Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[CH:19]=[CH:20]OCC.C(O)(C(F)(F)F)=O.Cl.[C:33]([O:37][C:38](=[O:44])[C@@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClC(Cl)C.O.ClCCl>[C:33]([O:37][C:38](=[O:44])[CH:39]([N:40]1[CH2:20][CH2:19][C:5]2[C:4](=[CH:9][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])=[CH:7][CH:6]=2)[C:3]1=[O:24])[CH:41]([CH3:42])[CH3:43])([CH3:35])([CH3:34])[CH3:36]
Reactant: CCOC=Cc1ccc(Oc2ccc(F)cc2F)cc1C(=O)OC
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C)(C)C)N1CCc2ccc(Oc3ccc(F)cc3F)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (1.2 g, 3.8 mmol) in dichloroethane (20 mL) was added 5 ml of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The crude reaction mixture was re-suspended in dichloroethane and D-valine t-butylester HCl (2.05 g, 9.75 mmol), triethylamine (1.36 mL, 9.75 mmol), and tiacetoxyborohydride (2.76 g, 13 mmol) were added. The reaction was stirred at room temperature for fifteen minutes and then at 60° C. for an additional 16 hours. The mixture was diluted with 100 mL dichloromethane and extracted with saturated brine (100 mL). The organic layer was concentrated, loaded onto a silica gel column and eluted with dichloromethane to yield 516 mg (77%) of 2-[7-(2,4-difluoro-phenoxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-butyric acid tert-butyl ester 10 as a light yellow solid. TLC, Rf=0.3 (2% MeOH CH2Cl2); 1H NMR (CDCl3) δ 0.93 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.6 Hz, 3H), 1.45 (s, 9H), 2.24 (m, 1H), 2.93 (m, 2H), 3.52 (m, 1H), 3.75 (m, 1H), 5.00 (d, J=6.7 Hz, 1H), 6.85 (m, 1H), 6.93 (m, 1H), 7.07 (m, 2H), 7.15 (d, J=8.3 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H). M+1 found 432.10; C24H27F2NO4 requires 431.19.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[C:50]([NH:60][C@H:61]([C:66](O)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>CCOC(C)=O.CC#N>[CH2:53]([O:52][C:50]([NH:60][C@@H:61]([CH2:62][CH2:63][S:64][CH3:65])[C:66]([NH:12][C@H:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][C@H:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:67])=[O:51])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Example 1, Alternative Step 9aii: Aminoester 1 (63 g, 0.16M, 1 eq.; the product of reductive deprotection of a known compound—(See e.g. R. J. Cherney, WO 2004/098516 and G. V. Delucca & S. S. Ko, WO 2004/110993) was placed in a round bottom flask and MeCN (500 mL) was added. EDAC (33.1 g, 0.17M, 1.1 eq), HOBt.H2O (21.2 g, 0.16M, 1.0 eq) and N-Cbz-L-methionine (46.7 g, 0.17M, 1.05 eq) were then added followed by TEA (48.0 mL, 0.35M, 2.2 eq). An exotherm to 38° C. was observed. The reaction mass was left to stir at RT. After 30 mins, HPLC indicated complete conversion. The reaction mass was diluted with EtOAc (2.5 L) and washed with KHCO3 (4×500 mL, 20 wt % aq. solution) and brine (500 mL). The organic phase was separated, dried over MgSO4 and concentrated. The residue was dissolved in TBME and reconcentrated to give ethyl (7R,8S)-8-{(2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyr-yl-amino}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 2 as a sticky semi-solid (76.2 g, 98% yield, 93 AP purity). 1H-NMR: (300 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.03 (d, J 9.0 Hz, 1H), 5.66 (d, J 8.0 Hz, 1H), 5.10 (s, 2H), 4.35-4.25 (m, 2H), 4.19-4.04 (m, 2H,), 3.98-3.86 (m, 4H), 2.87-2.80 (m, 1H), 2.55-2.45 (m, 2H), 2.18 (dd, J 14.0 Hz, 7.0 Hz, 1H), 2.08 (s, 3H), 2.05-1.67 (m, 6H), 1.26 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 10.01 min (Compound 2, 93.1 AP). HRMS: m/z 495.2166 [Calc: C24H35N2O7S 495.2165].
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:25]2[N:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[CH:27][CH:26]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(C)C)Oc2ccc(Cl)nc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)CCCC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 515.2 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:8]([C:14]3[C:18](=O)[CH2:17][CH2:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:2].Cl.[CH3:22][O:23][NH2:24]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:8]([C:14]3[C:18](=[N:24][O:23][CH3:22])[CH2:17][CH2:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:2]
Reactant: CC1(C)CN(C2=CCCC2=O)c2cc(C#N)ccc2O1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCC=C1N1CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
In 3 ml of pyridine was dissolved 0.3 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(5-oxo-1-cyclopenten-1-yl)-2H-1,4-benzoxazine followed by addition of 0.26 g of methoxyamine hydrochloride. The mixture was stirred at room temperature overnight and the solvent was then distilled off under reduced pressure. The residue was poured in water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled Off under reduced pressure. Finally the residue was washed with ethanol-ether to give 0.26 g of 6-cyano-3,4-dihydro-4-(5-methoxyimino-1-cyclopenten-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>N1C=CC=CC=1.C(OCC)(=O)C.[Cu-]=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=[Cu-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccccc2n1-c1ccc(C)cc1
Temperature: 120 °C
Yield: 100.1 %

Procedure:
2-Carboethoxy-indole (100 mg, 0.528 mmol, 1.0 eq.) was combined with 4-bromotoluene (0.16 ml, 1.32 mmol, 2.5 eq.) and copper(I) oxide (75.6 mg, 0.528 mmol, 1.0 eq.) in pyridine (0.53 ml, 1M) and heated at 120° C. for 2 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed twice with water, twice with 1N hydrochloric acid and once with aqueous saturated sodium hydrogen carbonate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with chloroform:hexane (1:2) to give the title A compound (147.6 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Cu][C:11]#[N:12].C(N)CN>CN1C(=O)CCC1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: N#Cc1ccc(N)c(F)c1

Procedure:
In NMP, compound [O], commercially available 4-bromo-2-fluoroaniline is cyanated with copper (I) cyanide and the resulting copper complex is decomposed with ethylene diamine (EDA) to yield compound [P], 4-amino-3-fluorobenzonitrile. Compound [P] is reacted with nitrosyl hydrogen sulfate (HSO4 --ONO2), prepared by mixing sodium nitrite and concentrated sulfuric acid in glacial acetic acid, and converted into the corresponding diazonium salt. The diazonium salt is brominated with copper (I) bromide in hydrobromic acid to yield compound [Q], 4-bromo-3-fluorobenzonitrile. Compound [Q] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [R], 4-bromo-3-fluorobenzimidate hydrogen chloride. In ethanol, compound [R] is reacted with gaseous ammonia to yield compound [S], 4-bromo-3-fluorobenzamidine hydrogen chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[C:58]([CH3:61])([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[C:58]([CH3:60])([CH3:61])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(C)(C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)C(C)(C)C)ccc1C(=O)N1CCCC1
Yield: 21 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2,2-dimethylpropylamine in tetrahydrofuran. Yield: 21%; Rfvalue: 0.18 (silica gel; ethyl acetate); C25H29ClN4O2 (452.98); mass spectrum: (M+H)+=453/455 (chlorine isotope).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[N:25]1C=C[CH:28]=[CH:27][C:26]=1CN>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([NH:4][CH2:1][C:2]1[CH:3]=[CH:28][CH:27]=[CH:26][N:25]=1)=[N:6][C:7]([C:23]#[N:24])=[C:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccn1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(NCc3ccccn3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (pyridin-2-ylmethyl)amine in place of allylamine and heating for 35 min instead of 1 h, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:22])=O.N1C=CC=CC=1.C(#N)C>O>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: COC(=O)CCc1oc(Cl)nc1-c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of methyl 3-[4-(3-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]propionate (3.0 g), phosphorus oxychloride (4 mL) was gradually added pyridine (0.86 mL) at room temperature and the mixture was stirred at 90° C. for 3 hrs. The reaction mixture was cooled and acetonitrile was added. The mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-chloro-4-(3-chlorophenyl)-5-oxazolyl]propionate (2.3 g, 72%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH:30][C:31](=[O:33])[CH3:32])[CH2:22][O:23]C1CCCCO1)[CH2:2][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][CH2:17][CH3:18]>CO.Cl>[OH:23][CH2:22][CH:21]([NH:30][C:31](=[O:33])[CH3:32])[CH2:20][O:19][CH2:1][CH2:2][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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC1CCCCO1)NC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCC(CO)NC(C)=O
Reaction time: 24 h
Yield: 83.1 %

Procedure:
A mixture of about 4.69 g of N-[1-[(octadecyloxy)methyl]-2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]acetamide in about 200 ml of methanol and about 4 ml of about 1N hydrochloric acid was stirred for about 24 hours and the methanol removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried and the solvent removed, giving about 3.2 g of the desired title compound, mp 82°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][O:20][C:19]=2[CH3:23])=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][O:20][C:19]=3[CH3:23])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cc1occc1COc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1occc1COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A mixture of (4-fluoro-phenyl)-boronic acid (300 mg, 2.1 mmoles), 3-(4-iodophenoxymethyl)-2-methyl-furan (123) (500 mg, 1.6 mmoles) and potassium acetate (0.6 g) in N,N-dimethylformamide (70 mL) was degassed, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90 mg) and the mixture was agitated at 95° C. for 12 hours under an argon atmosphere. The mixture was concentrated in vacuo, partitioned between water (100 ml) and diethyl ether (200 ml). The aqueous phase was re-extracted with diethyl ether, and the combined etheral phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124 (200 mg) as a solid. This material was used directly.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:19][C:20]1[C:25]([F:26])=[C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:25]([F:26])[C:20]=3[F:19])=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Reactant: CCCCOc1ccc(-c2cnc(Cl)nc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCC)nc3)cn2)c(F)c1F
Yield: 46.3 %

Procedure:
The reaction of 2 mmol of 5-(6-butoxypyridin-3-yl)-2-chloropyrimidine, 2.2 mmol of 2,3-difluoro-4-octylphenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 10 ml of toluene, 5 ml of ethanol and 5 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.42 g (46%) of colorless crystals, X 84 SC 73 SA 162 I.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]3[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[N:17]1.[Li+].[OH-].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]4[CH2:32][CH2:31]4)=[CH:24][CH:23]=3)=[N:17]2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1
Yield: 63.2 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-106 by using N-(4-chloro-3-(3-(4-(cyclopropylethynyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (Example-190, 0.100 g), LiOH (0.100 g), water (2.0 mL), THF (10.0 mL) to afford 0.050 g of the desired product. MS (m/z): 365.83 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a stirred solution of methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (14 g, 34.3 mmol) in anhydrous toluene (400 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (12.5 mL, 13.7 mmol). The mixture was cooled to −35° C. and then a 4.17M solution of catechoborane/toluene (11.7 mL, 48 mmol) was added over the course of 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. At this point the reaction mixture was diluted with EtOAc (300 mL) and treated with sat.aq. Na2CO3 (50 mL). The mixture was stirred vigorously for 10 min. The organic phase was separated and washed with sat. aq. Na2CO3 (5×100 mL), 0.1N HCl (1×100 mL), and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was triturated with ether to obtain 12 g (77%) of the desired (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J=1.8 Hz, 1H), 7.95 (dq, J=7.8, 0.8 Hz, 1H), 7.57 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.95 (s, 1H), 5.79 (s, 1H), 3.87 (s, 3H), 3.59 (d, J=1.8 Hz, 1H), 2.65 (s, 3H). LCMS (M+H)=410 and 412.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[F:26][C:27]1[CH:28]=[C:29]([C:34](=[O:62])[C:35](=[C:53]2[NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[CH:61][C:55]=3[NH:54]2)[C:36]([C:38]2[CH:39]=[C:40]([S:44]([NH:47][C:48](=[NH:52])[CH:49]([OH:51])[CH3:50])(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:30]=[C:31]([F:33])[CH:32]=1>C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]([C:34](=[O:62])[C:35](=[C:53]2[NH:54][C:55]3[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=3[NH:57]2)[C:36]([C:38]2[CH:39]=[C:40]([S:44]([NH:47][C:48](=[NH:52])[C:49](=[O:51])[CH3:50])(=[O:45])=[O:46])[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: CC(O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
Dess-Martin reagent (15 wt. % dichloromethane solution, 0.73 mL) was added to a dichloromethane (2 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide (90 mg), followed by stirring at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-oxopropanimidamide (57 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:14]1([CH3:31])[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)[CH2:12][CH3:13])C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]([C:14]1([CH3:31])[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(Nc2ccc3cnccc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCC(N)C1(C)CCC(Nc2ccc3cnccc3c2)CC1

Procedure:
66 mg (153 μmol) of {1-[4-(Isoquinolin-6-ylamino)-1-methyl-cyclohexyl]-propyl}-carbamic acid benzyl ester (80) were dissolved in 500 μL of dry methanol and 5 mg of palladium on activated charcoal (10%) were added. The mixture was stirred under a hydrogen atmosphere until conversion was complete. The catalyst was filtered off and the reaction mixture was evaporated to dryness to give the title compound, which was purified by reversed phase HPLC (water/acetonitrile) to give 30 mg of pure Example 111 as its trifluoroacetic acid salt. Rt=1.02 min (Method L). Detected mass: 298.2 (M+H+).