Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([F:36])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.O>[F:28][C:29]1[CH:34]=[C:33]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)[CH:32]=[C:31]([F:36])[N:30]=1
Reactant: Fc1cc(I)cc(F)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(F)nc(F)c2)c2cccnc21
Temperature: 80 °C

Procedure:
A suspension of 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (7.26 g, 18.9 mmol), 2,6-difluoro-4-iodopyridine (4.14 g, 17.2 mmol, Eur. J. Org. Chem., 2004, 1018 and Org. Lett. 2007, 5175), dichlorobis(triphenylphosphine) palladium(II) (0.482 g, 0.687 mmol) and 1M aqueous sodium carbonate (13.7 mL, 13.7 mmol) in dimethoxyethane/ethanol/water (7:2:3) (80 mL) was degassed and heated at 80° C. for 1.5 hours. After cooling, the suspension was filtered, washed with water and ether, and concentrated to give the crude title compound. The filtrate was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified using an ISCO Companion flash system eluting with dichloromethane/hexane (7:3 to 9:1) to give the title compound. The combined products were used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[NH:5][CH2:4][C:3]1([CH3:13])[CH3:12].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][C:21]([N:5]2[C:6](=[O:11])[CH2:7][C:8]([CH3:9])([CH3:10])[N:2]([OH:1])[C:3]([CH3:13])([CH3:12])[CH2:4]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1O
Reactant: O=C=Nc1ccccc1
Product: CC1(C)CC(=O)N(C(=O)Nc2ccccc2)CC(C)(C)N1O

Procedure:
Using the same conditions as in Example 4, 3.6 parts of 1-oxyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 2.6 parts of phenyl isocyanate were reacted together and afforded 6.0 parts of a red oil which was purfied by column chromatography on alumina to give 4-phenylcarbamoyl-1-oxyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a red solid of melting point 112° to 114°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH2:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl>[OH:17][CH2:16][CH2:15][NH:14][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Into an ice-cooled and stirred solution of 4-methoxycarbonylbenzoyl chloride 1 (53.6 g, 0.270 mol) in methylene chloride was dropwisely added a solution of 2-aminoethanol (36.3 g, 0.594 mol) in methylene chloride (40 ml) under nitrogen during 1 hr, and the mixture was stirred for 3 hr at room temperature. The resulting precipitate was collected by vacuum filtration, washed thoroughly with water and dried in vacuo at 50° C. to give N-(2-hydroxyethyl)-4-methoxycarbonylbenzamide 2 (53.3 g, 88% yield) as white powder: 1H NMR (CD3SOCD3)δ3.45 (t of t, 2H, J=5.4 and 5.9 Hz, CH2N), 3.64 (t, 2H, J=5.9 Hz, CH2 O), 3.90 (s, 3H, CH3O), 4.87 (brs, 1H, OH), 8.02 (d, 2H, J=9.3 Hz, 2,6-Ar-H), 8.05 (d, 2H, J=9.3 Hz, 3,5-Ar-H), 8.65 (t, 1H, J=5.4 Hz, NH).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[N+:17]([O-:9])[CH:18]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
39 g (0.16 mol) 3-chloroperbenzoic acid in 450 mL DCM (dried on sodium sulphate) were added dropwise within 2 h to 25 g (0.15 mol) 5-bromo-2-methylpyridine in 50 mL DCM. Then the reaction mixture was stirred for 20 h at RT and extracted with 15% potassium carbonate solution. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][C:102]1[CH:103]=[C:104]([OH:108])[CH:105]=[CH:106][CH:107]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:100][CH2:101][C:102]4[CH:107]=[CH:106][CH:105]=[C:104]([OH:108])[CH:103]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1cccc(O)c1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cccc(O)c6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 3-aminomethyl-phenol. MS (ES+) m/e 745.47 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCCC2O
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.3 %

Procedure:
6-Methoxytetralone (10 g, 0.057 mol) was mixed with 150 ml of dry ethanol and sodium borohydride (1.2 eq) was added by portions to the stirred mixture. The reaction mixture was left to stir at ambient temperature for 15 h. The reaction mixture was then concentrated by rotary evaporation, mixed with 100 ml of water and heated for 1 h at 45° C.. The resulting mixture was extracted into diethyl ether (3×80 ml). Combined organic extract was dried over Na2SO4 and concentrated by rotary evaporation to give 10.39 g of yellow oil which was used in the next step without additional purification.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.09 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH:4]([Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COCC(Br)c1ccccc1
Yield: 84.2 %

Procedure:
A solution of methylphenethylether (1.0 g, 7.34 mmol), NBS (1.96 g, 11.01 mmol) and AIBN (240 mg, 1.47 mmol) in carbon tetrachloride (30 ml) was heated under reflux for 2 hours. After cooling, the reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a crude 2-methoxy-1-phenylbromoethane (1.33 g, 84%) as brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[NH2:22][NH2:23].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[N:22][NH2:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NN
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=NN)n2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.1 %

Procedure:
In 2 ml of ethanol was dissolved 50 mg (0.17 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 26 mg (0.5 mmol)of hydrazine hydrate, and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was washed with n-hexane to precipitate the product, and 34 mg (yield 65%)of Compound I-11 was obtained by the filtration. mp 118-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([NH2:9])[CH2:11][CH2:10]2)[N:3]=1
Reactant: CC[Mg]Br
Reactant: Cc1ccnc(C#N)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(C2(N)CC2)n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1 eq) in dry THF under an argon atmosphere was added titanium isopropoxide (0.58 ml, 2.0 mmol, 1.2 eq) slowly at ambient temperature and the reaction mixture was stirred for 15 min. Ethyl magnesium bromide (1 M solution) in THF (4 ml, 4.0 mmol, 2.4 eq) was added via syringe slowly at ambient temperature (during the addition of EtMgBr, the reaction mixture turned black). Then the reaction mixture was stirred for an hour. BF3.EtO (0.36 ml, 2.6 mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 10 ml of water was added to the reaction mixture, which was then filtered through Celite and the bed washed with water and ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) and then extracted with DCM. The organic was washed with brine, dried over sodium sulphate and concentrated to get the crude product which was taken for coupling reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:19]3[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=3)[CH:23]=2)=[O:26])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: COc1ccccc1N1CCN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CC1
Yield: 28 %

Procedure:
This compound was synthesized from 1-(2-methoxy-phenyl)-piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (63 mg, yield 28%). 1H NMR (400 MHz, CDCl3) δ 8.22-8.19 (m, 2H), 7.69-7.60 (m, 2H), 7.08-7.04 (m, 1H), 6.96-6.89 (m, 3H), 4.02 (m, 2H), 3.89 (s, 3H), 3.64 (m, 2H), 3.18 (m, 2H), 3.04 (m, 2H). MS (ESI) m/z: Calculated for C21H19F3N4O3: 432.14. found: 433.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=O)=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:22][CH:23]=1)[S:6]([C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])(=[O:7])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCC=O)cc2)c(C)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCCN3CCCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.1 %

Procedure:
To a solution of N-(2-chloro-4-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.040 g, 0.08 mmol) in 0.5 mL methylene chloride was added piperidine (0.009 g, 0.11 mmol) and NaB(OAc)3H (0.034 g, 0.16 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% methanol/methylene chloride) afforded 0.052 g of the title compound. MS 541.1 (M+1)+
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.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.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:26]([C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
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(F)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 29.7 %

Procedure:
In a similar fashion compound to 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 (50.00 mg, 0.1702 mmol), 4-Fluorobenzaldehyde (23.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 20.09 mg (30%) of the title compound. (300 MHz, DMSO-d6) 13.31 (s, 1H), 8.18 (s, 2H), 7.96 (m, 1H), 7.77 (s, 1H), 7.41 (m, 2H), 7.23 (s, 2H), 6.40 (m, 2H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=398 (M+H), HPLC: 2.54 min. (G Method)
Reaction SMILES: [C:1]([O:4][C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:3])[CH3:2].[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23]>>[OH:24][C:22]([CH3:23])([CH2:21][CH2:20][CH2:19][CH:13]1[CH2:14][CH:15]2[CH2:18][CH:12]1[CH:17]=[CH:16]2)[CH2:2][C:1]([O:4][C:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])=[O:3]
Reactant: CC(=O)CCCC1CC2C=CC1C2
Reactant: CCC(CC)(CC)OC(C)=O
Product: CCC(CC)(CC)OC(=O)CC(C)(O)CCCC1CC2C=CC1C2
Yield: 91 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 3-ethyl-3-pentyl acetate was used instead of 1-ethylcyclopentyl acetate, and 5-(5-norbornen-2-yl)-2-pentanone was used instead of 5-norbornene-2-carbaldehyde. There was obtained 3-ethyl-3-pentyl 3-hydroxy-3-methyl-6-(5-norbornen-2-yl)hexanoate. Yield 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13]=[O:14]>C(O)(C)(C)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: Cc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reactant: C=O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to a mixture of 2,4-dichloro-6-nitrotoluene (1.03 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. It was stirred for 5 min at room temperature and for 30 min at 70° to 80° C. (oil bath temperature). The mixture was then allowed to cool to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (30 ml). The aqueous phase was post-extracted with EtOAc (2×30 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 30 ml, PE/EtOAc 10:1 110 ml, 9:1 100 ml, 8:1 360 ml, 7:1 80 ml). 2-(2,4-dichloro-6-nitrophenyl)ethanol (769 mg, 65%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:16]O>O>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccnc1O

Procedure:
To a solution of 2-hydroxynicotinic acid (3.0 g) in methanol 15 ml, 1 ml of concentrated sulfuric acid was added, and the reaction solution was heated to reflux for 2 hours. The reaction solution was cooled, then the solvent was distilled off under reduced pressure, and the residue obtained was diluted with water and extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a pale pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>CN(C)C=O.[Pd]>[CH2:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[NH2:19]
Reactant: O=C(/C=C/c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1cccc(CCCc2cccc(N)c2)c1
Reaction time: 72 h
Yield: 4.7 %

Procedure:
To a solution of (2E)-1,3-bis(3-nitrophenyl)prop-2-en-1-one (2.8 g, 0.0094 mol) in N,N-dimethylformamide (20 mL) was added 10% (by wt.) palladium on carbon and acetic acid (2.0 mL). The mixture was degassed with vacuum and purged with hydrogen three times before shaking on a Parr shaker for 72 hours under a hydrogen atmosphere. The mixture was filtered through celite, evaporated and purified by preparative LCMS (pH 10) to give the desired product (101 mg, 5%). LCMS for C15H19N2 (M+H)+: m/z=227.2.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:7]2[CH:8]3[CH2:16][C:15]([CH3:17])([CH3:18])[S:14][CH:9]3[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)(C)S1
Reactant: O=C(O)CCCN1CCCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1SC(C)(C)CC21

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-4H-thieno-[2,3-c][1]benzopyran with γ-pyrrolidinobutyric acid hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 there is obained obtained -dihydro-7-(3-methyl-2-octyl)-9-[4-(pyrrolidino)butyryloxy]-2,2,4,4-tetramethyl-4H-thieno-[ 2,3-c][1]benzopyran hydrobromide.
Reaction SMILES: FC1C=C(C2C3C(=CC=C(OC)C=3)C=NC=2C#N)C=CC=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])=[C:25]([C:42]#[N:43])[N:24]=1.ClC1C2C(=CC(OC)=CC=2)C(C2C=CC=C(F)C=2)=C(C#N)N=1>>[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:23]=[N:24][C:25]=1[C:42]#[N:43]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3F)c2c1
Agent: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Agent: COc1ccc2cnc(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2cnc(C#N)c(-c3ccccc3F)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile, using 1-chloro-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in place 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32](OCC)=[O:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:37].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH2:32][OH:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:37]
Reactant: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCCc5ccccc54)ccc3Cl)c2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(CO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-ethoxycarbonyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (87 mg) in tetrahydrofuran (1.6 mL) was added diisobutylaluminium hydride (0.99 mol/L toluene solution, 0.65 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−ethyl acetate) to give the title compound (63 mg).