Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].N[C:10]1[C:15]([C:16]#[N:17])=[N:14][C:13]([C:18]2[C:26]3[O:25][C:24]([CH3:28])([CH3:27])[CH:23]([OH:29])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=1>CO>[NH2:7][C:6]1[N:8]=[C:16]([NH2:17])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:18]3[C:26]4[O:25][C:24]([CH3:27])([CH3:28])[CH:23]([OH:29])[C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[N:5]=1
Reactant: N=C(N)N
Reactant: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2c(-c3cnc4nc(N)nc(N)c4n3)cccc2C1O
Reaction time: 0.08 h

Procedure:
A solution of 2.8 grams (0.052 mole) of sodium methoxide in 100 mL of methanol is stirred, and 1.9 grams (0.019 mole) of guanidine hydrochloride is added. Upon completion of addition, the reaction mixture is stirred for about 5 minutes and then is filtered to remove sodium chloride. The filtrate is then added to 4.5 grams (0.016 mole) of 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine. The stirring reaction mixture is then heated to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled and filtered. The filter cake is washed with water and dried, yielding 2,4-diamino-6-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pteridine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[Na+].ClCCl>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:24])[F:26])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 150 °C
Yield: 52 %

Procedure:
The mixture of 3-amino-6-chloropyridazine (0.6487 g, 5 mmol) and piperazin-1-yl-(2-trifluoromethylphenyl)methanone (1.936 g, 7.5 mmol) in NMP (30 mL) was heated at 150° C. for 24 hours. To the reaction mixture was added 10 mL of 1 N NaOH and 100 mL of dichloromethane, and the aqueous layer was separated and extracted twice by 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, evaporated to dryness. The crude compound was purified by flash chromatography to give yellow solid. Yield 52%, 1.37 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 4-{[1-(3-bromo-4-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (1.6 g, 4.57 mmol) and ytterbium(III) triflate hydrate (0.28 g, 0.457 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.42 mL, 4.57 mmol) and water (82 mg, 4.57 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.93 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5]O.S(Cl)([Cl:18])=O>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][Cl:18]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Solvent: ClCCl
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)c1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of OBS02002 (5.0 g, 16.12 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.76 mL, 24.18 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give a yellow oil which solidified on standing. The solid was stirred in n-hexane, filtered and air-dried to give OBS02003 as an off-white solid (5.01 g, 95%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.79; 1H-NMR (270 MHz, CDCl3)=3.05 (6H, s), 4.51 (2H, s), 7.32 (1H, dd, J=2.2, 8.4), 7.48 (1H, d, J=8.4), 7.62 (1H, d, J=2.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C(S(O[CH2:37][C@@H:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH3:39])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:39][C@@H:38]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH3:37])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccccc1S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 75 °C
Yield: 49 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (0.29 g, 0.75 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added (2S)-2-[(tert-butoxycarbonyl)amino]propyl toluenesulfonate (0.5 g, 1.50 mmol) and cesium carbonate (0.72 g, 2.25 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 25 mL of a solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the product (200 mg, 49%). 1H NMR (DMSO-D6) δ 1.15 (3H, d, J=6.1 Hz), 1.40 (9H, s), 3.79 (6H, m), 7.22-7.20 (3H, m), 7.59 (2H, d, J=8.4 Hz), 7.95-7.99 (3H, m) 8.40 (1H, s). LCMS m/z=542 (m+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[C:11]1([CH3:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:14][CH:11]1[CH2:13][CH2:12]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CC1(Br)CC1
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and commercially available bromo-methyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25][OH:26])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:40]([O:47][CH2:48][CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>[Cl-].[Na+].O>[CH2:40]([O:47][CH2:48][CH2:49][O:39][C:36]1[CH:37]=[CH:38][C:33](/[C:22](/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:17][CH:18]=2)=[C:23](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:24][CH2:25][OH:26])=[CH:34][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: BrCCOCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC/C(=C(/c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reaction time: 4 h

Procedure:
The reaction vessel was charged with sodium hydride (0.43 g, 0.0178 mol) and dimethyl formamide (34 ml). 4-[1-(4-Benzyloxyphenyl)-4-hydroxy-2-phenyl-but-1-enyl]phenol (5 g, 0.0118 mol) prepared by the method of U.S. Pat. No. 4,996,225 was dissolved to dimethyl formamide (6 ml), added to the mixture at room temperature and stirring was continued for half an hour. Then benzyl-(2-bromoethyl)ether (3.06 g, 0.014 mol) was added dropwise during 20 minutes to the reaction mixture and stirring was continued for additional 4 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. Organic layer was washed with 2 N hydrogen chloride solution and twice with water, dried and evaporated to dryness. The product was purified by flash chromatography (toluene: methanol, 9.8:0.2). Yield 2.8 g.
Reaction SMILES: ClC1C=C(S(NC23CCC(C4N5C6C=CN(S(C7C=CC(C)=CC=7)(=O)=O)C=6N=CC5=NN=4)(CC2)CC3)(=O)=O)C=CC=1.[NH:42]([C:44]1[N:45]=[C:46]2[CH:52]=[CH:51][N:50]([S:53]([C:56]3[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[C:47]2=[N:48][CH:49]=1)[NH2:43].[C:63]([O:67][C:68]([NH:70][C:71]12[CH2:78][CH2:77][C:74]([C:79](O)=[O:80])([CH2:75][CH2:76]1)[CH2:73][CH2:72]2)=[O:69])([CH3:66])([CH3:65])[CH3:64]>>[S:53]([N:50]1[C:47]2=[N:48][CH:49]=[C:44]([NH:42][NH:43][C:79]([C:74]34[CH2:75][CH2:76][C:71]([NH:70][C:68](=[O:69])[O:67][C:63]([CH3:65])([CH3:64])[CH3:66])([CH2:72][CH2:73]3)[CH2:78][CH2:77]4)=[O:80])[N:45]=[C:46]2[CH:52]=[CH:51]1)([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:54])=[O:55]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)c6cccc(Cl)c6)(CC4)CC5)n23)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1

Procedure:
The precursor to Example #H.1.1, 3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide, was prepared as shown in Scheme B. 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid are reacted following the conditions given in General Procedure A to give tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate. This hydrazide is cyclized using the conditions given in General Procedure C to afford tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate. This carbamate is deprotected using General Procedure I to yield 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine. This amine is sulfonylated using the conditions described in General Procedure N to give the precursor to Example #H.1.1. The reaction sequence detailed above is translated in the preparations and examples section to “using A from Preparation #9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, N from 3-chlorobenzenesulfonyl chloride”.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([CH:43]([CH3:45])[CH3:44])[CH2:11][CH:12]([OH:42])[C@@H:13]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:14][C@H:15]([CH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][N:26]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:22][CH:21]=1)[CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:42][C@@H:12]([CH2:11][C@H:10]([CH2:9][OH:8])[CH:43]([CH3:45])[CH3:44])[C@@H:13]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:14][C@H:15]([CH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][N:26]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:22][CH:21]=1)[CH:16]([CH3:17])[CH3:18].[OH:42][C@H:12]([CH2:11][C@H:10]([CH2:9][OH:8])[CH:43]([CH3:45])[CH3:44])[C@@H:13]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:14][C@H:15]([CH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][N:26]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:22][CH:21]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(O)C[C@H](COCc3ccccc3)C(C)C)C(C)C)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](CO)C(C)C)C(C)C)cc21
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](O)C[C@H](CO)C(C)C)C(C)C)cc21
Reaction time: 8 h
Yield: 14 %
Yield: 30 %

Procedure:
To a solution of tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (1.3 g, 2.1 mmol) in methanol 30 mL) was added 20% Pd(OH)2/C (26 mg). The mixture was hydrogenated under a balloon of H2 at rt overnight and filtered. The filtrate was evaporated and purified by preparative HPLC to give tert-butyl (3S,5S,6S,8S)-6-hydroxy-8-(hydroxymethyl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (0.33 g, 30% yield) as an oil and tert-butyl (3S,5S,6R,8S)-6-hydroxy-8-(hydroxymethyl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (0.15 g, 14%) as an oil. MS: 534 (M++1)
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:5]=1[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[CH2:33][C:34](Cl)=[O:35])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1>[CH3:32][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:22])[CH3:23])[C:25]=1[CH2:33][C:34]([NH:10][S:7]([CH2:6][C:5]1[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:9])=[O:8])=[O:35])[CH3:31]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Reactant: CC(C)c1cc(C(C)C)c(CS(N)(=O)=O)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(CS(=O)(=O)NC(=O)Cc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Yield: 12.1 %

Procedure:
A solution of 2,4,6-triisopropylbenzylsulfonamide (100 mg, 0.33 mmol), 2,6-diisopropylphenylacetyl chloride (75 mg, 0.34 mmol), and Et3N (47 μL, 0.34 mmol) in 10 mL THF was stirred at room temperature overnight. The solvent was evaporated and the residue was distributed between ethyl acetate and 0.1N HCl, the organic layer was washed with brine, dried, and evaporated. The pure product (20 mg, 12%) was isolated by column chromatography (4:1 hexane:EtOAc), m/e=499; NMR (CDCl3): δ 7.05-7.4 (m, 5H), 4.25 (s, 2H), 3.95 (s, 2H), 3.45-3.6 (m, 1H), 3.0-3.15 (m, 2H), 2.85-3.0 (m, 2H), 1.05-1.4 (m, 30H) ppm.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:50].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:50].[BrH:50].[CH2:45]([O:44][C:42]([C@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:7][C:6]([OH:49])=[O:5])=[O:48])[CH3:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:43])[CH3:46]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In 2 ml of acetic acid is dissolved 0.35 g of N-[N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction mixture, followed by shaking, and the supernatant layer is removed by decantation. The colorless precipitate is rinsed with ethyl ether and dried under reduced pressure to give 0.3 g of N-[N-[(R)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[N:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[N:13]=[C:12]([CH3:19])[C:11]=2/[C:10](=[N:25]/[NH:24][C:21]([NH2:23])=[NH:22])/[CH2:9]1
Reactant: Cc1nc(C)c2c(n1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1nc(C)c2c(n1)CC(c1ccccc1Cl)C/C2=N\NC(=N)N
Temperature: 90 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinazolin-5-one (0.20 g) and aminoguanidine hydrochloride (77 mg) were added ethanol (14 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 3 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-7-(2-chlorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinazoline hydrochloride (Compound 90) (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH2:13]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Br)[CH2:18][CH2:19]Br)[CH3:14].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:22][CH2:21][N:17]([C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH2:18][CH2:19]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(OC)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a stirred solution of 5-methoxy-1-indanone (1.0 g, 6.17 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (1.87 g, 6.17) in DMF (10 mL) at 50° C. was added NaH (0.370 g, 15.4 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to ambient temperature. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate over 30 min) to give the title compound (590 mg, 1.945 mmol). MS calculated for C17H22NO4 304.4. found (ESI) m/z 304.2 (M+H)+, retention time 1.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CO[C:16]1[C:20](OC)=[N:19][S:18](=[O:23])[N:17]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CO>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:16]2[C:20]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:5]3[C:4]([CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[N:19][S:18](=[O:23])[N:17]=2)=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC1=NS(=O)N=C1OC
Reactant: Cc1cc(Br)cnc1NCCCN
Solvent: CO
Product: Cc1cc(Br)cnc1NCCCNC1=NS(=O)N=C1NCc1ccc(F)cc1
Reaction time: 2 h
Yield: 41.1 %

Procedure:
3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (1.0 g) was reacted with 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.65 g) in methanol overnight. p-Fluorobenzylamine (0.51 g) was added and the reaction mixture was stirred for 2 hours. The product was filtered off and recrystallised from ethanol to yield 4-(p-fluorobenzylamino)-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide (0.77 g, 40%) m.p. 125°-126° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([N:28]1[CH2:27][C@H:26]2[C@H:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:12]
Reactant: CC(C(=O)O)c1ccccc1N(C)C
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1N(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
N,N'-Carbonyldiimidazole (0.85 g) is added to a solution of (RS)-2-[2-dimethylaminophenyl]propionic acid (1 g) in dichloromethane (30 cc) cooled to 5° C. and the mixture is then stirred for 30 minutes at this temperature. A solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.7 g) and triethylamine (1.4 cc) in dichloromethane (30 cc) is added. The reaction mixture is stirred at 20° C. for 16 hours, washed with water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with ethyl acetate and collecting 125 cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-2-[(RS)-2-(2 -dimethylaminophenyl)propionyl]-7,7-diphenyl-4-perhydroisoindolone (1.4 g) in the form of a white meringue.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OC)c1
Yield: 76.7 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.329 ml (5.181 mmol) of methyl iodide, there were added 85.5 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 4 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1 and 25/1) to obtain 159 mg (0.3975 mmol, 77%) of 2-methoxy-2'-hydroxy-5,5 '-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.96 (4H, m, 2CH2), 2.35 (2H, t, CH2), 2.36 (2H, t, CH2), 2.63 (2H, t, CH2), 2.66 (2H, t, CH2), 3.66 (6H, s, 2CH3), 3.87 (3H, s, CH3), 6.24 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 400 (M+)