Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([C:39]([O:41][CH3:42])=[O:40])[N:32]=[CH:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([C:39]([O:41][CH3:42])=[O:40])[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Product: COC(=O)c1ncn(CCCc2ccc(OCc3coc(/C=C/c4ccccc4)n3)cc2)c1C(=O)OC
Yield: 63 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with dimethyl 4,5-imidazoledicarboxylate to give dimethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxylate. The yield was 63%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](Cl)=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][N:25]=[C:17]([Cl:16])[CH:18]=2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1C(F)(F)F)c1ccnc(Cl)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
2.6 g (0.01 mol) of 4-chloro-2-trifluoromethylbenzenesulfonamide were dissolved in 20 ml of pyridine, 2-chloroisonicotinoyl chloride was added dropwise at room temperature. Agitation was then continued for 2 hr. at the same temperature. The reaction mixture was acidified by adding aqueous hydrochloric acid, and the precipitate thus formed was extracted by ethyl acetate. The organic layer obtained was dried and then concentrated to precipitate crude crystals, which were recrystallized by solvent mixture of n-hexane and ethyl acetate to produce 3.4 g (yield: 85.1%) of N-(4-chloro-2-trifluoromethylphenylsulfonyl)-2-chloroisonicotinamide as white crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>C1C=CC=CC=1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc2ccccc2c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.60 g of 2-naphthol, 1.19 g of sodium methoxide and 50 mg of potassium iodide is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The solution is maintained at reflux overnight and then poured into 100 ml of water. The mixture is then extracted with 2 × 75 ml of ether and the combined extracts are washed with 2 × 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) yields a green glass. Further elution with 200 ml of benzene yields the product as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CN(C)CCN
Product: CN(C)CCNc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-dimethylamino-ethylamine analogously to the preparation of Intermediate 113.1 as a colorless oil; 1HNMR (CDCl3) δ 9.20 (bs, 1H), 7.18-7.10 (m, 2H), 6.95 (d, 1H), 4.60 (s, 2H), 3.80 (s, 2H), 3.25-3.05 (m, 4H), 2.25 (s, 6H); HPLC: AtRet=1.26 min.
Reaction SMILES: C([O-])(=O)C.[Na+].[N-:6]=[N+:7]=[N-:8].[Na+].[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]1[C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21][O:20][CH2:19]1)=[O:16])([CH3:13])[CH3:12].O>CN(C=O)C.C(OCC)(=O)C>[N:6]([C@@H:23]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[NH:17][C:15](=[O:16])[O:14][C:11]([CH3:12])([CH3:10])[CH3:13])=[N+:7]=[N-:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N=[N+]=[N-]
Temperature: 95 °C
Yield: 80.4 %

Procedure:
Sodium acetate (129 g), sodium azide (102 g) and 1,5-anhydro-2,4-dideoxy-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-O-(methylsulfonyl)-L-threo-pentitol (232 g) were mixed in DMF (1 l) and stirred and heated at 95° C. for 6 h. Water (2 l) was added and the mixture thoroughly mixed, ethyl acetate 1.5 l) was added and the mixture stirred for 5 min. The phases were separated, the aqueous extracted with ethyl acetate (1 l), the combined organics washed with water (2×2 l), dried and reduced to dryness in vacuo to give 1,1-dimethylethyl [(3R,4R)-4-azidotetrahydro-2H-pyran-3-yl]carbamate (153 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.CN(CCN(C)C)C.[O:34]=[CH:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([O:39][C:38]([NH:37][CH2:36][CH:35]([C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)[OH:34])=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of LDA (prepared by adding n-butyllithium (20.0 mL, 49.3 mmol) to diisopropylamine (5.16 mg, 51.0 mmol) in THF (40 mL) at 0° C., stirred for 30 min) was added 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.00 g, 16.4 mmol) in TMEDA (15 mL, 99 mmol) drop-wise via syringe pump at −78° C. for 10 min. The mixture was stirred at the same temperature for 30 min, then tert-butyl (2-oxoethyl)carbamate (8.11 g, 51.0 mmol) in THF (20 mL) was added slowly by syringe pump for 15 min. The mixture was stirred at −78° C. for 30 min, quenched with saturated NH4Cl at −78° C., warmed up to rt and diluted with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (80 g, silical gel, MeOH/DCM, gradient 0-10%, monitor at 210 nm) to afford title compound. LC/MS: [(M+1)]+=403
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[NH2:7].[N:17]#[C:18][NH2:19].Cl>C(O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:7][C:18]([NH2:19])=[NH:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CN
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydrochloride (3 g, 12.52 mmol), cyanamide (0.684 g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was concentrated under reduced pressure before the residue was poured on potassium carbonate (1.730 g, 12.52 mmol) in water (60 mL) and then put in refrigerator o.n. The formed carbonate-salt was filtered off, and dried in vacuum oven o.n. The solid was washed with several portions of DCM, dried and used as such in next step (52.3%). MS (ES+) m/z 246.2 (M+H)+
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]([C:9](=[O:24])[CH2:10][CH2:11][CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][O:14]2)C(=O)O1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[O:24]=[C:9]([CH2:10][CH2:11][CH2:12][C:13]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:14][CH2:15][CH2:16][O:17]1)[CH2:5][C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: CC1(C)OC(=O)C(C(=O)CCCC2(c3ccccc3)OCCO2)C(=O)O1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(CCCC1(c2ccccc2)OCCO1)CC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Step AAH (4): To a solution of 2,2-dimethyl-5-(4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl)-1,3-dioxane-4,6-dione (4.0 g, 11.04 mmol) in xylene (30 mL) was added aniline (1.21 mL, 13.3 mmol). The r×n was stirred at 140° C. for 2 h. The crude reaction contents were directly loaded onto silica gel and purified by silica gel column chromatography (60% EtOAc/hexanes) to afford 3-oxo-N-phenyl-6-(2-phenyl-1,3-dioxolan-2-yl)hexanamide (3.0 g, 77% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 9.16 (br. s., 1 H) 7.54 (d, J=7.63 Hz, 2 H) 7.44 (d, J=7.02 Hz, 2 H) 7.28-7.39 (m, 5 H) 7.12 (t, J=7.48 Hz, 1 H) 3.97-4.07 (m, 2 H) 3.72-3.82 (m, 2 H) 3.53 (s, 2 H) 2.60 (t, J=7.32 Hz, 2 H) 1.89-1.97 (m, 2 H) 1.67-1.79 (m, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: CCCCn1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and butyl bromide (0.81 ml) to give Compound 4 (1.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:15]=[N:16][CH:17]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cncc(Br)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 5-bromopyridin-3-ol.
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12]>CCO.[Pd]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](O)[C@](C)(N)CO
Reaction time: 48 h

Procedure:
To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (30B, 22.1 g, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parr apparatus at 50 psi of H2 during a 48 h period at RT. The catalyst was removed by filtration through a Millipore* filter, and the solvent removed under vacuum (2 days. The viscous, colorless syrup was dissolved in abs. EtOH (30 mL). Dilution with abs. Et2O (300 mL) gave a cloudy liquid which was placed in a refrigerator for two days. During this time, colorless crystals formed. They were washed with Et2O and dried in a vacuum oven at RT for two days. The yield of (+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate was 25.6 g (97%) mp 117°-121°, (C, H, N).
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B78) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (304 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 65/30/5 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: Sc1ccccc1
Solvent: ClCCl
Product: O=C1c2c(O)cccc2C(Sc2ccccc2)c2cccc(O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (3.05 g) was dissolved in dichloromethane (100 ml) and thiophenol (1.1 ml) was added. The red-brown solution became yellow-green, and was then left, with stirring, at room temperature for 5 hours. Removal of the solvent gave a yellow solid which, after recrystallisation from a hexane/chloroform mixture (10:1), afforded 1,8-dihydroxy-10-phenylthio-9-anthrone (2.89 g, 87%) as pale yellow needles, melting point 156°-157° C. (Found: C 71.8, H 4.2, S 9.95; C20H14O3S requires C 71.85, H 4.2, S 9.6%.)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:37])[CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[CH:29]=2)[CH2:24]1.COC1C(OC)=CC=C2C=1CCC(NC)C2>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:37])[CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[CH:29]=3)[CH2:24]2)=[O:14])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCN)CC2
Agent: CNC1CCc2c(ccc(OC)c2OC)C1
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2

Procedure:
The title compound of this paragraph is prepared from 4,5-dimethoxy-2-nitrophenylacetic acid (5.25 g, 0.0217 mol) and of 1-amino-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (6.04 g, 0.0218 mol) analogously to Example R(c). Yield: 8.6 g. Rf value: 0.8 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:16]([NH2:18])[CH3:17].CO>>[CH2:16]([NH:18][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CCN
Solvent: CO
Product: CCNCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
Into a 100 mL round bottom flask was placed tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g, 9.38 mmol). To this was added 2M ethanamine in methanol (23.44 ml, 46.9 mmol). A condenser was attached to the flask and the solution was stirred at reflux (100° C.) overnight. The solution was cooled and concentrated in vacuo to afford the title compound (2.4 g) which was carried forward without further purification. MS(ES)+ m/e 259.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1.Cl.Cl[Sn]Cl>CO>[CH3:13][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])[CH3:1]
Reactant: CN(C)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: CN(C)Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 11 (1.2 g, 6.67 mmol) in methanol (100 mL) were sequentially added conc. HCl (10 mL) and SnCl2 (5 g, 26.67 mmol). The reaction mixture was stirred at room temperature overnight before it was partitioned between water and EtOAc (200 mL each). The organic layer was separated and washed with water (150 mL), brine (150 mL) and dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 12 (500 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:45](=[O:47])[CH3:46])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
1-Acetyl-N-{3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl}-4-piperidinecarboxamide (Example 303) (18 mg, 6.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and acetyl chloride (3.4 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (18 mg, 0.031 mmol, Yield 93%) as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:20])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:21][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([NH:20][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: CN(C)C(=O)N1CC2CC(N)(Cc3ccccc3)CC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1
Yield: 56.3 %

Procedure:
5-Amino-5-benzyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14f (0.1 g, 0.35 mmol) was dissolved in 4 mL of the solvent mixture of dichloromethane/N,N-dimethylformamide (V/V=1/1) followed by addition of (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (66.5 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol). The reaction mixture was reacted at 40° C. for 12 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-5-[2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14g (87 mg, yield 56%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:17][CH2:16]1.[H-].[Na+].[CH3:35]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:32][CH3:35])=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:17][CH2:16]1
Reactant: CI
Reactant: COc1ccc2c(C)noc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c(C)noc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
65 mg of 1-(1-(2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide obtained in Example 1 was dissolved in 1 ml of N,N-dimethylformamide, and then, 7.2 mg of 60% sodium hydride was added thereto. The reaction solution was stirred at room temperature for 5 minutes, and 11.2 μl of methyl iodide was then added to the reaction solution. After completion of the reaction, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), so as to obtain 17 mg of the subject compound.