Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Yield: 86.7 %

Procedure:
Methyl 4-chlorobenzoate (171 mg, 1.00 mmol) reacted with 4-methoxyphenylboronic acid (200 mg, 1.31 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF at 100° C. for 4 h to give the title compound (210 mg, 89%) as a white solid: 1H-NMR (500 MHz, CDCl3): δ 8.09 (d, 2H, J=8.35 Hz), 7.63 (d, 2H, J=8.30 Hz), 7.59 (d, 2H, J=8.71 Hz), 7.01 (d, 2H, J=8.73 Hz), 3.95 (s, 3H), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 167.02, 159.77, 145.14, 132.32, 130.05, 128.31, 128.16, 126.40, 114.31, 55.32, 52.03. GC/MS (EI): m/z 242 (M+), 211, 139.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:14](=[O:39])[NH:15][C@H:16]([C:22](=[O:38])[NH:23][C@@H:24]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([C@@:27]1([CH3:30])[CH2:29][O:28]1)=[O:26])[CH2:17][O:18][CH:19]([F:21])[F:20])[CH2:9][O:10][CH:11]([F:13])[F:12])(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:7][C@@H:8]([CH2:9][O:10][CH:11]([F:13])[F:12])[C:14]([NH:15][C@H:16]([C:22](=[O:38])[NH:23][C@@H:24]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:25]([C@@:27]1([CH3:30])[CH2:29][O:28]1)=[O:26])[CH2:17][O:18][CH:19]([F:20])[F:21])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COC(F)F)NC(=O)[C@@H](N)COC(F)F)CO1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of the compound of Formula XIV(a), ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethylcarbamoyl}-2-difluoromethoxy-ethyl)-carbamic acid tert-butyl ester (2.68 g, 4.62 mmol) in dichloromethane (10 mL) at 0° C. was added TFA (10 mL), and the resulting mixture was stirred for 1 hr. Excess TFA was evaporated to dryness, and the residue obtained was triturated with ether in hexanes (2×20 mL) to provide the compound of Formula XV(a), (S)-2-amino-N—{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethyl}-3-difluoromethoxy-propionamide TFA salt (2.34 g, 85%), as a pale-yellow solid. 1H NMR (300 MHz, d6-DMSO): δ (ppm) 7.42-7.32 (m, 3H), 7.23 (dd, 2H), 6.85 (wd, 1H), 6.71 (br s, 1H), 6.68 (wd, 1H), 6.10 (w t, 1H), 5.98 (wt, 1H), 5.12 (br s, 1H), 4.78 (td, 1H), 4.51 (td, 1H), 4.29 (m, 1H), 4.30-3.99 (m, 2H), 3.97 (dd, 1H), 3.85 (dd, 1H), 3.21 (d, 1H), 3.10 (dd, 1H), 2.86 (d, 1H), 2.81 (dd, 1H), 1.45 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][C:42]([CH3:54])=[C:43]([CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][C@H:49]([O:52][CH3:53])[CH2:48]3)[N:44]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[CH3:53][O:52][C@H:49]1[CH2:50][CH2:51][N:47]([CH2:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=4)=[CH:35][CH:36]=3)[O:41][C:42]=2[CH3:54])[CH2:48]1
Reactant: CO[C@H]1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CO[C@H]1CCN(CCc2nc(-c3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)oc2C)C1
Yield: 36.8 %

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.003 g, 0.015 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.016 g, 0.059 mmol), distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.24 g, 1.11 mmol), 2-(4-bromophenyl)-4-{2-[(3S)-3-methoxypyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Example 117) (0.27 g, 0.74 mmol) and potassium carbonate (0.31 g, 2.22 mmol) to give the title compound as a white solid (0.12 g): MS (m/e): 441(M+1).
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=O)[O:28]CC)=[CH:22][CH:21]=1>CN(C)C=O>[F:17][C:18]([F:32])([F:33])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[NH:1][C:27]2=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=C(N)c1ccccn1
Reactant: CCOC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccn2)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
1.0 g of ethyl 3-amino-3-(2-pyridyl)-2-propenoate was added dropwise to a 20 ml dimethylformamide solution of 0.26 g of sodium hydride (purity: 55%) under stirring at 0° C. This solution was stirred at room temperature for 15 minutes and then added with 1.3 g of ethyl 4-trifluoromethoxyphenylcarbamate. The mixed solution was stirred at 100° C. for 3 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved by adding 100 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 20 ml of concentrated hydrochloric acid and 50 g of ice. Then precipitated crystals were filtered out and dried under reduced pressure to obtain 1.0 g of 3-(4-trifluoromethoxyphenyl)-6-(2-pyridyl)-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:35][C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:34][CH:33]=2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCOCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was condensed with 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: CCNCCO
Reactant: Fc1ccc(-n2ccc3cc(OCC=CCBr)ccc32)cc1
Product: CCN(CC=CCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)CCO

Procedure:
In analogy to example 3.3, 5-(4-Bromo-but-2-enyloxy)-1-(4-fluoro-phenyl)-1H-indole and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-but-2-enyl}-amino)-ethanol as colorless viscous oil, MS: 369 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.[NH:10]([CH2:14][CH2:15]O)[CH2:11][CH2:12]O>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][CH2:15][CH2:14][NH:10][CH2:11][CH2:12][O:8]2)=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: OB(O)c1ccc(Cl)s1
Product: Clc1ccc(B2OCCNCCO2)s1
Yield: 28 %

Procedure:
The title compound (28%, crystals) was prepared from 5-chlorothiophen-2-boronic acid and diethanolamin.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>C(#N)C.C(N(CC)CC)C>[CH2:49]([CH:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:48][CH2:47]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCN1CCC(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a suspension of 2.19 g (6.86 mM) of 1-(4-aminobutan-1-yl)-4-benzylpiperidine dihydrochloride and 3.87 ml (27.8 mM) of triethylamine m in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:34]=[CH:33][C:32]([OH:35])=[CH:31][N:30]=2)[CH:24]=[CH:23][N:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:4]=[C:5]([CH:8]=[CH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=4)[O:6][CH:7]=3)=[CH:31][N:30]=2)[CH:24]=[CH:23][N:22]=[N:21]1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1cnc(CCCCn2ccnn2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3cnc(CCCCn4ccnn4)nc3)co2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-chlormethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.144 g, 0.50 mmol), 2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidin-5-ol (0.078 g, 0.357 mmol) and cesium carbonate (Cs2CO3) (0.175 g, 0.536 mmol) in DMF (10 ml) is kept at 80° C. for 2 h. After cooling ethyl acetate (25 ml) is added, the mixture is washed with sat. NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate (100%)->ethyl acetate/methanol 9:1) and 2-(4-[1,2,3]-triazol-1-yl-butyl)-5-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine can be isolated as a white solid. Yield 40 mg (24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: Clc1ncccn1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1cc(-c2ccc(Oc3ncccn3)cc2)n(-c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a suspension of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (ref hydrogenation below) (60 mg, 180 μmol) and Cs2CO3 (140 mg, 400 μmol) in acetonitrile (2 mL) was added 2-chloropyrimidine (66 mg, 580 μmol). The suspension was then heated to 80° C. in an oil bath. After stirring for 16 hours at 80° C. the suspension was filtered through a plug of silica gel (1 g), which was eluted with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane to afford 2-(4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)pyrimidine (55 mg, 75% yield) as a white powder. MS(ES): 417 [M+H]+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3cccc4ccccc34)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1cccc2ccccc12

Procedure:
The 2-trifluoroacetamido-3-napthyl-6-benzoyl-imidazo[1,2-a]pyridine (8.25 g, 18.0 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 4.73 g. (73%). EA, MS(FD).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>O1CCCC1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nccn1C(=O)c1c(Cl)cccc1Cl

Procedure:
20.5 g of 2-methylimidazole and 25.3 g of triethylamine are dissolved in 200 ml of tetrahydrofuran. To this solution are added dropwise, within 15 minutes at reflux temperature, 52.4 g of 2,6-dichlorobenzoyl chloride (dissolved in 100 ml of tetrahydrofuran). The mixture is refluxed for 30 minutes, and subsequently freed from triethylamine hydrochloride by filtration in vacuo. The filtrate is concentrated to dryness in a rotary evaporator and the residue is recrystallised from 130 ml of acetonitrile. The crystals are filtered off with suction, washed with acetonitrile, and dried at 60° C. in vacuo to thus obtain 46.0 g (72.2% of theory) of the product, m.p. 116°-119° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=[C:4]([NH:25][CH2:26][C@@H:27]([OH:29])[CH3:28])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
In a two-necked round-bottom flask, [4-[2-chloro-6-(2(S)-hydroxy-propylamino)-pyrimidin-4-yl]-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile (370 mg, 0.9 mmol), 3-pyridine boronic acid (143.27 mg, 1.17 mmol), bis(triphenylphosphine)palladium (II) dichloride (18.88 mg, 0.027 mmol), and potassium carbonate (75.98 mg, 0.72 mmol) were dissolved in a mixture of acetonitrile and water (10 mL, 1:1, v/v) through which nitrogen gas was then flowed for 10 min and heated at 75° C. for 3 hours. After completion of the Suzuki coupling reaction, the reaction mixture was dissolved in water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under vacuum. The purification of the concentrate by chromatography produced the title compound (274 mg, 67.1%).
Reaction SMILES: [Cl-].[CH:2]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]([NH:37][C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1)=[O:36])[C:8]([CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([CH3:4])[CH3:3].C1CCN2C(=NCCC2)CC1>CO>[CH:2]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]([NH:37][C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1)=[O:36])[C:8]([CH:10]=[P:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)c1cc(C(=O)C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of [3-isopropyl-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyltriphenylphosphonium chloride (3.3 g) in methanol (50 ml) is added DBU (1 ml), and the mixture is stirred at room temperature for two hours. The precipitated crystals are collected by filtration, washed with methanol, and dried to give [3-isopropyl-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphorane (2.27 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])O)[S:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([CH2:17][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:14][C:12]=3[N:13]=2)[CH2:5][CH2:6]1
Reactant: OC(c1cc2cnc(NC3CCOCC3)nc2s1)c1ccccc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccccc1Cc1cc2cnc(NC3CCOCC3)nc2s1

Procedure:
The alcohol (140 mg) obtained in Example 2A was stirred with triethylsilane (1.0 mL) and trifluoroacetic acid (1.5 mL) in dichloromethane (5 mL) for 4 hours. The solvents were removed. The residue was diluted with toluene (5 mL) and then concentrated. This dilution-concentration process was repeated three times. Purification with preparative TLC (50% EtOAc/Hexanes) gave the final product. It was converted to the hydrochloride salt with 1N HCl in ether to yield 65 mg of the salt. MP: 217-219° C. MS: 344 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][NH:5][C:4]([CH2:7][C:8]([O:10]CC)=[O:9])=[CH:3]1.CO.O.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[NH:6][NH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3]1
Reactant: CCOC(=O)Cc1cc(=O)[nH][nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(=O)[nH][nH]1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a suspension of ethyl (5-oxo-2,5-dihydro-1H-pyrazol-3-yl)acetate obtained in Reference Example 117 (5.00 g, 29.4 mmol) in THF (20 mL)-methanol (20 mL)-water (20 mL) was added 5N aqueous sodium hydroxide solution (11.0 mL, 88.0 mmol) at room temperature, and the mixture was stirred under heating at 80° C. for 3 hr. The reaction mixture allowed to cool to room temperature, and concentrated under reduced pressure, and the residue was diluted with water, and acidified with 6N hydrochloric acid. The precipitated solid was collected by filtration, and washed with water, and dried under nitrogen stream to give the title compound as a white powder (3.43 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8](=[N:21][C:22]#[N:23])/[N:9]=[C:10]2\[S:11][CH:12]=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:34][C:35]([CH3:37])=[O:36].[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8](=[N:21][C:22]#[N:23])/[N:9]=[C:10]2\[S:11][C:12]([C:35]([OH:36])([CH3:37])[CH3:34])=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(=NC#N)/N=c1\scc(C)n1CC1CCC1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)O)c(C)n1CC1CCC1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of Example 110D (101 mg, 0.269 mmol) in anhydrous tetrahydrofuran (4 mL) at −78° C. was added lithium diisopropylamide (2 M, 0.404 mL). After 5 min acetone (46.9 mg, 0.808 mmol) was added and the reaction was stirred for 0.5 hrs. Saturated ammonium chloride solution (2 mL) was added to quench the reaction at this temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-20% ethyl acetate in hexane) to afford the title compound (65 mg, 86%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.67 (s, 6H) 1.81-1.94 (m, 4H) 2.00-2.08 (m, 2H) 2.50 (s, 3H) 2.68-2.81 (m, 1H) 3.91 (s, 3H) 4.30 (d, J=7.12 Hz, 2H) 6.91-6.96 (m, 1H) 7.33-7.38 (m, 2H); MS (DCI/NH3) m/z 433 (M+H)+. Anal. calcd C21H25ClN4O2S 90.6 EtOH: C, 57.95; H,6.19; N, 12.24. Found: C, 57.86; H, 6.13; N, 11.85.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].O.[NH2:16][NH2:17]>CO>[C:8]1([S:5]([CH2:4][C:3]([NH:16][NH2:17])=[O:2])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Solvent: O
Solvent: CO
Product: NNC(=O)CS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of 5.0 g (0.023 mol) of benzenesulfonyl-acetic acid methyl ester in 10 mL of MeOH at RT, 3.50 g (0.070 mol, 3 eq) of hydrazine hydrate were added. After one hour, the solvent and the excess of hydrazine were removed under reduced pressure, yielding 4.90 g (quantitative) of benzenesulfonyl-acetic acid hydrazide as a colorless oil, MS: 232 (MNH4+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19]([C:21]([OH:26])([CH2:24][CH3:25])[C:22]#[CH:23])[CH3:20]>C(NCC)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:20]#[C:19][C:21]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:23])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)(C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2)CC
Reaction time: 0.5 h

Procedure:
8.93 g (25 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 24 hours with 3.03 g (27 mmol) of 3-ethyl-1-pentyn-3-ol, 100 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 60 ml of diethylamine. A further 0.87 g (7.7 mmol) of 3-ethyl-1-pentyn-3-ol as well as 50 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 50 mg of copper(I) iodide were added thereto and the mixture was stirred at the boiling temperature for 0.5 hour. The reaction mixture was subsequently evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After decolorizing the crude product with active charcoal and crystallization from ethyl acetate there was obtained 8-fluoro-3-(3-ethyl-3-hydroxy-1-pentynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 135° -136°.