Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH2:63][CH3:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH2:63][CH3:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:46])([CH3:45])[CH3:47]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCOc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.7 %

Procedure:
To a solution of 120 mg (0.74 mmol) of 1H-indole-7-carboxylic acid and 240 mg of TBTU (0.74 mmol) in 8 ml DMF, were added 0.64 ml (3.72 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 309 mg (0.94 mmol) of (4-tert-butyl-benzyl)-[2-(3-ethoxy-phenyl)-ethyl]-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 110 mg off-white foam (31%). MS (ISP) 455.7 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]13[C:25]2[C:16](=[CH:17][C:18]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[CH:24]=2)[O:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=CC=C[CH:33]=2)[C@@:28]2([C:46]3[C:37](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[N:26]1[CH:37]=[CH:46][CH:28]=[CH:29][C:34]=1[CH2:33][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:8]1=[O:13]
Reactant: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: O=C1N(Cc2ccccn2)c2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (41%) as a colorless solid: mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ8.75 (s, 1H), 8.60-8.53 (m, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.69-7.61 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 6.30 (s, 1H), 5.17 (ABq, 2H), 4.87 (ABq, 2H), 4.24-4.03 (m, 4H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:21]=2[N:20]=C(NCCN(C)C)N=1)[CH2:28][CH2:27][CH2:26]C3.C(O)(C(F)(F)F)=[O:38]>C(Cl)Cl.N>[N+:17]([C:22]1[CH:23]=[C:24]2[C:29]([CH2:28][CH2:27][CH2:26]2)=[CH:30][C:21]=1[NH:20][C:10](=[O:11])[CH3:12])([O-:16])=[O:38]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.27 mL, ca. 5.3 mmol) was added dropwise to a stirred solution of TFAA (0.8 mL, 5.3 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 177 (153 mg, 0.5 mmol) and TFA (0.20 mL, 2.7 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 177 (37 mg, 24%) and (ii) 1,4-dioxide 178 (47 mg, 29%) as a red solid: mp (MeOH) 148-151° C.; 1H NMR δ 8.02 (s, 1H, H-10), 7.98 (s, 1H, H-5), 7.35 (br s, 1H, NH), 3.63 (br t, J=6.0 Hz, 2H, CH2N), 2.98-3.04 (m, 2H, CH2), 2.91-2.96 (m, 2H, CH2), 2.61 (br t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 1.83-1.92 (m, 4H, H-7, H-8); 13C NMR δ 149.4, 148.7, 138.8, 136.5, 128.9, 120.1, 115.8, 57.6, 45.2 (2), 38.9, 30.3, 29.4, 22.3, 22.0. Anal. calcd for C15H21N5O2.1½H2O: C, 54.5; H, 7.3; N, 21.2. Found: C, 54.4; H, 6.3; N, 20.7%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25].CCOCC>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=2[CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(O)c1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 100 °C
Yield: 100.5 %

Procedure:
In a microwave vial 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) was dissolved in N,N-Dimethylformamide (10 mL) to give a pale yellow solution. Potassium carbonate (1469 mg, 10.63 mmol) and 2,3-dimethylphenol (433 mg, 3.54 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 100° C. for 1 hour. After cooling the reaction was dilued with 25 mL of Et2O. The organic phase was washed with 3 times 25 mL of water, 10 mL of saturated brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a yellow solid (865.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=S)[NH:9][C:10]=2[CH:11]=1.[NH3:16]>>[NH2:16][C:8]1[CH:7]2[CH2:13][CH2:14][CH2:15][CH:6]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:10]=2[N:9]=1
Reactant: Fc1ccc2c(c1)NC(=S)C1CCCC21
Reactant: N
Product: NC1=Nc2cc(F)ccc2C2CCCC12
Yield: 99 %

Procedure:
Analogously to Example 4, 7-Fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (170 mg, 0.77 mmol) in 7N methanolic ammonia solution (20 ml) is reacted to form 160 mg (99%) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:11]([C:8]1[C:7](=[O:14])[N:6]2[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:13])[CH2:29][CH3:30]
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2ccc(C)cn2c1=O
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at -18° C. during 20 minutes. After stirring for 5 minutes, 5.2 (0.088 mol) of propylamine dissolved in 80 ml of chloroform are dropped to the above solution at -18° C. during 60 minutes. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 17.5 g (89.2%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 126°-128° C.
Reaction SMILES: [Na+].CS([CH2-])=O.[H-].[Na+].[CH3:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]#[CH:17])([OH:15])[CH2:11][CH2:10]1.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CS(C)=O>[CH3:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]#[CH:17])([O:15][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:11][CH2:10]1
Reactant: C#CC1(O)CCN(C)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Yield: 53.6 %

Procedure:
To a stirred solution of dimsyl sodium prepared from 43.0 g of sodium hydride (50% in oil, washed three times with hexanes) and 1100 ml of dimethylsulfoxide was added, in aliquots, 125 g of N-methyl-4-ethynyl-4-piperidinol at a rate such that the temperature remained below 23°. When the addition was complete, 167 g of 2,5-difluoronitrobenzene was added slowly dropwise at a rate such that the temperature remained below 21°. When the addition was complete, the mixture was poured into ice, extracted twice with ether, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was filtered through 800 g of silica gel (70-250 mesh) and eluted with 3 l of 10% methanol/dichloromethane. Evaporation of solvent provided an oil, which crystallized on standing to yield 134 g (54%) of product. Recrystallization from cyclohexane provided the analytical sample, mp 70°-73°.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[S:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][CH:18]=1>ClCCl>[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][C:18]=1[CH:8]1[N:9]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:11][S:7]1
Reactant: CC1=CSCC(=O)N1
Reactant: c1cscn1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCSC1C1=C(C)NC(=O)CS1
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
Ethylchloroformate (3.6 g) was added dropwise to a solution of thiazole (5.7 g) in dichloromethane (72 ml) under ice-cooling, and the mixture was stirred for 30 minutes. Then, 5-methyl-2H-1,4-thiazin-3(4H)-one (3.6 g) was added dropwise to the mixture. The reaction mixture was further stirred at ambient temperature for 5 hours. The mixture was washed with 2N hydrochloric acid and successively with water, was dried over anhydrous magnesium sulfate and the solvent was removed. The residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1) as an eluant and was recrystallized from ethanol to give the titled compound (1.9 g, yield 23.8%) as white needles.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:18]3[C:13](=[CH:14][C:15]([O:39][CH3:40])=[C:16]([O:37][CH3:38])[CH:17]=3)[C:12]2=[O:41])=[CH:7][CH:6]=1)(=O)C.[H-].[Na+].CI.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:38][O:37][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:39][CH3:40])[C:12](=[O:41])[N:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH3:1])=[CH:6][CH:7]=1)[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]2[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CI
Product: CNc1ccc(-n2c(C(=O)OC)c(-c3cc(OC)c(OC)c(OC)c3)c3cc(OC)c(OC)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of the compound obtained in Example 94 (260 mg) in tetrahydrofuran (3 ml) is added 60% sodium hydride (28 mg) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added dropwise methyl iodide (58 μl), and the mixture is stirred for five hours. To the reaction mixture are added dilute hydrochloric acid and chloroform. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure. To the residue is added a mixture of methanol and 2M hydrochloric acid (1:1) (10 ml), and the mixture is heated under reflux for 16 hours. The reaction mixture is cooled to room temperature, and concentrated under reduced pressure to remove the methanol. To the resulting aqueous layer is added aqueous sodium hydrogen carbonate solution to adjust the pH value to pH 8. The mixture is extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 6,7-dimethoxy-3-methoxycarbonyl-2-[4-(methylamino)phenyl]-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (170 mg) as listed in Table 7.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH2:18]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[O:16]=[C:14]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: c1ccc(CCC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(CCc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-phenethyl-piperidine [J. Amer. Chem. Soc., 72, 4953. (1950)] according to the method described in Example 1c. Melting Point: 128-132° C. (diethylether)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:21]>C(COC)OC.CCOCC>[Br:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(CO)cc1CNC(=O)OC(C)(C)C
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(CBr)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.65 g of t-butyl N-[5-(hydroxymethyl)-2-methoxybenzyl]carbamate was dissolved in 20 ml of dimethoxyethane, 0.53 ml of phosphorus tribromide was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.76 g of the title compound from the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([O:17]C)=[O:16])[C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[OH-].[K+].O>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: COC(=O)c1cc2nc(C)n(C)c2cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(C(=O)O)c(C(=O)O)cc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of dimethyl 1,2-dimethyl-5,6-benzimidazoledicarboxylate (2.80 g, 10.7 mmol), potassium hydroxide (1.49 g; 26.7 mmol), water and methanol is stirred at room temperature for 16 hours and then concentrated in vacuo. The resultant residue is taken up in a minimal amount of water, cooled, acidified to pH 3 with hydrochloric acid and filtered to give the title product as pink crystals (2.28 g, 91.2%), mp 308°-312° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[O:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: c1ccc(-c2coc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)co2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Phenyl-1,3-oxazol-2-yl)piperazine (391 mg, 0.807 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (370 mg, 1.61 mmol), diisopropylethylamine (0.141 ml, 0.807 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 44.0 mg (14.1%) of the desired product. mp 171-172° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.C(O)(=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[NH2:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][NH:30][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:18]
Reactant: CCCCCCCCC(=O)O
Reactant: NCCO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCCCCCCCC(=O)N1CC(=NOC)C[C@H]1C(=O)NCCO

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, nonanoic acid, and 2-aminoethanol, the title compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=342.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1)[CH3:2].[C:11]([CH2:14][C:15](=O)[CH3:16])(=O)[CH3:12].Cl.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:15]([CH3:16])=[CH:14][C:11]([CH3:12])=[N:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1cnc(NN)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cnc(-n2nc(C)cc2C)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 34.7 %

Procedure:
5-Ethyl-2-hydrazinopyrimidine (400 mg, 2.89 mmol) was suspended in 3 mL of water, and acetylacetone (314 μL, 3.04 mmol) and 2 mol/L hydrochloric acid (330 μL) were added thereto and stirred at room temperature for 23 hours. 2 mL of sodium hydroxide aqueous solution was added to the reaction mixture to adjust the pH to 12. The mixture was extracted with ethyl acetate three times, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→10:90) and silica gel column chromatography (methylene chloride:methanol=100:0→95:5) to give 203 mg of the title compound (yield 35%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][N:4]2[CH2:3][CH2:2]1)=[CH:13][CH:12]=[CH:11][N:10]=4.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:8]2[C:7]3[CH2:6][CH:5]4[N:4]([CH2:3][CH2:2][CH2:1]4)[CH2:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=3)=[CH:23][CH:24]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cccnc31)CN1CCCC1C2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (1 g, 4.6 mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8 mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reaction mixture was stirred at RT overnight. The progress of reaction mass was monitored by LCMS. The reaction mixture was quenched with ice cold water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (10×100 mL) followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography followed by reverse phase HPLC to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C:11]3[N:16]=[C:15]4[N:17]([C@@H:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH3:29])[C:18](=[O:27])[N:19](C(OC(C)(C)C)=O)[C:14]4=[CH:13][CH:12]=3)[C:7]=2[CH:36]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:27]=[C:18]1[N:17]([C@@H:28]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH3:29])[C:15]2=[N:16][C:11]([N:8]3[C:7]4[CH:36]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=4[N:10]=[CH:9]3)=[CH:12][CH:13]=[C:14]2[NH:19]1
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(-n3cnc4ccc(C#N)cc43)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1cccnc1)n1c(=O)[nH]c2ccc(-n3cnc4ccc(C#N)cc43)nc21
Yield: 86.4 %

Procedure:
A solution of tert-butyl 5-(6-cyano-1H-benzo[d]imidazol-1-yl)-2-oxo-3-((R)-1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (72) (57 mg) in methylene chloride (1 mL) was treated with TFA (1 mL) for one hour. The mixture was concentrated and the resulting TFA salt was converted to the HCl salt by dissolving it in 5 mL EtOH and adding 0.5 mL of conc. HCl, then concentrating the solution in vacuo. The process was repeated and the resulting residue was dissolved in a minimum amount of methanol and triturated with the addition of ethyl ether. After 3 triturations, 3-(2-oxo-3-((R)-1-(pyridin-3-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-3H-benzo[d]imidazole-5-carbonitrile (73) HCl salt (39 mg) was isolated as a tan colored solid: 1H-NMR (CD3OD) δ 9.9 (br s, 1H), 9.2 (s, 1H), 9.0 (m, 2H), 8.5 (s, 1H), 8.3 (m, 1H), 8.2 (m, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 6.3 (q, 1H), 2.3 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([CH3:21])=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:11][O:10]1.[NH:22]1[CH:26]=NC=[N:23]1.CC(C)([O-])C.[K+].[CH3:33][N:34](C)C=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]([CH3:21])=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([OH:10])[CH2:11][C:33]1[N:34]=[N:23][NH:22][CH:26]=1
Reactant: CN(C)C=O
Reactant: CC(=Cc1ccc(F)cc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(=Cc1ccc(F)cc1)C(O)(Cc1c[nH]nn1)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To 40 ml of N,N-dimethylformamide Were dissolved 2.0 g of 2-(2,4-difluorophenyl)-2-[1-methyl-2-(4-fluorophenyl)-ethenyl]-oxirane, 1.9 g of 1,2,4-triazole and 1.6 g of potassium t-butoxide. After 4 hours of stirring at 100° C., the reaction solution was cooled to room temperature, poured into ice water and then extracted with ethyl acetate. The resulting organic layer was washed with water and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation under a reduced pressure, the resulting residue was purified by a silica gel column chromatography (ethyl acetate) to obtain 1.6 g of 2-(2,4-difluorophenyl)-2-[1-methyl-2-(4-fluorophenyl)-ethenyl]-1-triazolyl-2-ethanol with a yield of 36%.