Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH3:14]>O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:12])[NH2:14]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccccc2c1
Yield: 52 %

Procedure:
A solution of 2-naphthoyl chloride (5.70 g, 29.9 mmol) in tetrahydrofuran (60 ml) was added dropwise to a mixture of 28% aqueous ammonia (20 ml) and tetrahydrofuran (30 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hrs. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitates were collected by filtration and dried to give 2-carbamoylnaphthalene (2.68 g, 52%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:44][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[CH:34]=[C:29]([Cl:28])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 56.1 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)quinolin-3-yl)ethanone (42.4 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38.4 mg, 0.133 mmol) to afford the desired product (28.4 mg, 56%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.17 (s, 1H), 8.02-7.94 (m, 2H), 7.77 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.20 (s, 2H), 4.41 (s, 2H), 3.27 (br s, 4H), 2.78 (s, 3H), 2.07 (br s, 4H). ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 95.1% (AUC), tR=10.81 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH:26](O)[CH2:27][CH3:28])[CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:48]1[C:56]2[C:51](=[CH:52][C:53]([C:57]3[N:61]=[CH:60][N:59](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:58]=3)=[CH:54][CH:55]=2)[C:50]([C:81]2[CH:82]=[C:83]([OH:87])[CH:84]=[CH:85][CH:86]=2)=[N:49]1.Cl>O1CCCC1>[NH:58]1[C:57]([C:53]2[CH:52]=[C:51]3[C:56](=[CH:55][CH:54]=2)[NH:48][N:49]=[C:50]3[C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([O:87][CH2:28][CH2:27][CH2:26][CH:22]3[CH2:23][CH2:24][CH2:25][NH:20][CH2:21]3)[CH:82]=2)=[N:61][CH:60]=[N:59]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CCC(O)C1CCCNC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCCC2CCCNC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 3-piperidylpropanol (0.379 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 24 h and poured into aqueous 6 N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0–20% methanol/ethyl acetate elution. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.0847 g, 32% yield). 1H NMR (CD3OD) δ 8.71 (m, 1H), 8.34 (s, 1H), 8.10 (dd, 1H), 7.67 (dd, 1H), 7.60 (dt, 1H), 7.53 (m, 1H), 7.45 (t, 1H), 7.01 (m, 1H), 4.14 (t, 2H), 2.61 (m, 2H), 2.53 (s, 4H), 2.05 (m, 2H), 1.65 (m, 4H), 1.50 (m, 2H). ES-MS (m/z) 403 [M+1]+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][N:25]([O:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[S:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)(=[O:13])=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A mixture of 1,4-benzodioxan-6-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb 23, 1994; 60 mg; 0.253 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,4-benzodioxan-6-sulfonyl chloride (12 mg, 0.051 mmol) was added and the reaction was heated for an additional 30 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate (125 mg, 86%) as a white solid. HL-NMR (chloroform-D3): 1.20 (m, 6H), 1.60 (m, 5H), 2.07 (m, 2H), 2.90 (m, 4H), 3.09 (b, 1H), 3.67 (m, 2H), 3.90 (m, 4H), 4.23 (m, 1H), 4.31 (m, 4H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.95 (d, 1H) 7.25 (m, 7H). MS(ESI): 655(M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]1=[O:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]2=[O:34])[CH2:10][CH2:9]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Cc1cn(COCC[Si](C)(C)C)c(=O)n(CCCCl)c1=O
Product: Cc1cn(COCC[Si](C)(C)C)c(=O)n(CCCN2CCN(c3ccccc3Cl)CC2)c1=O

Procedure:
substituting 1-(2-chlorophenyl)piperazine and 3-(3-chloropropyl)-5-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CCO>[CH:18]1([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (158 mg, 0.658 mmol) and cyclohexylmethylamine (0.100 mL, 0.790 mmol) were stirred in 3 mL of EtOH containing triethylamine (0.140 mL, 0.987 mmol) at 75° C. for 24 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 217 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.98-1.09 (m, 2H), 1.17-1.28 (m, 3H), 1.31 (s, 9H), 1.65-1.73 (m, 2H), 1.74-1.80 (m, 2H), 1.82-1.84 (m, 1H), 1.85-1.88 (m, 1H), 3.15 (dd, J=6.64, 5.47 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.23 (br.s, 1H), 7.82 (dd, J=9.18, 2.54 Hz, 1H), 8.10 (d, J=2.54 Hz, 1H), 8.11-8.13 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][NH2:24])(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26]>C(O)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26]
Reactant: NNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-chloro-3-nitrobenzenesulfonohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 78 mg of the title compound (77%) as a yellow solid in 73% purity by HPLC (Rt: 3.65, 5.39, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:18][C:6]1[CH:5]=[C:4]([N:19]2[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:36])[C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]- acetamide (VIII-A, R1=COCH3, R2=H, X1═X2=F) (0.13 g) is dissolved in 5 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.2 g) is added and the resulting suspension is stirred at 25° C. for 72 hours. An additional 0.2 g of monoperoxyphthalic acid is added and the reaction is stirred an additional 48 hours. The reaction mixture is filtered and the filtrate is concentrated to afford a light-yellow oil. This material is chromatographed on silica gel using 20% methanol (saturated with ammonia) in chloroform as eluent to afford 55 mg of the N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].CCN(CC)CC.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloropyridin-3-amine (R-1) (5 g, 38.9 mmol) in THF (100 mL) was added Et3N (4.72 g, 6.5 mL, 46.7 mmol), followed by ethyl 2-chloro-2-oxoacetate (5.84 g, 4.78 mL, 42.8 mmol) in THF (5 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc, and washed with aqueous saturated NaHCO3. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound, which was used for the next step without further purification. MS (m/z): 229 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([C:15](C)(C)[O:16][SiH2]C(C)(C)C)[CH:12]=[C:11]([C:24](C)(C)[O:25][SiH2]C(C)(C)C)[CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1
Reactant: COC(=O)CCCC#Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCC#Cc1cc(CO)cc(CO)c1
Reaction time: 1.25 h
Yield: 85.9 %

Procedure:
To a cooled (0° C.) solution of 6-[3,5-Bis-(tert-butyl-dimethyl-silyloxymethyl)-phenyl]-hex-5-ynoic acid methyl ester (140 mg) in anhydrous tetrahydrofurane (0.3 mL) was slightly added a solution of tetrabutylammonium fluoride 1 M in THF (716 μL). After 75 min at rt, ethyl acetate (20 mL) was added and the organic phase was washed three times with water (5 mL) and once with a saturated aqueous solution of sodium chloride (5 mL), dried over sodium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using gradient elution with a mixture of heptane (A)/ethyl acetate (B), (gradient: 50% A: 50% B down to 10% A: 90% B) to give 6-(3,5-Bis-hydroxymethyl-phenyl)-hex-5-ynoic acid methyl ester (64.3 mg) as a pale yellow oil. LC/MS (Method A3): ES: m/z 263 (M+H)+; RT=0.62 min
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1.C(Cl)(=O)[C:24](Cl)=[O:25]>ClCCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([N:12]=[C:24]=[O:25])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxamide (120 mg, 1 equiv) and oxalyl chloride (106 μl, 3 equiv) in 1,2-dichloroethane (2.0 ml) was heated to reflux for 24 h. The mixture was cooled to room temperature and purified by column chromatography (0 to 100% ethyl acetate in hexanes) to give 68 mg of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carbonyl isocyanate (52% yield) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](C(O)=O)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:17])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccc(Cl)cc2cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: Nc1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Yield: 20 %

Procedure:
7-Chloroisoquinoline-3-carboxylic acid (3.1 g, 14 mmol) was dissolved in 6 N HCl (50 mL), and the mixture was heated under reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in tert-butanol (100 mL), and triethylamine (2.8 g, 28 mmol) and diphenylphosphoryl azide (5.6 mL, 26 mmol) were added. The mixture was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressure. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (500 mg, 20% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.62 (s, 1H), 7.66 (d, J=9 Hz, 1H), 6.86 (d, J=2.4, 1H), 6.75 (dd, J=2.4 and 9 Hz, 1H), 6.52 (s, 1H), 5.83 (s, 1H), 3.83 (s, 3H); MS: m/z 174.1 (M+H+).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH3:19][CH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:28](Cl)=[O:29])[CH2:21]1>>[CH3:19][CH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:28]([N:11]2[C:5]3=[N:6][C:7]4[C:2]([C:3](=[O:18])[N:4]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=3)=[CH:1][CH:10]=[CH:9][CH:8]=4)=[O:29])[CH2:21]1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CC1CCCCCC(C(=O)Cl)C1
Product: CC1CCCCCC(C(=O)n2c3ccccc3n3c(=O)c4ccccc4nc23)C1

Procedure:
6-(3-Methylcyclooctanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and 3-methylcyclooctanoyl chloride.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14](C(=O)C(F)(F)F)[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[F:1][C:2]1[C:7]2[N:8]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2n1-c1c(F)cccc1OC21CCNCC1

Procedure:
To a solution of 9′-fluoro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (170 mg, 0.45 mmol) dissolved in MeOH (2.7 mL) was added K2CO3 (130 mg, 0.94 mmol) in one portion at rt. The reaction was monitored by LCMS until no starting material remained. Water was added (10 mL), and the organic solvent removed under vacuum. The product was extracted with dichloromethane (3×30 mL), the organic phases were combined, dried with sodium sulfate, filtered, concentrated to a white solid, which was used directly in next step without further purification (104 mg, 82%). ESI-MS m/z calc. 283.1, found 284.1 (M+1)+; Retention time 0.94 minutes (3 min run).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:10]=[C:11]=[S:12])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].[CH:16]([NH:18][NH2:19])=O>O1CCCC1>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[C:11](=[S:12])[NH:19][N:18]=[CH:16]2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: NNC=O
Reactant: COC(=O)c1cc(N=C=S)ccc1OC
Solvent: C1CCOC1
Product: COc1ccc(-n2cn[nH]c2=S)cc1C(=O)O
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Treat a mixture of 5-isothiocyanato-2-methoxy-benzoic acid methyl ester (6.90 g, 30.91 mmol) and formic hydrazide (2.04 g, 34.0 mmol, Aldrich Chemical Company) under an argon atmosphere via syringe with anhydrous tetrahydrofuran (40 mL). After three hours, concentrate in vacuo to remove the solvent, mix the residue with 1 M NaHCO3 solution (total of 300 mL employed) in portions and transfer to a 500 mL round bottom flask. Reflux for 3 days under an argon atmosphere. Filter the hot solution, acidify with concentrated hydrochloric acid (25 mL), chill the mixture in an ice bath and collect the precipitate by vacuum filtration. Wash the filter cake with dichloromethane and dry in vacuo to afford 7.12 g of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid. Combine the filtrates and concentrate in vacuo to afford another crop of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (1.24 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:30]([F:33])([F:32])[F:31])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([NH:44][C:21]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:10]3[CH:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]3[C:30]([F:31])([F:32])[F:33])=[CH:17][CH:16]=2)=[O:22])(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 549 [M+H]+, 547 [M−H]−, 1 H-NMR (CDCl3) δ 2.92 (2H, t, J=7.3 Hz), 3.40-3.60 (2H, m), 6.60 (1H, br), 7.24-7.45 (7H, m), 7.51 (2H, d, J=9.0 Hz), 7.77 (2H, d, J=9.0 Hz), 7.82 (2H, d, J=6.9 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15](C4N=C(CN(CC)CC)ON=4)=[C:11]3[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[C:7]=2[CH:29]=1.[CH3:30][C:31](C)=[O:32]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([C:13]4[N:14]=[C:31]([CH2:30][N:9]([CH2:10][CH3:11])[CH2:8][CH3:7])[O:32][N:12]=4)=[N:14][CH:15]=[C:11]3[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[C:7]=2[CH:29]=1
Reactant: CC(C)=O
Reactant: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Agent: Cl
Product: CCN(CC)Cc1nc(-c2ncc3n2-c2ccc(Cl)cc2C(=O)N(C)C3)no1
Yield: 42 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.17 ml (1.65 mmol) of diethylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The crystals were filtered off under suction, the filtrate was extracted once with ethyl acetate and the extract was evaporated. The combined crude products were chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1, 2:1). There were obtained 124 mg of 8-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted in acetone with ethereal hydrochloric acid into the hydrochloride. By crystallization from acetonitrile there were obtained 108 mg (42%) of 8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.9) of m.p. 191°-205° (dec.).