Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6](=[N:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].O>CCCCCC.O1CCCC1>[CH3:20][Si:17]([CH3:19])([CH3:18])[C:16]#[C:15][CH:14]([N:13]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24]
Reactant: C[Si](C)(C)C#CCN=Cc1ccccc1
Reactant: C=CC(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCC(C#C[Si](C)(C)C)N=Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
53.6 ml of a 1.6M solution of n-butyllithium in hexane was added drop-by-drop over 20 minutes to a solution of 18.0 g of 1B in 700 ml of dry tetrahydrofuran at -70° C. The resulting mixture was stirred for 20 minutes at -70° C., when 7.2 g of freshly distilled methyl acrylate was added over 14 minutes. The resulting mixture was stirred for 30 minutes at -70° C., when 16.5 ml of water was added drop-by-drop. The resulting mixture was allowed to warm slowly to room temperature; the solvent was evaporated; the residue was diluted with water and the resulting mixture was extracted with ether. The ether extract was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated. The residue (a dark thick oil) was distilled in a Kugelrohr apparatus to give methyl 6-(trimethylsilyl)-4-(benzylideneamino)-5-hexynoate (3A), b.p.: 140°-142° C. (0.01 Torr.).
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[Si](C)(C)C)=[CH:18]/[C:19]2[S:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1.C([Li])CCC.[C:34]1([CH3:53])[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:35]=1[B:42](F)[C:43]1[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=1[CH3:51]>C(OCC)C.O.C(#N)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[B:42]([C:43]2[C:44]([CH3:51])=[CH:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])[C:35]2[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:34]=2[CH3:53])=[CH:18]/[C:19]2[S:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(/C(=C/c2ccc(C)s2)[Si](C)(C)C)cc1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Agent: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COc1ccc(/C(=C/c2ccc(C)s2)B(c2c(C)cc(C)cc2C)c2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a nitrogen atmosphere, N-iodosuccinimide (1.1 g, 5.0 mmol) was added to an acetonitrile solution of (Z)-(1-(4-methoxyphenyl)-2-(5-methyl-2-thienyl)-ethenyl)trimethylsilane (0.3 g, 1.0 mmol) at 0° C. The mixture was stirred for 5 hours while maintaining at 0° C., and then applied to an alumina column for concentration. In a nitrogen atmosphere, the residue obtained was dissolved in diethyl ether, and n-butyl lithium (0.9 mL, 1.4 mmol) was added dropwise at −78° C. The mixture was stirred for 1 hour while maintaining at −78° C., and dimesityl boron fluoride (0.37 g, 1.56 mmol) was then added thereto. The mixture was stirred at room temperature for 12 hours, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried with magnesium sulfate, followed by filtration. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) and recrystallization (diethyl ether). Thus, (E)-(1-(4-methoxyphenyl)-2-(5-methyl-2-thienyl)ethenyl)-bis(2,4,6-trimethylphenyl)borane was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](CO)([OH:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1>C1COCC1.O.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][C:29](=[O:31])[CH2:30]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CC(O)(CO)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Nc1nccn2c(C3CC(=O)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol (7.282 g, 17.69 mmol) in THF-water mixture (200 mL, 3:1) was added NaIO4 (4.542 g, 21.23 mmol) and the reaction was stirred at rt overnight. The reaction mixture was diluted with DCM (500 mL) and the DCM layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel using DCM:MeOH as eluent (0%→2%) yielded the desired compound as a yellow solid. MS (ES+): m/z 406.15 [MH+]. HPLC: tR=2.23 min (OpenLynx, polar—5 min). 1H NMR (400 MHz, CDCl3) δ 3.60-3.36 (m, 2H), 3.82-3.92 (m, 3H), 5.31 (br, 2H), 7.21 (dd, J=12.8, 4.8 Hz, 2H), 7.48-7.56 (m, 3H), 7.91-7.98 (m, 3H), 8.18-8.20 (m, 2H), 8.28 (d, J=8.0 Hz, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6](C2C=CC=CC=2)[N:5]=[C:4]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[C:3]=1[C:22]#[N:23].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>>[NH2:23][CH:22]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([C:30]([O:32][CH3:33])=[O:31])[N:1]=[C:2]2[N:6]=[N:5][C:4]([C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[CH:17]=3)=[C:3]12
Reactant: N#Cc1c(-c2cc3ccccc3s2)nn(-c2ccccc2)c1N
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=C(C(=O)OC)C(N)C2=C(c3cc4ccccc4s3)N=NC2=N1

Procedure:
Using 3.16 g (10 mmol) of 5-amino-3-(benzothiophen-2-yl)-1-phenylpyrazole-4-carbonitrile and 1.42 g (10 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 218° to 220° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Yield: 93.2 %

Procedure:
Diethyl 2-aminomalonate hydrochloride (12.7 g) and benzyloxycarbonyl chloride (11.9 g) are treated in the same manner as described in Reference Example 19-(3) to give diethyl 2-(N-benzyloxycarbonylamino)malonate (17.3 g), m.p. 36.5°-37° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-amino-phenol (Aldrich) according to the method described in Example 1c. Melting Point: 98-100° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[O:21][CH:22]=1>>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1/[CH:24]=[CH:23]/[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(/C=C/c2ccco2)n1
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)co1)\c1ccco1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-(2-furyl)ethenyl]oxazole to give 2-[(E)-2-(2-furyl)ethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 122-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:12]1[N:16]=[CH:15][NH:14][N:13]=1)=[O:11].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:12]1[N:16]=[CH:15][N:14]([C:19](=[O:20])[N:18]([CH3:22])[CH3:17])[N:13]=1)=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)c(S(=O)c2nc[nH]n2)c(C)c1
Product: Cc1cc(C)c(S(=O)c2ncn(C(=O)N(C)C)n2)c(C)c1

Procedure:
3-(2,4,6-Trimethylphenyl)sulfinyl-1H-1,2,4-triazole and dimethylcarbamoyl chloride were employed to synthesize the title compound as in Example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:1].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: OCc1ccc(Cl)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
From 4-chlorobenzyl alcohol (5.0 g; 35 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 24 h at 100° C. The yield was 0.56 g (32%). Mp 127–129° C.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]=2[C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[O:21][C:20]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:17][CH:18]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Boron tribromide (3.4 g, 15.8 mmol) was added to a solution of 4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.5 g, 6.3 mmol) in DCM at 0° C. & the mixture was stirred for 1 h (reaction was monitored by TLC). Upon complete consumption of the starting material, the mixture was quenched with chilled water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-(3-(4-hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.8 g, 93.2%) as yellow solid. 1H NMR: 500 MHz, CDCl3: δ 9.6 (s, 1H), 7.95 (d, 2H), 7.75 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 1.5 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cn2)CC1
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a stiffed solution of 2,5-dibromopyridine (10 g, 42.19 mmol, 1.00 equiv) in toluene (1000 mL) under nitrogen at −78° C. was added dropwise n-BuLi (18 mL, 2.5 M in toluene). After 1 h at −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.25 mmol, 1.19 equiv) in toluene (200 mL) was added dropwise while stirring. After an additional 2 h of stirring at −78° C., the reaction was then carefully quenched by the addition of 300 mL of water. The resulting mixture was extracted with 3×500 mL of ethyl acetate. The combined organic layers were washed with 1×300 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) to yield 6.5 g (42%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:26]([F:29])([F:28])[F:27].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:26]([F:27])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:30])([F:1])[F:31])[CH:20]=1)=[O:41]
Reactant: Nc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from {3-[3-(2-trifluoromethylphenyl)-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 230-232° C.; MS (EI) m/z 587(M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[F:36])([C:15]([F:18])([F:17])[F:16])[N:14]=1)(C)(C)C.[Cl:38]CCl>FC(F)(F)C(O)=O>[ClH:38].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[F:36])([C:15]([F:18])([F:17])[F:16])[N:14]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)(F)F)CCOC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c(C3(C(F)(F)F)CCOCC(N)=N3)c2)nc1
Reaction time: 0.75 h

Procedure:
(5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamic acid tert-butyl ester (63.3, 0.121 mmol) was dissolved in 0.68 mL dichloromethane and 0.23 mL trifluoroacetic acid. The solution was stirred at for 45 minutes and then evaporated at room temperature. The residue was dissolved in EtOAc and extracted with saturated aqueous NaHCO3 solution. The layers were washed with brine and EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude product was dissolved in THF, 0.3 mL HCl solution 1 mol/L in diethyl ether was added and the mixture was evaporated. The residue was crystallized from wet ethanol and TBME to give 52.4 mg of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([SiH2:12][O:13][C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[C:22]([CH3:24])[CH:23]=[C:17]2[CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:23]1[C:22]([CH3:24])=[N:21][N:18]2[CH:19]=[CH:20][C:15]([C:14]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:13][SiH2:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:16][C:17]=12)=[O:5]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1c(C)nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc12
Temperature: 120 °C
Yield: 91.8 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid methyl ester (2.47 ml, 26.0 mmol, 4.0 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridine (2.6 g, 6.49 mmol) in THF (20 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 15 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (2.9 g, 92%). 1H NMR (400 MHz, d6-DMSO): δ=8.76 (d, J=7.8 Hz, 1H), 8.11 (br s, 1H), 7.61-7.59 (m, 4H), 7.44-7.35 (m, 6H), 7.10 (dd, J=7.1/1.9 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H), 1.03 (s, 9H). MS (ES+): 487 (M+H)+.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][Cl:14])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.CC1OCCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([OH:15])[CH2:13][Cl:14])=[CH:10][CH:11]=1
Reactant: O=C(CCl)c1ccc(Br)cc1
Agent: B
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: CC1CCCO1
Product: O[C@@H](CCl)c1ccc(Br)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Borane dimethylsulfide (2.0 kg, 24.8 moles, 94% w/w) was mixed in toluene (8 L) at tjacket=20° C. (R)-(+)-Methyl-CBS-oxazaborolidine (2.6 kg, 2.74 moles, 1M) as a toluene solution was added. The charging vessel was rinsed with toluene (0.5 L) and tjacket was set to 45° C. 1-(4-Bromo-phenyl)-2-chloro-ethanone (7.84 kg, 33.6 moles), which is commercially available from Jiangyan Keyan Fine Chemical Co. Ltd, was dissolved in 2-MeTHF (75 L) in a separate vessel and when tinner was above 40° C. in the first vessel, the 2-MeTHF solution was added during 3 h. The latter vessel was rinsed with 2-MeTHF (2 L) and added to the reaction mixture, which was left stirring at tjacket=45° C. for 1 h. Analysis of a sample on HPLC indicated full conversion at this point using the following gradient method (mobile phase 20-95% B; A: 5% CH3CN in H2O with 0.1% TFA, B: 95% CH3CN in H2O with 0.085% TFA, 10 min run) on Chromolith Performance RP-18e, 4.6×100 mm. The reaction mixture was cooled to tjacket=10° C. before slow quench with MeOH (36 L). The first liter of MeOH was added during 30 min. and the rest during additional 30 min. MeOH was distilled off under vacuum at tjacket=50° C. The organic solution left was cooled to tjacket=20° C., washed with 1M HCl in H2O (7 L conc HCl+73 L H2O) and concentrated under vacuum at tjacket=50° C. to approximately 40 L. Example 1 obtained in a 2-MeTHF solution can be stored at 10° C. for 20 h or used directly in the next synthetic step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.C(O)(=O)C.[OH:51][CH:52]([CH2:55]O)[CH:53]=[O:54].C([BH3-])#N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][N:30]([CH2:55][CH:52]([OH:51])[CH2:53][OH:54])[CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=CC(O)CO
Reactant: Fc1cncc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6CCNCC6)cc45)cc32)c1
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: OCC(O)CN1CCC(c2cc3c(-c4ccc5ncn(Cc6cncc(F)c6)c5c4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of Example 12D trifluoroacetate salt (60 mg), triethylamine (0.06 mL, 0.422 mmol) and acetic acid (42 mg, 0.703 mmol) in dichloromethane (2 mL) was added 2,3-dihydroxypropanal (25.3 mg, 0.281 mmol) and MP-cyanoborohydride (224 mg, 0.563 mmol) and the mixture was stirred at room temperature for 2 days. The solid was filtered and rinsed with 10 mL 50% methanol/dichloromethane. The filtrate was concentrated and purified by reverse-phase HPLC (Phenomenex Luna C8 AXIA column, 100 Å), eluting with a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water with 10 mM ammonium acetate to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 1.65-1.79 (m, 2 H) 1.91-1.98 (m, 2 H) 2.12-2.25 (m, 2 H) 2.29-2.43 (m, 2 H) 2.65-2.76 (m, 1 H) 2.95-3.05 (m, 2 H) 3.33-3.46 (m, 2 H) 3.60-3.71 (m, 1 H) 5.67 (s, 2 H) 6.11 (s, 1 H) 7.09 (d, J=4.88 Hz, 1 H) 7.57 (dd, J=8.54, 1.53 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.75-7.86 (m, 2 H) 8.15 (d, J=4.88 Hz, 1 H) 8.42 (s, 1 H) 8.46-8.51 (m, 2 H) 11.29 (s, 1 H). MS (ESI) m/e 501 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[O:27])[CH3:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([O:17][C:15]2[C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[N:14]=2)=[C:19]([CH3:28])[CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1cc(C)c(Oc2nc(Cl)nc3ccn(Cc4ccccc4)c23)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
In a sealed tube was added 1-(4-(5-benzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylphenyl)ethanone (111 mg, 0.27 mmol), 4-aminobenzonitrile (129 mg, 1.1 mmol), TFE (1.7 mL) and TFA (0.2 mL, 2.16 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (9:1-100% EtOAc), to give the product as an off-white solid (68 mg, 51%).