Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:42]2[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 66 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 of Example 100 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=2:1) to obtain the title compound (66%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:44][CH:45]=[C:39]([CH:40]=[CH:41]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:48])[CH3:47])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:41][CH:40]=[C:39]([CH:45]=[CH:44]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:47])[CH3:48])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(N)nc2)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
160 mg (0.23 mmol) of tert-butyl(S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate were dissolved in 6 ml of dichloromethane and, after addition of the same volume of TFA, stirred at RT. After 5 h, the mixture was concentrated and purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, mixed with 1N hydrochloric acid, concentrated further and finally freeze dried. 108 mg of the title compound were obtained as hydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:12][C@@H:13]2[NH:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(SC[C@H]2CCC(=O)N2)cc1
Reaction time: 72 h
Yield: 98.3 %

Procedure:
To a solution of (R)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Helvetica Chimica Acta 1990, 73, 122-32; Tetrahedron: Asymmetry 2007, 18, 664-670) (1.05 g, 3.9 mmol) in CH3CN (30 mL) was added 4-methoxybenzenthiol (0.55 g, 3.9 mmol) and Cs2CO3 (5 g, excess). The reaction mixture was stirred for 3 days. To the solution was added EtOAc (50 mL) and H2O (30 ml). The organic phase was separated. The solvents were removed by evaporation to give the title compound as an oil (0.91 g, 98%). TLC and NMR indicated that the product was pure enough for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OB(O)c1cccnc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccnc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and pyridine-3-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [Si](O[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]([O:24][CH2:25][O:26][CH3:27])[CH3:23])[C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:47]1CCCC1>ClCCl>[OH:47][CH2:23][CH:22]([O:24][CH2:25][O:26][CH3:27])[CH2:21][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)[N:18]=[CH:9][C:10]1=[O:28]
Reactant: COCOC(C)Cn1c(=O)c(O[Si](C)(C)C(C)(C)C)nc2ccc(OC)cc21
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COCOC(CO)Cn1c(=O)cnc2ccc(OC)cc21
Reaction time: 3 h
Yield: 80 %

Procedure:
1-[3-{[Tert-butyl(dimethyl)silyl]oxy}-2-(methoxymethoxy)propyl-7-methoxyquinoxalin-2(1H)-one (863 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 ml). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 2.74 ml, 2.74 mmol) was added to this solution under cooling on ice, and the mixture was stirred for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium bicarbonate water. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 495 mg (80%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.CN(C)C=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18](O)=[N:19][CH:20]=1>O>[Br:14][C:15]1[CH:16]=[CH:17][C:1](=[O:4])[N:19]([CH3:18])[CH:20]=1
Reactant: Oc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1cc(Br)ccc1=O
Reaction time: 16 h
Yield: 214.5 %

Procedure:
With cooling with ice, potassium carbonate (5.96 g, 43.1 mmol) and methyl iodide (1.29 mL, 20.7 mmol) were added to a dimethylformamide (50 mL) solution of 5-bromo-2-hydroxypyridine (3.0 g, 7.24 mmol), and stirred at that temperature for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, ethyl acetate/hexane=1/1) to obtain the entitled compound (2.92 g, 90%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].S(=O)(=O)(O)[OH:17].N>>[OH2:17].[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([NH2:15])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Cc1[nH]c(-c2ccccc2)nc1CC#N
Agent: N
Product: Cc1[nH]c(-c2ccccc2)nc1CC(N)=O
Product: O

Procedure:
A mixture of 9.86 (0.05 mole of 5-methyl-2-phenyl-4-imidazoleacetonitrile and 15 ml of concentrated sulfuric acid is stirred and warmed on a steam bath until solution is complete (about 25 minutes). The warm mixture is poured onto excess ice and basified with a slight excess of concentrated aqueous ammonia. Recrystallization from ethanol (95%)-water affords the product, 5-methyl-2-phenyl-4-imidazoleacetamide hydrate, m.p. 186°-188°C. The melting point can be changed to 202°-4°C by thoroughly grinding in an agate mortar. The product can also be made to melt over the range of about 186°-204°C by very slowly raising the oilbath temperature. Treatment with mineral acid, e.g., sulfuric or hydrobromic acid, affords the corresponding acid addition salt.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15][C@H:14]1[CH2:23][OH:24]>ClCCl>[CH:20]1([CH2:19][C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C@H:14]([CH2:23][OH:24])[CH2:15]2)[CH2:21][CH2:22]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.6 g, 3.7 mmol) was added drop-wise to a solution of rel-[(2S,4R,5S)-5-amino-2-(cyclopropylmethyl)-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C71) (1.10 g, 3.7 mmol) in dichloromethane (30 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 1.14 g, 2.47 mmol, 67%. LCMS m/z 461 [M+H+].
Reaction SMILES: C([C@H:5]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:33])[CH:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28]([NH2:32])=[N:27][CH:26]=[CH:25]3)=[O:21])[CH3:18])[CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:32][C:28]1[C:29]2[C:24](=[CH:23][C:22]([C:20]([NH:19][C@@H:17]([CH3:18])[C:16]([N:13]3[CH2:12][CH2:11][CH:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])[CH2:15][CH2:14]3)=[O:33])=[O:21])=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CC(NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 594 mg of tert-butyl (S)-[[1-(2-[[(1-amino-6-isoquinolinyl)carbonyl]amino]-1-oxopropyl)piperidin-4-yl]oxy]acetic acid in 8 mL of dioxane was added 3 mL 36% hydrochloric acid and stirred at room temperature for two hours. The solution was concentrated and trituration of the residue with diethyl ether yielded 560 mg of the title compound. HPLC Supelcosil LC-18-DB column using a gradient elution system of 20% A/80% B to 20% A/20% B/60% C over 40 min at a flow of 0.25 ml/min (A: 0.5M phosphate buffer pH 2.1, B: water, C acetonitril/water 3/2 v/v). Rt=22.4 min.
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)CC1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C1C=CC=CC=1.[CH2:35]([O:37][C:38](=[O:61])[CH:39](OC(=O)C)[C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:61])[CH2:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]
Reactant: CCOC(=O)C(OC(C)=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 61 %

Procedure:
According to the procdure described in Example 13 for the preparation of (4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-acetoxy-2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester was hydrogenolyzed to provide in 61% yield 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester as a white solid, mp 77-78° C. 1H NMR: δ 7.71 (d, 2H, J=8.5 Hz), 7.63-7.59 (m, 4H), 7.45 (t, 2H, J=7.4 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.64 (d, 1H, J=2.9 Hz), 6.34 (d, 1H, J=3.3 Hz), 4.22 (q, 2H, J=7.2 Hz), 3.76 (s, 2H), 1.30 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H18O3 : C, 78.41; H, 5.92. Found: C, 78.16; H, 5.92.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1.CI>O>[Br:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][O:16][CH3:3])[CH:10]=1
Reactant: OCc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1cncc(Br)c1
Reaction time: 1 h

Procedure:
Sodium hydride (61% in oil) (11 mg) was added to a DMF (0.9 ml) solution containing (5-bromopyridin-3-yl)methanol (34 mg) under ice cooling, followed by stirring for 1 hour. Then, methyl iodide (17 μl) was added, followed by stirring at room temperature for 13 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a light yellow solid of 3-bromo-5-(methoxymethyl)pyridine (26.5 mg) was thus obtained.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[O:8].[C:12](O)(=O)C>O1CCCC1>[CH3:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH:7]([OH:8])[CH3:12]
Reactant: CC(=CC=O)C(C)C
Reactant: CC(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)CC(C)C(C)C
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Methylmagnesium chloride (CH3MgCl) in tetrahydrofuran (THF) (3 M, 1.8 L) was charged into a flame-dried 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a dropping funnel. The reaction flask was cooled with an external bath to about 15-20° C. 3,4-Dimethyl-pentenal (prepared as above) (422 g) was fed over about 2-3 hours to allow the exotherm temperature at about 30-35° C. After the feeding was completed, the reaction mass was aged for about 2 hours. GC analysis determined a conversion rate of about 96%. The reaction mixture was poured into a mixture of ice and acetic acid (300 g). The organic layer was separated and washed sequentially with brine (500 mL) and sodium carbonate (5%, 300 mL), and further fractional distilled to provide 4,5-dimethyl-hexan-2-ol (410 g) with a boiling point of 114° C. at 90 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:19][CH2:18][CH2:17][CH2:16][C@@:13]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:38])=[O:37]
Reactant: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a solution of (R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.046 mmol) in CH2Cl2 (2 mL) was added Et3N (13 μL, 2 equiv) and MsCl (6 μL, 1.55 equiv) at 0° C. After 5 min, the mixture was warmed to rt and stirred for 1 h. The mixture was concentrated, acidified with 5% aq HCl to pH=˜6 and purified by preparative HPLC to afford 3-((R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (6.8 mg, 29%). LC-MS (3 min) tR=1.83 min., m/z 514, 516 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:6]1[CH:7]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:21]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1ccco1
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1ccco1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
Furan-2-yl-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 2-furoyl chloride, and indole according to GP 2. Yield, 72%. 1H-NMR (DMSO-d6): δ=6.19 (“d”, J=2.1 Hz, 1H), 6.51 (dd, J=3.4 Hz, J=1.7 Hz, 1H), 6.61 (d, J=7.9 Hz, 1H), 6.71 (d, J=3.4 Hz, 1H), 6.95-7.08 (m, 3H), 7.17-7.27 (m, 2H), 7.41 (“t”, J≈7.5 Hz, 1H), 7.48-7.56 (m, 2H), 7.63-7.65 (m, 2H), 7.88 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 10.70 (s, 1H); (+)-ESI-MS: m/z=391 [M+H]+, 274 [M-indole+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([CH3:43])[C:40]([NH2:42])=[O:41])#[CH:32].F[B-](F)(F)F.CCN(CC)CC>O1CCOCC1.[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>[NH2:42][C:40](=[O:41])[CH:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]#[C:32][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1)[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate K8 (2.054 g, 4.597 mmol), 2-(2-ethynylphenyl)propanamide K7 (1.027 g, 5.929 mmol), CuI (0.017 g, 0.089 mmol), PdCl2(PPh3)2 (0.062 g, 0.088 mmol) and t-Bu3PH.BF4 (0.025 g, 0.087 mmol) in dioxane (20 mL) and Et3N (2.5 mL, 18 mmol) under a nitrogen atmosphere was heated in the microwave at 110° C. for 40 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (50-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A65 (2.121 g, 79%). 1H NMR (400 MHz, d6-DMSO) δ 10.48-10.33 (m, 1H), 8.82-8.73 (m, 1H), 8.09-7.97 (m, 1H), 7.64-7.55 (m, 2H), 7.56-7.44 (m, 2H), 7.41-7.34 (m, 1H), 7.29-7.22 (m, 1H), 7.01 (s, 1H), 4.39-4.29 (m, 1H), 4.18-3.99 (m, 3H), 2.99-2.80 (m, 2H), 2.02-1.94 (m, 2H), 1.83-1.70 (m, 2H), 1.41 (s, 9H), 1.39-1.31 (m, 3H).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC>O1CCCC1>[CH3:13][C:9]1[N:8]=[C:7]([C:6]2[C:2]([B:17]([OH:22])[OH:18])=[C:3]3[CH2:16][CH2:15][CH2:14][N:4]3[N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3c(c2B(O)O)CCC3)n1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 72.3 %

Procedure:
Place tetrahydrofuran (28.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.44 g, 5.18 mmol) and triisopropyl borate (3.10 mL, 13.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.4M n-butyllithium in hexanes (8.80 mL, 12.4 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (10 mL) and extract with chloroform (2×100 mL). Combine the organic layers, dry over solid sodium chloride, and remove the solvent under reduced pressure to afford an oil. Purify the oil by normal phase flash chromatography (120 g Biotage KP-Sil 40L: 100% ethyl acetate in hexanes for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to yield 910 mg (73%) of the title compound. MS ES+ m/e 244 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O.[CH3:17][N:18]=[C:19]=[O:20]>C1COCC1>[CH:14]1([C:12]2([CH3:11])[N:18]([CH3:17])[C:19](=[O:20])[N:6]3[C:2](=[N:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=43)[NH:1]2)[CH2:16][CH2:15]1
Reactant: CC(=O)C1CC1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CN1C(=O)n2c(nc3ccccc32)NC1(C)C1CC1

Procedure:
2-Aminobenzimidazole, cyclopropyl methyl ketone and methyl isocyanate were reacted as in Example 26 using THF as a cosolvent with the excess ketone. Working up the reaction mixture gave none of the expected 10-N-methylcarbamoyl derivative of the title compound but, rather, the title compound itself, recrystallized from acetone to give a solid, mp 200° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[CH2:13]([C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][O:25][B:26](OC)[O:27][CH3:28].OCC(C)(CO)C>C1COCC1>[CH2:13]([C:19]1[CH:23]=[C:22]([B:26]2[O:27][CH2:28][C:5]([CH3:6])([CH3:7])[CH2:24][O:25]2)[S:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCc1ccsc1
Reactant: COB(OC)OC
Reactant: CC(C)NC(C)C
Agent: CC(C)(CO)CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1csc(B2OCC(C)(C)CO2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Diisopropylamine (7 ml, 50 mmol) was dissolved in dry THF (200 ml). The mixture was cooled down to 0° C., at which point n-BuLi (31 ml 1.6 M, 50 mmol) was added. After stirring the mixture at 0° C. for 30 min, it was cooled down to −78° C. and 3-hexylthiophene (8.1 ml, 45 mmol) was added dropwise. After stirring at −78° C. for 1 h the reaction was let warm up to room temperature, and the mixture was stirred for 1 h. Then, the reaction was cooled down to −78° C., and trimethylborate (15 ml, 134 mmol) was added. After 10 min, the reaction was warmed up to room temperature, and stirred overnight. Quenching with 10% HCl/H2O (40 ml) followed, and the aqueous layer was extracted with ether. The ether phase was washed with water, brine, dried over magnesium sulfate and the solvent was removed under vacuum. 250 ml toluene were added to the remaining oil, followed by neopentyl glycol (7.02 g, 67.4 mmol). The mixture was sparged with argon, and heated up to 100° C. After 24 h, the solvent was removed under reduced pressure. Hexanes were added to the remaining residue, and the hexanes phase was purified by column chromatography (99:1 to 97:3 hexanes:acetone). The product was obtained as a colorless oil (9.9 g, 79% yield). 1H-NMR (ppm, CDCl3): 0.85 (3H, t, J=6.24 Hz), 1.00 (6H, s), 1.22-1.33 (6H, m), 1.59 (2H, m), 2.59 (2H, t, J=7.76 Hz), 3.73 (4H, s), 7.13 (1H, s), 7.38 (1H, s); 13C-NMR (ppm, CDCl3), 14.1, 21.9, 22.6, 29.0, 30.1, 30.6, 31.7, 32.0, 72.4, 122.9, 126.5, 137.0, 144.5; ESI-MS (m/z) found: 218.1742 [M+H], calculated: 218.1753.