Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>C1COCC1>[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH:24]([OH:25])[CH3:1])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in THF (3 M, 0.85 mL, 2.56 mmol, 1.3 equiv) was added to a solution of 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1, 800 mg, 2.0 mmol, 1 equiv) in THF (25 mL) at 0° C., and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between pH 7 phosphate buffer solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 70% EtOAc in hexane) to provide tert-butyl 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2) as a white foam. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=8.8 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.78 (br t, 1H, J=7.1 Hz), 7.64 (s, 1H), 7.61 (br t, 1H, J=7.1 Hz), 7.42 (dd, 1H, J=8.6, 1.5 Hz), 6.66 (s, 1H), 5.05 (m, 1H), 1.58 (d, 3H, J=6.6 Hz), 1.27 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1(OCC)[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH3:2].OS([O-])(=O)=O.[K+]>C1(C)C=C(C)C=C(C)C=1>[CH3:2][CH2:1][O:3][C:4]1[C@:5]2([CH2:21][CH2:20][C@H:19]3[C@@H:10]([CH2:11][CH2:12][C:13]4[CH:14]=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=43)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6]
Reactant: CCOC1(OCC)CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: CCOC1=CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C

Procedure:
5 g of 17,17-diethoxy-3-methoxy-estra-1,3,5(10)-triene is dissolved in 20 ml of mesitylene and after addition of 0.3 g of KHSO4 under inert gas is heated within 30 minutes to 40 minutes to 140° C. to 160° C. and is gradually distilled off from the solvent. Then, it is heated for 2 more hours in a vacuum at this temperature and the remaining solvent is distilled off. The remaining residue is used in the next step in the form of an oil without purification. IR[cm-1 ]: 1500, 1575, 1620 (aromatic); 1620 (enol ether superimposed).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:1]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a 6 ml tetrahydrofuran solution of 114 mg (0.323 mmol) of the compound obtained in Example 44, 49 μl (0.63 mmol) of methanesulfonyl chloride and 90 μl (0.65 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. Then, 23 μl (0.3 mmol) of methanesulfonyl chloride was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain 123 mg (75%) of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.O(N(C)[C:16](=[O:18])[CH3:17])C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CON(C)C(C)=O
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cncnc1
Temperature: -78 °C
Yield: 40.9 %

Procedure:
5-Bromopyrimidine (3.18 g, 20 mmol) was dissolved in 50 mL of tetrahydrofuran. While cooled to −78° C., 15 mL of 1.6 M n-butyllithium in hexane solution was added dropwise with stirring. After the solution was stirred for 30 minutes, a solution of N-methoxyl-N-methylacetamide (2.58 g, 25 mmol) in tetrahydrofuran solution (10 mL) was added slowly. The mixture was stirred at −78° C. for 1 hour and then allowed to be warmed slowly. When the temperature of the mixture was at 0° C., aqueous ammonium chloride solution was added. The solution obtained was extracted with ethyl acetate for 3 times. The pooled extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 5% methanol/methylene chloride as eluent to obtain 1 g of the title compound (45% yield). MS (M+1)=123.05.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(F)cc2)cc1
Product: CSc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccc(F)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0.599 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as pale yellow crystals (197 mg, 77.4%). Melting point: 140.6-143.4° C. (acetone-water).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: Nc1ccccc1
Agent: [N-]=C=S
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)Nc2ccccc2)CCCCC1
Reaction time: 144 h

Procedure:
To 8.4 grams (.0363 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 3.39 grams (.0363 moles) of aniline. The reaction mixture was diluted with pentane and stirred for 6 days. The pentane was stripped from the reaction mixture to leave a white solid weighing 11.5 grams (97% crude yield). The product melted at 110°-113° C. and its infrared spectrum had strong bands at 1515 and 1550 cm-1 and moderate NH bands at 3150 and 3280 cm-1 and the isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[C:21](=[CH:23][C:24]#[N:25])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.C(O)C>C(O)C.[Co]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[C:21](=[CH:23][CH2:24][NH2:25])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCC=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]acetonitrile (125 mg, 0.382 mmol) in ethanol (2.4 mL) were added Raney cobalt (1.2 g) and 2N ammonia/ethanol solution (1.2 mL), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Examples 6 and 7 without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:33][CH2:34][CH2:35][N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:34][CH2:35][N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: c1ncn(CCNC2CCCC2)n1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCn2cncn2)C2CCCC2)c1)c1ccncc1
Yield: 38.9 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.040 g), cyclopentyl-(2-[1,2,4]triazol-1-yl-ethyl)-amine (0.05 g) and EEDQ (0.040 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 2 h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol (95:5 v/v) to give the title compound as a yellow oil (0.022 g).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12]>>[CH3:9][C:10]([Si:2]([CH3:4])([CH3:1])[Cl:3])([CH3:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)=C(C)C
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(C)(C)[Si](C)(C)Cl
Reaction time: 1 h

Procedure:
100 ml (0.92 mol) of dimethylchlorosilane and 3.8 g (0.028 mol) or aluminium chloride are introduced into a 500 ml three-necked flask with a reflux condenser and dropping funnel. Within 1 hour, 109.5 ml (0.92 mol) of tetramethylethylene are added dropwise. The reaction temperature is maintained in the range from 25° to 30° C. by external cooling. After 4 hours, undissolved aluminium chloride is filtered off from the reaction solution which is then distilled.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2cnc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (88.51 mg, 0.53 mmol) as starting materials, and isolated (12 mg, 7.8%) as white solid, LC-MS (UV peak area, ESI) 97.53%, 435.51 (M+H).
Reaction SMILES: C[N:2](C)C.O1C(CCl)C1.[OH-].[Na+].[OH:12][CH:13]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]([OH:17])[C@H:14]1[NH2:15]>>[NH2:2][C:13]1([O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]([OH:17])[C@H:14]1[NH2:15])[OH:12]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCC1CO1
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(N)O
Reaction time: 24 h

Procedure:
For the synthesis, pH of the trimethylamine solution was first adjusted to 2.0 to increase the boiling point. Then epoxypropyl chloride at same molar ratio was added dropwise and the pH was maintained at 9 using IM NaOH solution. Glucosamine was then added at same molar ratio and reaction was proceeded by stirring for 24 h. Throughout the reaction pH was maintained at 9.0 product was extracted using ethanol, methanol and tri hydrofluoride and quaternized amino glucosamine was obtained as a dark brown fluffy solid. Structure of newly synthesis was confirmed by elemental analyses and FT-IR. The result of elemental analysis was demonstrated in table 1 and the result of FT-IR was shown in FIG. 1. Bend absorption observed at 1480 cm.sup.-1 in QAGlc by FT-IR, clearly confirmed the quaternization of glucosamine (substitution of N(CH3)3 group).
Reaction SMILES: COC1C=CC(C(C)C#N)=CC=1.[C:13]([C:15]1([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[CH:23]=[O:24])C[CH2:16]1)#[N:14]>>[C:13]([CH:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH:23]=[O:24])[CH3:16])#[N:14]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1
Product: COc1ccc(C(C)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 13 in the same manner of Compound 2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([C:11]#[N:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1>>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:11]#[N:12])=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: N#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: N#Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (6 mg) by Suzuki coupling according to the General Procedure A to give 402. MS (Q1) 363 (M)+
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[Na].[CH3:15][SH:16]>C(Cl)Cl.CN1C(=O)CCC1>[CH3:15][S:16][CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: CS
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CSCC(O)C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (202 mg, 1.10 mmol), prepared in the previous step, in DCM (20 mL) was dissolved in NMP (20 mL) and methanethiol sodium salt (297 mg, 4.24 mmol) was added. The mixture was stirred, heating to 80° C. under argon overnight and then cooled to ambient temperature and poured onto water. After extraction with ethyl acetate, the organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-50% ether) to afford the product.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 245.3, 153 mg, 0.480 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 132 mg, 0.590 mmol, 1.10 equiv), EDC.HCl (204 mg, 1.01 mmol, 2.00 equiv, 95%) and 4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equiv, 95%) were added to the reaction. The resulting solution was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (2:1) as eluent. The crude product (˜150 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 7 min, up to 100% in 2 min, down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 62 mg (29%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.75-7.67 (m, 2H), 7.49-7.34 (m, 5H), 4.89-4.80 (m, 1H), 3.75-3.72 (m, 1H), 3.64-3.59 (m, 1H), 3.27-3.23 (m, 1H), 3.05-2.90 (m, 2H), 2.83 (q, 2H), 2.40 and 2.30 (2 singlets, amide rotamers, ArCH3, 3H), 2.27-1.97 (m, 6H), 1.90-1.70 (m, 4H), 1.40 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:42])[C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][CH2:10][CH:9]([C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)[N:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][C:33]([N:32]([CH3:42])[CH3:31])=[N:38][CH:37]=3)=[CH:3][CH:4]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(-c2ccc(N3C(c4ccc([N+](=O)[O-])cc4)CCC3c3ccc([N+](=O)[O-])cc3)cc2)cn1
Yield: 95.6 %

Procedure:
The product from Example 86A (25.7 mg, 0.055 mmole) was combined in a microwave tube with 6-(dimethylamino)pyridine-3-ylboronic acid (17.49 mg, 0.105 mmole), tribasic potassium phosphate (24.70 mg, 0.116 mole) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.504 mg, 3.84 μmole). The tube was sealed and a solvent mixture of THF (2 mL) and water (0.6 mL) added via syringe. The reaction mixture was sparged with nitrogen at room temperature for three minutes during which time the solution turned black in color. Chromatographic analysis indicated that the reaction was complete. The contents of the microwave tube were partitioned between brine (3 mL) and ethyl acetate (3 mL). The water was drawn off and the organic phase dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography on silica gel from 2 up to 20% ethyl acetate in hexane to provide the title compound (26.8 mg, 96% yield) as an orange solid as a mixture of stereoisomers. MS ESI(+) m/z @ 510.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)c(Cl)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)c(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 36.9 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.34042 mmol), 3-Chloro-4-morpholin-4-yl-benzaldehyde (84.5 mg, 0.374 mmol), and Ammonium acetate (52.5 mg, 0.681 mmol) were reacted to produce 62.66 mg (37%) of the title compound. (300 MHz, DMSO-d6) 13.35 (s, 1H), 8.28 (d, J=5 Hz, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.52 (m, 1H), 7.38 (m, 2H), 7.25 (s, 1H), 6.38 (m, 2H), 5.14 (t, J=16 Hz, 8 Hz, 1H), 3.76 (m, 4H), 3.54 (s, 4H), 2.91 (s, 1H), 2.81 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.22 (d, J=9 Hz, 1H), 1.39 (d, J=9 Hz, 1H). MS=466 (M-Cl+), HPLC: 1.76 min. (G Method)
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH2:27][CH3:28])=[N:18][N:19]3[CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH:22]1([N:19]2[C:20]3[C:16](=[CH:15][CH:14]=[C:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=4)=[O:12])[CH:21]=3)[C:17]([CH2:27][CH3:28])=[N:18]2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)OC)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of 380 mg (0.971 mmol, 1.0 equiv) 4-[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-benzoic acid methyl ester, 4 mL 1N NaOH and 20 mL methanol was heated to reflux for 40 minutes. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator, and the residue diluted with 150 mL H2O, acidified to pH=1, and extracted 2×50 mL ethyl acetate. The organic extracts were combined, washed 1×25 mL each H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate, and drying at high vacuum, room temperature gave 298 mg (81%) of a white crystalline solid: mp 249-251° C.; Anal. calcd for C22H23N3O3: C, 70.00; H, 6.14; N, 11.13. Found: C, 69.66; H, 6.13; N, 11.08.
Reaction SMILES: ClC1C2C(C3C=CC=CC=3F)=NC(C)(C)C(=O)N(C)C=2C=CC=1NC(NCCO)=O.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([N:49]=C=O)[CH:47]=[CH:48][C:43]=2[N:42]([CH2:52][CH2:53][OH:54])[C:41](=[O:55])[C:40]([CH3:57])([CH3:56])[N:39]=1>>[NH2:49][C:46]1[CH:47]=[CH:48][C:43]2[N:42]([CH2:52][CH2:53][OH:54])[C:41](=[O:55])[C:40]([CH3:56])([CH3:57])[N:39]=[C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[C:44]=2[CH:45]=1
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc(N=C=O)ccc2N(CCO)C1=O
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(NC(=O)NCCO)c2Cl
Product: CC1(C)N=C(c2ccccc2Cl)c2cc(N)ccc2N(CCO)C1=O

Procedure:
From 6.5 g (0.018 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1-(2-hydroxyethyl)-3,3-dimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (b) of Example 4, via [5-(o-chlorophenyl)-2,3-dihydro-1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, 1,-[5-o-chlorophenyl)-2,3-dihydro-1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea of melting point 175°-176° (ethanol/ethyl acetate).