Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]cnc2c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1ncc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Reaction time: 3 h
Yield: 66.3 %

Procedure:
78.8 g of 5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one [CAS No. 76756-58-6] (Shih-Fong Chen and Raymond P. Panzica, Journal of Organic Chemistry 46, p 2467, 1981) was suspended in 2.5 L of dichloromethane at room temperature, and 78.8 of triethylamine was added thereto. 176 g of trityl chloride was added to the mixture, which was then stirred for three hours. 7.5 L of ethyl acetate was added to the mixture. After being washed successively with 3 L of water and 3 L of a saturated sodium chloride solution, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 136.5 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (20:80 to 0:100).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[SH:32]>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[S:32][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F
Reactant: Sc1ccc(Cl)cc1Cl
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1Sc1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in Example 11, Step A, the title compound was prepared using 2-fluoro-4-[5-(2-morpholin-4-yl-ethyl)-imidazol-1-ylmethyl]-benzonitrile (0.15 g, 0.477 mmol) and 2,4-dichlorothiophenol (0.086 g, 0.477 mmol).
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[C:31]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:41])[NH:12][C@:11]2([C:43]([NH:45][S:46]([CH:49]3[CH2:51][CH2:50]3)(=[O:48])=[O:47])=[O:44])[CH2:42][C@H:10]2[CH2:9][C:8]([F:53])([F:52])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:31]1[C:22]([O:21][C@H:19]2[CH2:18][N:15]3[C:16](=[O:17])[C@@H:2]([NH:1][C:70]([C:67]4[CH:66]=[C:65]([CH3:64])[O:69][N:68]=4)=[O:71])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:52])([F:53])[CH2:9][C@@H:10]4[CH2:42][C@@:11]4([C:43](=[O:44])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[NH:12][C:13](=[O:41])[C@@H:14]3[CH2:20]2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: Cc1cc(C(=O)O)no1
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5nc4-c4nc5ccccc5s4)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-6-amino-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 14a, 16.1 mg, 0.020 mmol) was added DMF (200 μl) and diisopropylethylamine (25 μl, 0.14 mmol). To the yellow solution was added 5-methylisoxazole-3-carboxylic acid (3.85 mg, 0.030 mmol) followed by HATU (13.89 mg, 0.037 mmol). The reaction mixture was stirred at rt 2 h, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 36 μl, diluted with EA). The solution was concentrated under reduced pressure and purified by prep-TLC (dichloromethane/EA=1/1, 2×) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2- yloxy)-14a-(cyclopropylsulfonylcarbamoy1)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (14.3 mg, 81% yield). MS (ESI): m/z=877.1 [M+H], 875.2 [M−H]. Example 14 provided an IC50 of between 0.1 and 0.5 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1-con1 background.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:33]3[CH:23]=[CH:24][C:25]4[O:29][C:28]([F:30])([F:31])[O:27][C:26]=4[CH:32]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Product: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 5-bromo-2,2-difluoro-benzo[1,3]dioxole. Off-white solid. MS (ESI): 485.1 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[C:10]#[C:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[C:9](=[O:13])[C:10]#[C:11][CH3:12])[CH:24]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC#CC(=O)Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#CC(=O)N(Cc1cccc(C(=O)OC)c1)c1ccccc1I
Reaction time: 0.17 h

Procedure:
A mixture of but-2-ynoic acid (2-iodo-phenyl)-amide (2.85 g, 10 mmol) and cesium carbonate (4.89 g, 15 mmol) in DMF (20 ml) was stirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester (2.52 g, 11 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate/hexane=1:4 to afford the product 3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid methyl ester as yellow solid (3.03, 70%). MS calcd. for C19H16INO3 433.3, obsd. (ESI+) [(M+H)+] 434.1.
Reaction SMILES: [ClH:1].CCOCC.[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[CH2:18][S:17](=[O:37])(=[O:36])[C:16]2[CH:38]=[CH:39][CH:40]=[CH:41][C:15]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[CH2:18][S:17](=[O:37])(=[O:36])[C:16]2[CH:38]=[CH:39][CH:40]=[CH:41][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](C(=O)NC1CS(=O)(=O)c2ccccc2N(Cc2ccccc2)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)NC1CS(=O)(=O)c2ccccc2N(Cc2ccccc2)C1=O
Reaction time: 3 h
Yield: 100 %

Procedure:
1 M HCl in Et2O (4 mL, 4.00 mmol, Eq: 40) was added to a solution of tert-butyl (S)-1-(5-benzyl-1,1,4-trioxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate in MeOH (1.5 mL). After 3 h, the mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (45 mg, 100%). MS m/z 402.0 (MH+)
Reaction SMILES: [P:1](=[O:93])([S:84][CH2:85][O:86][C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[O:59]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1>C(O)(=O)C.O.CO>[P:1](=[O:93])([S:84][CH2:85][O:86][C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[OH:59])[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)OP(=O)(OC(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)SCOC(=O)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](C(O)OP(=O)(O[C@]3(O)C[C@H](n4cc(C)c(=O)[nH]c4=O)O[C@@H]3CO)SCOC(=O)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The totally protected dimeric phosphorothioate triester (3a) is dissolved in a mixture of acetic acid/water/methanol (8:1:1, v:v:v) (10 ml). The reaction is left with stirring at ambient temperature for 5 hours. The reaction medium is then evaporated and the residue is coevaporated several times with water and toluene. The residue is then chromatographed on a silica gel column using a gradient of methanol (0 to 10%) in dichloro-methane as eluent. The fractions containing the product (4a) are collected, concentrated under reduced pressure, and then the residue is coevaporated several times with dioxane and lyophilized in dioxane. (4a) is obtained in the form of a white powder (98 mg, 85%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]1.CI.[C:31](=O)([O-])O.[Na+]>O.CN(C)C=O>[CH3:31][N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=3)[C:4]2=[O:3])[CH2:23][C:24]1=[O:28]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(-c2cccn(CCN3CCNC(=O)C3)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(-c2cccn(CCN3CCN(C)C(=O)C3)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
With cooling with ice, sodium hydride (60% oil suspension, 50 mg) was added to an N,N-dimethylformamide (10 ml) solution of methyl 4-{2-oxo-1-[2-(3-oxopiperazin-1-yl)ethyl]-1,2-dihydropyridin-3-yl}benzoate (380 mg), followed by stirring for 5 minutes, and then methyl iodide (70 μl) was added. With cooling with ice, the reaction mixture was stirred for 1.5 hours. Water with ice (20 ml) and aqueous saturated sodium hydrogencarbonate solution (10 ml) were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain methyl 4-{1-[2-(4-methyl-3-oxopiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoate (350 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:11]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (5.00 g, 16.1 mmol), 4-methoxycarbonylphenylboronic acid (2.90 gm, 16.1 mmol), and tetrakis-(triphenylphosphine)palladium(0) (0.932 g, 0.807 mmol) in a flask was flushed with nitrogen. Toluene (70 mL), MeOH (14 mL), and a 2 N aqueous solution of sodium carbonate (18 mL, 37 mmol) were added and the reaction was heated in a 120° C. oil bath for 4 hr. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)isonicotinate (2.0 gm). MS (ESI) m/z 365.0 and 367.0 (M+H). 1H NMR (CDCl3) δ ppm 8.15 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.71 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 3.94 (6H, d, J=5.19 Hz).
Reaction SMILES: [CH3:1]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+].CO[C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=C[C:17]=1C.[C:36]([O:39][CH2:40][CH3:41])(=O)C.C1(C)C=CC=CC=1>>[CH3:36][O:39][C:40]1[CH:41]=[CH:1][C:33]([CH2:19][CH2:20][NH:21][N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])=[CH:34][C:16]=1[CH3:17]
Reactant: COc1ccc(CNN2C(=O)c3ccccc3C2=O)cc1C
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: Cc1ccccc1
Product: COc1ccc(CCNN2C(=O)c3ccccc3C2=O)cc1C
Reaction time: 8 h
Yield: 65 %

Procedure:
N,N-dimethylformamide (20 ml), methyl iodide (0.7 ml) and potassium carbonate (3.12 g) were added to 2-(4-methoxy-3-methylbenzylamino)isoindole-1,3-dione (1.67 g) prepared in the Step 15-1-2, and the mixture was stirred overnight. Methyl iodide (0.35 ml) was added thereto, and the resulting mixture was stirred for another 5 hours. Thereafter, an ethyl acetate-toluene (3:1) solution was added thereto. The resulting mixture was washed with water and a saturated saline solution in order, and then dried over sodium sulfate and concentrated under a reduced pressure. To the resulting residue, diethyl ether was added, and the mixture was stirred at a room temperature. The precipitate was separated by filtration, washed with diethyl ether, and dried under a reduced pressure to give the title compound (1.15 g, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[CH2:8][C:7]1=[O:26])[CH3:2].[C:28](N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].ICC(C)C.Cl>C1COCC1.CCCCCC.O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:7](=[O:26])[CH:8]([CH2:29][CH:28]([CH3:31])[CH3:30])[C:9]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=2[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:12]1)[CH3:2]
Reactant: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Reactant: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2CC1=O
Agent: CC(C)CI
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2C(CC(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
134 mg of the compound from Example 22A (0.35 mol) are dissolved in 1.35 ml of THF. At −78° C., 0.52 ml of a 1 M solution of 3-tert-butylimino-1,1,1,5,5,5-hexakis(dimethylamino)-3-(tris(dimethylamino)phosphoranylidene)amino-1λ5,3λ5,5λ5-1,4-triphosphazadiene (P4-t-Bu; 328 mg, 0.52 mol) in n-hexane is added drop wise, and the reaction solution is stirred at −78° C. for 30 min. 191 mg of 1-iodo-2-methylpropane (1.04 mol) are added drop wise, and the mixture is stirred at −78° C. for a further 2 h. The reaction solution is mixed with 10 ml of 1 N hydrochloric acid and water and extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 87 mg (57% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48](=[NH:51])[NH:49]O)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:57]=[C:56]([CH3:58])[CH:55]=[C:54]([CH3:59])[CH:53]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[N:51]=[C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[O:7][N:49]=3)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:53]=[C:54]([CH3:59])[CH:55]=[C:56]([CH3:58])[CH:57]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)CC(=O)O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=N)NO)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4noc(CC(C)C)n4)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of isovaleric acid (0.025 mL in 4 mL methylene chloride) was added 1-hydroxybenzotriazole (37.8 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.6 mg) and the reagents allowed to mix for 30 minutes. At this time a solution of {2-[2-(3,5-dimethylphenyl)-5-(N-hydroxycarbamimidoyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (81 mg in 3 mL methylene chloride) was added and the reaction stirred at room temperature. After 2 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to give the title compound (81 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Mg]Br.CN(C)[C:16]1[S:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[C:17]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)=[O:28]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:16]1[S:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[C:17]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)=[O:28]
Reactant: Br[Mg]c1ccccc1C1OCCO1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C3OCCO3)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of 2-(1,3-dioxolan-2-yl)phenylmagnesium bromide (15 mL of 0.5 M/THF, 7.5 mmol) to a stirred solution of (2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (650 mg, 1.48 mmol) in THF (5 mL) at r.t. Stir the reaction mixture at r.t. for 2 h and quench with aq. NaHCO3. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate to afford [2-(2-[1,3]dioxolan-2-yl-phenyl)-6-methoxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone. Use the product without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH:2]=[CH2:3].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.O>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (1.27 g) and 4-allyloxyquinaldic acid (1.2 g) in dimethylformamide (30 ml) were heated at 100° for 4 hours. 5-Aminotetrazole (1.33 g) was added and the mixture was stirred at 100° for 1 hour and cooled. Water (30 ml) was added and the solid was collected and dissolved in hot aqueous dimethylaminoethanol (15 ml, 5%). The solution was filtered and the filtrate was acidified with glacial acetic acid. 4-Allyloxy-N(1H-tetrazol-5-yl)quinaldamide was collected and dried, m.p. 260° (d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].N1C=CC=CC=1.C1(C)C=CC=CC=1.[F:27][C:28]1[CH:36]=[C:35]([CH2:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[F:27][C:28]1[CH:36]=[C:35]([CH2:37][CH2:38][CH3:39])[CH:34]=[CH:33][C:29]=1[C:30]([O:13][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([F:10])([F:11])[F:9])=[C:6]([F:12])[CH:5]=1)=[O:31]
Reactant: CCCc1ccc(C(=O)Cl)c(F)c1
Reactant: Oc1cc(F)c(C(F)(F)F)c(F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(C(=O)Oc2cc(F)c(C(F)(F)F)c(F)c2)c(F)c1
Yield: 90.5 %

Procedure:
Then, 1.2 g (6.1 mmol) of 3,5-difluoro-4-trifluoromethyl-phenol, 0.7 ml of pyridine, and 2 ml of toluene were mixed. To this mixture was added dropwise 3 ml of toluene solution containing 6.1 mmol 2-fluoro-4-propylbenzoyl chloride at room temperature in 10 minutes. After the dropping was finished, they were reacted at 50° C. for 2 hours. After finishing of the reaction, 10 ml of water was added to the reaction product and then extracted with 30 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.0 g of a crude 3,5-difluoro-4-trifluormethylphenyl 2-fluoro-4-propylbenzoate. This product was recrystallized from a mixed solvent of heptane/ether (1/1) to obtain 1.1 g (yield: 50.2%) of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.C(OCC)(=O)C.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.92 h

Procedure:
A stirred mixture of 8-chloro-6-phenyl-1-(2-phthalimidoethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, ethyl acetate solvate (37.6 g., 0.0675 mole) and absolute ethanol (340 ml.) is treated with hydrazine hydrate (7.43 g.) and warmed, under nitrogen, in an oil bath to 75° during 65 minutes, the bath is kept at this temperature for an additional 55 minutes. The mixture is then cooled in an ice bath, and the solid is collected by filtration and washed with absolute ethanol and methylene chloride. The combined filtrate is mixed with ice cold salt water and extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (1 kg.) with methanol and the resulting product is crystallized from methylene chloride diethyl ether to give 1-(2-aminoethyl)-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in 2 crops: 5.29 g. of melting point 198°-200° C. dec., and 2.37 g., of melting point 194°-196.5° C. dec. The analytical sample is crystallized from methanol-ethyl acetate and has a melting point of 205°-207° C.