl (6 N, 2 L) mechanically under nitrogen at 35° C. Add a solution of NaNO2 (72.1 g, 1044 mmol) in water (300 mL) over 1 hour while warming the slurry to 50° C. Heat the mixture an additional 30 minutes then allow to cool to room temperature and stir overnight. Heat the mixture to 50° C., then add a solution of NaNO2 (36 g in 150 mL of water) over 30 minutes. Stir the mixture for 2 hours then heat to 60° C., allow to cool slowly to room temperature over 3 hours. Filter the resulting slurry, and wash the cake with water (3×600 mL). Partially air-dry (180 g). Slurry the wet solid in i-PrOH (1 L) and EtOH (1 L) at reflux, add THF (350 mL) to effect complete dissolution. To the solution add water (400 mL), and cool to 10° C. over 3 hours. Filter and wash with EtOH (2×300 mL), then diethyl ether (3×150 mL). Air-dry overnight to afford 1-hydroxy-4-nitroisoquinoline (62.62 g, 79% yield) as a light brown solid. (ES+): m/z 191 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12].C(NC)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([N:13]([CH2:11][CH3:12])[CH3:14])=[O:9])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ncc(Br)cn1
Agent: CCNC
Solvent: ClCCl
Product: CCN(C)C(=O)c1ncc(Br)cn1
Temperature: 25 °C

Procedure:
5-Bromo-pyrimidine-2-carbonyl chloride (1600 mg, 7.225 mmol) was dissolved in dichloromethane (25 ml) and triethylamine (4.03 ml, 28.9 mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml) followed by 10% citric acid (50 ml) and brine (50 ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3): (1.4 g, 79.4%) as a brown oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([N:15]=[C:16]=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>CCOCC>[OH:2][CH2:1][CH2:3][NH:4][C:16]([NH:15][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:17]
Reactant: NCCO
Reactant: O=C=NC1CCCc2ccccc21
Solvent: CCOCC
Product: O=C(NCCO)NC1CCCc2ccccc21

Procedure:
To a stirred solution of 2.42 grams (0.04 mole) or ethanolamine in 200 ml. of ether is added a solution of 6.95 grams (0.04 mole) of 1,2,3,4-tetrahydro-1-naphthyl isocyanate in 150 ml. of ether over a period of 30 minutes. Additional ether is added to facilitate stirring as the product precipitates. One hour after the isocyanate addition is complete, the mixture is filtered. The filter cake is washed with ether and dried to give 8.61 grams white solid, melting point 146° C. to 149° C. Recrystallization from nitromethane gives the analytical sample, melting point 147° to 149° C. Analysis calculated for C13H18N2O2 : C, 66.64; H, 7.74; N, 11.96. Found: C, 66.35; H, 7.78, N, 11.90.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:30]([NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Reactant: O=C=Nc1ccccc1
Product: CCCCCCCCc1ccc(N(Cc2ccccc2)C(=O)Nc2ccccc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-octylphenyl)amine (2.0 g) and phenylisocyanate (0.91 mL) as starting materials, N-benzyl-N-(4-octylphenyl)-N′-phenylurea (1.9 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][O:11][C:12]([CH2:14][C:15](=[CH2:19])[C:16]([O-:18])=[O:17])=[O:13].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:19][CH:15]([CH2:14][C:12]([O:11][CH3:10])=[O:13])[C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CSc1ccc(Cl)c(Cl)c1)C(=O)O

Procedure:
A mixture of 3,4-dichlorobenzenethiol (1.15 ml), sodium 3-methoxycarbonyl-2-methylenepropionate (1.50 g), methanol (40 ml), and triton B (40% methanol solution, 5 drops) was refluxed for 20 hours. The reaction mixture was concentrated in vacuo. To the resulting residue was added a diluted hydrochloric acid, and a separated oil was extracted with diethyl ether. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 2.34 g of 3-(3,4-dichlorophenylthio)-2-methoxycarbonylmethylpropionic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16](OC=C)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C=COC(=O)CCCCC
Agent: CCOC(=O)CC(O)c1ccc(Cl)cc1
Product: CCCCCC(=O)OC(CC(=O)OCC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 312 h

Procedure:
The mixture of 5.0 g of ethyl 3-(4-chlorophenyl)-3-hydroxypropionate, 1.6 g of vinyl caproate and 2.0 g of lipase PS was stirred at room temperature for 13 days. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 2.1 g of (-)-ethyl 3-(4-chlorophenyl)-3-hydroxypropionate and 2.7 g of (+)-ethyl 3-(4-chlorophenyl)-3-caproyloxypropionate, respectively.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH2:28][C:29]#[N:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:19]=[C:20](/[C:28](=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([OH:7])=[CH:15][CH:14]=2)/[C:29]#[N:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCCOCOc1ccc(C=O)cc1
Product: N#C/C(=C\c1ccc(O)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 17.1 %

Procedure:
4-Methoxyethoxymethoxybenzaldehyde (420 mg) and 3,5-bis(trifluoromethyl)phenylacetonitrile (506 mg) were subjected to condensation in accordance with process A of (production process 2), and the resultant product was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (122 mg, yield: 17%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH3:11])[N:10]=[C:4]2[CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]([OH:33])[C:8]3[N:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]4=[N:10][C:9]=3[CH3:11])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: Cc1nc2cc(Br)ccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(Br)ccn34)cc2COc2cc(F)ccc21
Yield: 100.8 %

Procedure:
[step 3] Using 7-bromo-3-iodo-2-methylimidazo[1,2-a]pyridine (3.2 g, 9.5 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.7 g, 5.9 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{3-fluoro-8-[hydroxy(7-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.0 g, 99%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(OCc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-benzyloxyaniline (97 mg, 0.486 mmol) similar to Example 13 and isolated as a yellow oil (161 mg, 90%). 1H NMR (CDCl3): 8.78-8.76 (m, 1H), 8.48-8.45 (m, 1H), 7.79-7.74 (m, 1H), 7.68 (s, 1H), 7.42-7.29 (m, 6H), 7.24 (t, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J=0.8, 8.0 Hz, 1H), 6.77-6.74 (m, 1H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[N:7]([N:8]=[C:9]([C:15]4[N:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:17]=[CH:18][N:19]=4)[CH:10]=3)[C:6]=2[CH:25]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[N:7]([N:8]=[C:9]([C:15]5[N:16]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:17]=[CH:18][N:19]=5)[CH:10]=4)[C:6]=3[CH:25]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 80 °C
Yield: 89.8 %

Procedure:
9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (207 mg, 0.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (232 mg, 0.75 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (10 mol %), and potassium carbonate (138 mg, 1.0 mmol) were charged to a reaction vial, the atmosphere evacuated and back-filled with nitrogen. DMF (1 mL) was added, degassing repeated, and the mixture heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 20 to 60% ethyl acetate in cyclohexane) to give 4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert butyl ester as a white crystalline solid (232 mg, 90%). LCMS: RT=4.87 min, M+H+=517.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[CH:9]=[C:10](I)[C:3]=12.Cl.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1)[N:30]([CH3:43])[CH2:29][CH2:28]2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.CO.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:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[CH:9]=[C:10]([C:33]3[CH:32]=[C:31]4[C:27]([CH2:28][CH2:29][N:30]4[CH3:43])=[CH:26][C:25]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Br)ccnc32)C1
Reactant: CN1CCc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: CN1CCc2cc(F)c(-c3cn(C4CN(C(=O)OC(C)(C)C)C4)c4nccc(Br)c34)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a mixture of tert-butyl 3-(4-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (D31) (118 mg, 0.247 mmol), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline, hydrochloride (85 mg, 0.271 mmol) in DME (2 mL) and MeOH (0.222 mL) was added bis(triphenylphosphine)palladium(II) chloride (17.32 mg, 0.025 mmol) and 2M sodium carbonate aq. solution (1.234 mL, 2.468 mmol). The mixture was stirred at 60° C. for 1 hour. The mixture was cooled to RT. Water (30 mL) was added and was extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered and solvent removed in vacuo to give a residue which was purified on normal phase chromatography eluting with ethyl acetate in cyclohexane (0-50%) to give the title compound (84 mg). LCMS (A): m/z (M+H)+ 501/503, C24H26BrFN4O2 requires 500/502 (acidic).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC>CN(C)C=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:25]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C#N)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 57.3 %

Procedure:
To a solution of 300 mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production Example I-14-b in 10 ml dimethylformamide were added 376 mg of tri-n-butyl(phenyl)tin and 54 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 150° C. for 45 minutes. After removing the solvent by distillation, the residue was dissolved in 1.5 ml of ethyl acetate and the mixture was adsorbed by 1.5 g of silica gel. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=3:97 to 1:19) and the resulting amorphous powder was crystallized from diisopropyl ether, to give 117 mg of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:17]([O:19]CC)=O.[CH2:22]([N:25]=[C:26]=[S:27])[CH:23]=[CH2:24].[OH-].[K+]>C(O)C.O>[CH2:22]([N:25]1[C:17](=[O:19])[C:3]2[C:4]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:1][C:26]1=[S:27])[CH:23]=[CH2:24]
Reactant: C=CCN=C=S
Reactant: CCOC(=O)C1=C(N)c2ccccc2CC12CCCCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Temperature: 85 °C

Procedure:
Ethyl 4′-amino-1′H-spiro[cyclohexane-1,2′-naphthalene]-3′-carboxylate 18 (Scheme 8, 1.66 g, 5.82 mmol) and allyl isothiocyanate (0.600 ml, 6.13 mmol) were dissolved in Ethanol (9.69 ml) and refluxed at 85° C. for 10 h. A solution of potassium hydroxide (0.653 g, 11.63 mmol) in Water (9.69 ml) was then added and the reaction mixture was refluxed for 3 h. The cooled r×n mixture was acidified to pH 3.0-3.5. The precipitate was filtered off, washed with water and recrystallized from butanol.
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:38]>>[CH3:38][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:18][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:32]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:39])=[O:20]
Reactant: Oc1cccc(C(F)(F)F)c1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3cccc(C(F)(F)F)c3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-3-trifluoromethyl-phenol and 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 111 mg (6%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O5F3 508, found 509 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Cl.[CH2:47]([N:54]1[CH:58]=[CH:57][N:56]=[C:55]1[CH2:59]Cl)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:59][C:55]4[N:54]([CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[CH:58]=[CH:57][N:56]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine (5 mmol) and 1-benzyl-1H-imidazol-2-ylmethylchloride hydrochloride to give the title compound.