Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([CH:33]=[O:34])C>>[CH2:22]([O:34][C:33]1[CH:11]=[CH:6][C:5]([CH2:13][N:12]2[C:11]3[C:10]4[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=4[O:8][CH2:7][C:6]=3[C:5]3[C:13]2=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(OCc3ccccc3)cc2)-c2ccccc2OC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (100 mg, 0.398 mmoL) in DMF (2 mL) was added NaH (60%, 24 mg, 0.598 mmoL) at 0° C. After 10 minutes, benzyl chloride (139 mg, 0.598 mmoL) was added dropwise into the reaction mixture at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layers from the two extractions were combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 4:1 as eluent) to yield the title compound as a pale solid.
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:19]([C:21]1[CH:29]=[CH:28][C:24](C(Cl)=O)=[CH:23][CH:22]=1)#[N:20].[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:18])=[O:7])=[CH:28][CH:29]=1)#[N:20]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)c3ccc(C#N)cc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=480.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.CCN=C=NCCCN(C)C.Cl.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)O)c2c(=O)n1Cc1ccccc1Cl
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)N3CCOCC3)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 4 (16.0 mg, 26 μmol), 4-dimethylaminopyridine (0.6 mg, 5.2 μmol), and EDC hydrochloride (5.3 mg, 28 μmol) in DMF (0.5 mL) was added morpholine (2.3 μL, 26 μmol). The reaction mixture was stirred at RT overnight and then diluted with water (5.0 mL). The resulting solid was collected by filtration and purified by flash column chromatography, eluting with 0-7% methanol in DCM to afford the title compound, Example 5, (7.0 mg, 57%) as a yellow solid: m/z 689/691 (M+H)+ (ES+); Rt 3.54 min; 1H NMR (500 MHz, DMSO-d6) δ: 1.71 (2H, quin), 2.43-2.49 (2H, m), 2.52-2.55 (2H, m), 3.20-3.26 (2H, m), 3.28-3.33 (4H, m), 3.44 (2H, t), 5.28 (2H, s), 5.72 (2H, s), 6.17 (1H, d), 6.78 (1H, t), 6.87 (2H, d), 7.02 (1H, t), 7.10 (1H, d), 7.32 (2H, d), 7.60 (1H, d), 7.67 (1H, d), 7.79 (1H, t), 8.16 (1H, s), 9.75 (1H, s).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][CH:21]1[CH2:23][O:22]1>C1COCC1>[CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH2:5][CH2:20][CH:21]1[CH2:23][O:22]1
Reactant: ClCC1CO1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC1CO1
Temperature: -75 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a stirred solution of trimethyl(prop-1-ynyl)silane (3 g, 26.7 mmol) in dry THF (100 mL) cooled at −72° C., was added drop by drop 2.5 N nBuLi in hexane solution (10.5 mL, 26.2 mmol). The resulting mixture was stirred at −75° C. for 1 h 30. Then 2-(chloromethyl)oxirane (2.42 g, 26.2 mmol) in dry THF (2 mL) was slowly added. The resulting mixture was stirred at −72° C. for 1 h 30, then warmed up to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford 4.50 g trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (Yield: 100%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:11][CH:10]=1.CC1(C)CC(=O)OC(=O)C1>>[O:5]=[C:4]1[CH2:3][CH2:2][C:1](=[O:6])[N:8]1[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CCC2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and succinic anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 251 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([C:23]#[N:24])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.CO>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Reaction time: 18 h

Procedure:
Combine 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic diethyl ester (1.3 g, 3.24 mmol) and cobalt(II)chloride hexahydrate (1.54 g, 6.48 mmol) in methanol (50 mL). While maintaining the temperature at or below 20° C. with an ice-bath, add portionwise sodium borohydride (2.17 g, 57 mmol). After the addition is complete, allow the reaction mixture to stand at ambient temperature for 18 hours. Evaporate the reaction mixture invacuo to obtain a residue. Partition the residue between dichloromethane and 1M hydrochloric acid solution. Extract the aqueous layer several times with dichloromethane, combine the organic layers, dry over Na2SO4, filter, and concentrate invacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 20/1 ethyl acetate/methanol. Remove residual solvent inuacuo at 82° C. to give the title compound: Rf= 0.74 (silica gel, 5/1 ethyl acetate/methanol); mp; 116°-118° C. Elemental Analysis calculated for C16H21NO5 : C 62.53; H 6.89; N 4.56; Found: C 62.52; H 6.85; N 4.50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:29]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30]1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)c1cc2c(ncn2-c2cccc(Br)c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Nc1cccc(Br)c1
Product: CCOC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 85 °C
Yield: 97.5 %

Procedure:
A flask containing a mixture of ethyl 1-(3-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (334 mg, 1 mmol, prepared according to the procedure described for example 1 except using 3-bromoaniline in the first step) and 3-thiophene boronic acid (256 mg, 2 mmol) was degassed and placed under a nitrogen atmosphere To this was quickly added tetrakis(triphenylphosphine)palladium(0) (173.3 mg, 0.15 mmol) in one portion followed by degassed solutions of 1,4-dioxane (5 mL) and aqueous sodium carbonate (2 M, 3 mL). The reaction mixture was heated at 85° C. under nitrogen for 24 hours after which time it was cooled, filtered and concentrated in vacuo. The resulting crude material was chromatographed over silica gel eluting with MeOH:CH2Cl2 0%→2%] to afford 329 mg (97.5%) of ethyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate. 1H NMR (400 MHz, CDCl3): δ=8.02 (s, 1H), 7.75-7.72 (m, 1H), 7.58-7.53 (m, 3H), 7.48-7.41 (m, 3H), 6.98 (d, J=1.2 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). MS (ES+): m/z 338.13 (100) [MH+].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][C:23]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:24][CH:25]=1
Reactant: Brc1ccc2ncnc(-c3cccs3)c2c1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 60 °C

Procedure:
0.18 mL chlorosulfonic acid and 0.19 mL thionyl chloride were added to 0.1 g of 6-bromo-4-(2-thienyl)quinazoline (compound in Production Example 96) under ice-cooling in a stream of nitrogen, and the mixture was heated for 13 hours at 60° C., then neutralized by adding water and a sodium bicarbonate solution and extracted with dichloromethane. 5-(6-Bromoquinazolin-4-yl)-thiophen-2-sulfonyl chloride obtained by drying the organic layer over anhydrous sodium sulfate was dissolved in 3 mL tetrahydrofuran, then 0.3 mL morpholine was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was removed, and the positional isomers were separated and purified by silica gel column chromatography (ethyl acetate/hexane) to give 57 mg of the title compound (colorless crystals).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:29][NH:28][CH2:27][CH2:26][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:14]=2)=[CH:5][CH:4]=1.[CH2:30](N(CC)CC)[CH3:31].ICC.Cl.C([OH:43])C>CO>[OH2:43].[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:29][N:28]([CH2:30][CH3:31])[CH2:27][CH2:26][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[N:14]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2nc3c(c(-c4ccc(Cl)cc4)n2)CNCC3)cc1
Reactant: CCO
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCI
Solvent: CO
Product: CCN1CCc2nc(Nc3ccc(C(F)(F)F)cc3)nc(-c3ccc(Cl)cc3)c2C1
Product: O
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(4-trifluoromethylphenylamino) -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine monohydrochloride (0.70 g, 1.73 mmol), triethylamine (0.5 mL, 3.6 mmol) and iodoethane (0.14 mL, 1.73 mmol) in ethanol (20 mL) was heated to reflux overnight. The mixture was cooled to room temperature, concentrated in vacuo, and chromatographed (silica gel, 5% methanol in methylene chloride). The hydrochloride salt was prepared by adding concentrated hydrochloric acid to a solution of the free base in methanol and recrystallized from acetone to give 0.21 g (28%) of 4-(4-chlorophenyl)-6-ethyl-2-(4-trifluromethylphenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride monohydrate. m.p. 273°-275° C. MS: 433 (MH+).
Reaction SMILES: [N:1]([CH:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[N+:2]=[N-:3].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.FC(F)(F)C(O)=O.[NH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:19][CH2:18][CH2:17][O:16][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[NH:51][CH2:52][CH2:53][NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH:8]=1)[CH3:25]
Reactant: NCCNC(=O)C(F)(F)F
Reactant: CCOC(=O)COCCOC(COc1cccc(C(=O)O)c1)N=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COCCOC(COc1cccc(C(=O)NCCNC(=O)C(F)(F)F)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
3-[2-Azido-2-(2-ethoxycarbonylmethoxyethoxy)ethoxy]benzoic acid (0.212 g, 0.6 mmol) was stirred with N,N′-disuccinimidyl carbonate (0.184 g, 0.72 mmol) and DMAP (0.088g, 0.72 mmol) in dry DMF (1 ml) at room temperature. After 10 minutes, trifluoroacetic acid salt of N-(2-amino-ethyl)-2,2,2-trifluoroacetamide (0.194 g, 0.72 mmol) was added followed by diisopropylethylamine (DIPEA) (0.251 ml, 1.44 mmol). The reaction mixture was then stirred at room temperature for 17 hours. All the solvents were evaporated under reduced pressure and the residues were partitioned between DCM (50 ml) and aqueous NaH2PO4 (1 N, 50 ml). The aqueous layer was further extracted with DCM (2×25 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (1×20 cm). The title compound, eluted with 1% methanol in DCM, was obtained as an oil (0.255 g, 86.6%). ES-MS, m/z 490.10 (M−1).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:15]C)(=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Na]>CO>[C:10]([O:12][CH2:13][C:5]1[O:6][CH:2]=[CH:3][CH:4]=1)(=[O:11])[CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: OCc1ccco1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
196 parts by wt. of furfuryl alcohol and 132 parts by wt. dimethyl malonate (stoichiometric proportions) are mixed and 0.5-0.75% wt. sodium metal added. The mixture is heated to a temperature in the range from 214°-240° F. under a nitrogen atmoshpere. Methanol is evolved and removed as the reaction progressed. After a period of 4 hours, a waxy solid is obtained. The liquid product obtained after washing with water is difurfuryl malonate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a room temperature solution containing 10 g of 4-bromo-3-fluorobenzoic acid (45.7 mmols) in 228 mL of dichloromethane was added 1.67 g of DMAP (13.7 mmols), 11.3 g of EDCI (59.2 mmols), and 5.11 mL of morpholine (59.4 mmols). After stirring at ambient temperature for 18 h, 20 mL of water was added to the reaction mixture. The layers were separated, and the organic layer was washed with water (3×20 mL), dried over MgSO4, and filtered through a frit. The resulting solution was concentrated to a pale yellow oil which was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60A , 85 ml/min, A: EtOAc, B: hexanes, A: 50% for 5 min, then 50-70% for 8 min) to give 8.62 g (66%) of title compound as a yellow oil. MS (ES) m/e 288 [M+]+.
Reaction SMILES: C(O[C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])(C)(C)C.[F:39][C:40]([F:45])([F:44])C(O)=O.C(N(CC)CC)C.FC(F)(F)C(OCC)=O>C(Cl)Cl.C1COCC1>[F:39][C:40]([F:45])([F:44])[C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:16]2)=[O:12])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNC(=O)C(F)(F)F)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 2 h

Procedure:
{2-[(1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (25 mg, 0.049 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 h. Solvent and excess TFA was removed by evaporation, and to the residue were added THF (3 mL), triethylamine (0.034 mL, 0.24 mmol), and ethyl trifluoroacetate (2 mL). The resulting mixture was refluxed overnight, then concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated, and the crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 12.7 mg of the title compound as a light yellow solid. MS: (+) m/z 511.33 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)=[O:28]>C(#N)C>[Cl-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:31]=[N:32][CH:33]=[N:34][CH:35]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCl)Nc1cncnc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1cncnc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (115 mg) in acetonitrile (2 mL) was treated with 2-chloro-N-pyrimidin-5-yl-acetamide (Example 52a) (66 mg) to give a dark brown solution that was stirred at room temperature overnight. The resulting solid was filtered off, washed with cold acetonitrile (2 mL) and pentane (3 mL) and dried under vacuum at 45° C. to give the title compound as a tan solid (151 mg).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([OH:13])=O)[CH2:3]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([NH2:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:48][C:11](=[O:13])[CH2:10][CH:4]2[CH:5]3[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]3)[CH2:3]2)([CH3:46])[CH3:47])=[CH:43][CH:44]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: O=C(O)CC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH3:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[NH:24][C:22](=[O:23])[C:18]2[NH:19][N:20]=[N:21][C:17]=2[N:16]=1>C(#N)C.C(OCC)C>[CH3:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[NH:24][C:22](=[O:23])[C:18]2[NH:19][N:20]=[N:21][C:17]=2[N:16]=1.[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: CCCOc1ccccc1-c1nc2nn[nH]c2c(=O)[nH]1
Solvent: CCOCC
Solvent: CC#N
Product: O=[N+]([O-])[O-]
Reaction time: 0.5 h

Procedure:
0,5 ml of a solution nitric acid 65%/ acetonitrile (2,7 ml/7,3 ml) was added at 0° C. to a solution of Zaprinast (0,5 g, 1,84 mmoles) in acetonitrile (10 ml) and the obtained mixture was stirred in the dark and under a nitrogen atmosphere for 30 minutes. The solution was then diluted with diethyl ether and the formed precipitate filtered, washed with diethyl ether and dried under vacuum.( 0,4 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[OH2:1].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2occc2c1
Product: O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2occc2c1

Procedure:
To a solution of 5-bromobenzofuran (4.7 g, 23.8 mmol),dissolved in 100 mL of anhydrous tetrahydrofuran at -78° C. under a nitrogen atmosphere, was added 15.0 mL of a 1.6 M hexanes solution of n-butyllithium (23.8 mmol). The reaction was warmed to 0° C. and stirred for 15 minutes. Sulfur dioxide gas was bubbled through this mixture for 20 minutes at 0° C. and the reaction concentrated under vacuum. The residue was dissolved in 250 mL of water. To this solution were added 15.6 g (190 mmol) of sodium acetate and 8.3 g (73.7 mmol) of hydroxylamine-0-sulphonic acid. This reaction was stirred at room temperature for 1.5 hours. The solution was extracted with diethyl ether (2×150 mL). The combined organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography of the residue with 18% ethyl acetate/hexanes on silica gel provided 2.3 g (10.0 mmol) of 5-benzofuransulfonamide. The 5-benzofuransulfonamide was reacted with 4-chlorophenylisocyanate (10.0 mmol), as described in Method A above, to obtain 1.4 g of the title product as a solid. 1H NMR (CD3SOCD3): δ0.62 (bs, 1 H), 9.02 (s, 1 H), 8.38 (d, J =2 Hz, 1 H), 8.20 (d, J =2Hz, 1 H), 7.96 (dd, J =2, 9 Hz, 1 H), 7.86 (d, J =9 Hz, 1 H), 7.38 (d, J =9 Hz, 2 H), 7.30 (d, J =9 Hz, 2 H), 7.20 (d, J =2 Hz, 1 H).