Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH3:21])[CH:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[C:9]3[C:13]([O:19]C)=[CH:14][C:15]([O:17]C)=[CH:16][C:8]=3[O:7][C:6]=2[CH:21]=1.Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[C:9]3[C:13]([OH:19])=[CH:14][C:15]([OH:17])=[CH:16][C:8]=3[O:7][C:6]=2[CH:21]=1
Reactant: COc1cc(OC)c2c(c1)Oc1cc(Br)ccc1CC2=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1Cc2ccc(Br)cc2Oc2cc(O)cc(O)c21
Temperature: 195 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To 395 mg (F.W. 349.18, 15.75 mmol) of dimethoxylated compound (27) was added 2.0 g of pyridine hydrochloride and stirred at 195° C. for 1.5 hours and then, ice water was slowly added thereto. The resulting solution was extracted with ethyl acetate and the extract was washed with 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution in the order named. The extract thus washed was dried with anhydrous magnesium sulfate and then, concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:2). Furthermore, the product thus obtained was recrystallized from dioxane and dioxane-hexane to obtain 223 mg (61%) of the title compound. (TLC; ethyl acetate:hexane=1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[N:25]1([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:33]1[CH2:34][CH2:35][CH2:36][CH:31]([CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:32]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CNCC(CN2CCCC2)C1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC(CN3CCCC3)C2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-(pyrrolidin-1-ylmethyl)piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.05 minutes; C26H29Cl2N5O2 (514.45); mass spectrum: (M+H)+=514.2.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:13]3[C:12](=[O:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([C:6]2[C:15]([C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[O:27])=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:13]3[CH:12]([OH:35])[CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)C1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O)C1
Reaction time: 20 h

Procedure:
625.3 g of 2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one were reduced at 0° to −5° C. in 6 liters of tetrahydrofuran using 56.4 g of IR,2S-aminoindanol and 800 g of boranediethylaniline complex. Quenching of the reaction was carried out after approximately 20 hours using 500 ml of 1,2-ethanediol. The tetrahydrofuran was distilled off, the resulting oil was taken up in ethyl acetate and the organic phase was dried and concentrated after washing with 2 N hydrochloric acid and saturated sodium hydrogen carbonate solution. The residue was recrystallized hot from cyclohexane. A total of 574 g of colorless crystals having a purity of 99.4% according to HPLC (e.e. 97.4%) resulted.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)=[N:5][C:6]([S:29][CH3:30])=[N:7][C:8]=1[CH:9]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:2].[CH2:40]=O>>[C:1]([C:3]1[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)=[N:5][C:6]([S:29][CH3:30])=[N:7][C:8]=1[CH:9]=[CH2:40])#[N:2]
Reactant: C=O
Reactant: CSc1nc(C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Product: C=Cc1nc(SC)nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Temperature: 25 °C

Procedure:
A solution of 5-cyano-2-methylthio-4-(3-nitro-phenyl)-6-[(triphenylphosphanylidene)-methyl]-pyrimidine (example 27a, 7.04 g,)) in TBF (64 ml) was treated with aqueous formaldehyde (37 wt. %, 3.55 ml) at 60° C. for 1 h. After the mixture was cooled to room temperature, it was diluted with EtOAb (100 ml) and washed with water (2×50 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc=9/1 to 3/2 (v/v) as the eluent.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:43])[C:31](OC3C=CC([N+]([O-])=O)=CC=3)=[O:32])[CH:25]=2)=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10].O>CN(C)C=O>[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:43])[C:31]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:32])[CH:25]=2)=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)C(=O)OC
Reactant: CCCCCCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cn2)c1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
70 μl (0.45 mmol) of heptylamine are added to a solution of 110 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-(6-{3-[methyl(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)propanoate in 3 ml of dimethylformamide. The reaction medium is heated at 80° C. for 3 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 6/4 and then 5/5 heptane/ethyl acetate mixture. 50 mg (50%) of methyl 2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH:27]C(OCC3C=CC=CC=3)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]=2[CH:10]=[CH:9]1)[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH2:27])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCCn1ccc2c(NC[C@H](N)C(=O)OC(C)(C)C)nc(C)nc21

Procedure:
709 mg of 4-[4-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-butyric acid ethyl ester were dissolved in 40 ml of ethanol and 1 ml of acetic acid and were hydrogenated over 100 mg of Pd/C (10%) during 4 h at room temperature. The catalyst was removed by filtration, the solvent was removed in vacuo. The residue was dissolved in 60 ml of DCM and stirred with 10 ml of brine and additional 5 g of NaHCO3. The phases were separated, the aqueous phase was extracted with DCM, the combined organic phases were dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 475 mg.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1>CC(N(C)C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-chloro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)=[C:8]([F:23])[C:7]=1[F:24])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:14][CH2:13]2)=[C:8]([F:23])[C:7]=1[F:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Temperature: 30 °C
Yield: 91.2 %

Procedure:
The compound (9) (55.0 g), p-toluenesulfonic acid (1.8 g) and toluene (300 ml) were mixed and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was dissolved in a mixed solvent of toluene (150 ml) and Solmix A-11 (150 ml), and palladium on carbon (3.0 g) was added and then the mixture was stirred at room temperature under an atmosphere of hydrogen until hydrogen absorption had ceased. After the completion of the reaction, palladium on carbon was removed and the solvent was distilled off. The resulting residue was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and heptane as an eluent. The product was further purified by recrystallization from Solmix A-11 to give 8-(4-butoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decane (10) (47.8 g). The yield based on the compound (9) was 84.0%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]=[N:18][N:19]([CH3:20])[C:11]=3[C:10](=[O:21])[C:9]=2[CH:8]=1.COC1C=CC=CC=1CC1C=CC2NC3C=NN(C)C=3C(=O)C=2C=1>>[OH:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]=[N:18][N:19]([CH3:20])[C:11]=3[C:10](=[O:21])[C:9]=2[CH:8]=1
Reactant: COc1cccc(Cc2ccc3[nH]c4cnn(C)c4c(=O)c3c2)c1
Agent: COc1ccccc1Cc1ccc2[nH]c3cnn(C)c3c(=O)c2c1
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(O)c4)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 1 in EXAMPLE 17 using 7-(3-methoxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 19, step 4), instead of 7-(2-methoxybenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 168-170° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.78 (s, 1 H), 4.82-4.78 (m, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 1.88-1.74 (m, 2 H), 1.70-1.60 (m, 2 H), 0.88 (t, J=7.5 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OCl3 (M+H)+: 386.0594; found m/z 386.0614.
Reaction SMILES: [C:1]([OH:6])(=[S:5])[CH:2](C)O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11]>>[C:1]([S:5][CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10]([OH:12])=[O:11])(=[O:6])[CH3:2]
Reactant: CC(O)C(O)=S
Reactant: C=C(C(=O)O)C(F)(F)F
Product: CC(=O)SCC(C(=O)O)C(F)(F)F

Procedure:
A mixture of thiolactic acid (50 g.) and 2-(trifluoromethyl)acrylic acid [M. W. Buxton, et al., J. Chem. Soc., 366 (1954)](66 g.) is heated on the steam bath for one hour and then stored at room temperature for eighteen hours. The reaction mixture is distilled in vacuo to give 3-acetylthio-2trifluoromethylpropanoic acid.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH2:9][C:10]2[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][O:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: OCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.9 %

Procedure:
A solution of 6-(triphenylmethoxymethyl)pyridine-2-methanol (16.8 g, 44 mmol) in CH2Cl2 at 0° C. was treated with triphenylphosphine (17.3 g, 66 mmol) and carbon tetrabromide (17.5 g, 52.8 mmol), stirred at 0° C. for 2.5 h then concentrated in vacuo to approximately a quarter of the original volume. The resulting solution was filtered through a pad of silica, washed with hexane:EtOAc (1:1) and the filtrate concentrated in vacuo to give the title compound (16.8 g, 86%) as a cream solid; NMR δH (400 MHz, DMSO) 4.14 (2H, s), 4.61 (2H, s), 7.27-7.48 (16H, m), 7.68 (1H, d, J 7.5 Hz) and 7.90 (1H, t, J 7.5 Hz); Rf (Hexane:EtOAc (2:1))=0.84
Reaction SMILES: [N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[CH:9][C:8]=2[Cl:21])[CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:5](=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[Cl:21])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccc(O)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(azetidin-1-yl)-2-[4-(benzyloxy)-2-chlorophenyl]ethanone (520 mg, 1.65 mmol) was dissolved in ethanol (2 ml) and palladium hydroxide on carbon (20%) (116 mg, 0.165 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. to afford the title compound. LC/MS (m/z): 226 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:5]1([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:1]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][O:22][CH2:21][CH2:20][OH:19])[CH2:26][CH2:27]2)=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1Sc1ccccc1
Reactant: OCCOCCN1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1Sc1ccccc1)N1CCN(CCOCCO)CC1
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out without isolation of intermediates in a one pot synthesis. Toluene (30 ml) and phosgene solution (20% in xylene, 9.1 ml, 17.16 mmol) were charged into a reaction flask. The mixture was cooled to −50° C. A mixture of 2-phenylsulfanylphenylamine (3 g, 14.9 mmol), triethylamine (2.4 ml, 17.1 mmol) and toluene (5 ml) was charged into the reaction flask at −50° C. during 5 min. The mixture was allowed to reach room temperature and it was stirred at room temperature for 1.5 h. Then the reaction mixture was added to another reaction flask at −10-0° C., containing the cooled mixture of 1-[2-(hydroxyethoxy)-ethyl]-piperazine, triethylamine (2.7 ml) and toluene (20 ml). The reaction mixture was stirred at room temperature for 1.5 h. Precipitated triethylamine hydrochloride was filtered off. The resulting toluene solution was washed twice with saturated NaCl-water (10 ml), dried with K2CO3 and evaporated in vacuo. The yield of 4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)-amide was 4.76 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: Nc1c(C(=O)C2CCCCC2)cc(Br)cc1[N+](=O)[O-]
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1c(C(=O)C2CCCCC2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution of (2-amino-5-bromo-3-nitro-phenyl)-cyclohexyl-methanone (600 mg, 1.83 mmol) in DME (25 mL) was added, successively, pyridine-3-boronic acid 1,3-propanediol cyclic ester (388 mg, 2.38 mmol), (tetrakistriphenylphosphine) palladium(0) (212 mg, 0.18 mmol), and 1N NaHCO3 (3.7 mL, 3.7 mmol). The resulting mixture was stirred at 90° C. for 90 minutes then cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, hexanes to 3:1 hexanes:EtOAc) to afford 527 mg (89%) of the title compound as a pale orange solid: 1H NMR (CDCl3, 500 MHz) δ 8.92 (d, 1H), 8.69 (d, 1H), 8.66 (d, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 7.71 (dd, 1H), 3.36 (m, 1H), 1.88 (m, 3H), 1.77 (m, 1H), 1.40-1.61 (m, 3H), 1.24-1.32 (m, 2H), 0.89 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][C:12]1([O:25][C:26]([O:28][CH3:29])=[O:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C:10]#[C:11][C:12]1([O:25][C:26]([O:28][CH3:29])=[O:27])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)OC1(C#CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)OC1(C#CCO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate (450 mg, 1.02 mmol) in 30 mL of anhydrous THF was added TBAF (800.5 mg, 3.06 mmol) at 0° C. under N2. After stirring for 1 h at 0° C., the reaction mixture was quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 290 mg of title compound. MS (ES) M+H expected 313.25, found 313.47. 1H NMR (CHLOROFORM-d) δ: 4.36 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.80-3.70 (m, 2H), 3.41-3.29 (m, 2H), 2.24-2.13 (m, 2H), 2.00 (ddd, J=13.2, 9.3, 3.9 Hz, 2H), 1.95 (s, 1H), 1.48 (s, 9H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:19].[K+].[C:21]([OH:24])(=O)C>>[O:13]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:21]([NH2:19])=[O:24])[O:12]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: [C-]#N
Reactant: CC(=O)O
Agent: [K+]
Product: NC(=O)C1(c2ccccc2)OC(=O)c2ccccc21
Temperature: 120 °C

Procedure:
A mixture of 2-benzoylbenzoic acid (75 g), potassium cyanide (35 g), and glacial acetic acid (175 mL) was heated at 115-125° C. in a sealed pressure bottle for 70 h. After cooling to ambient temperature, the precipitated solid was collected by filtration, washed with water and ethanol then crystallized from ethanol to give the title compound (45 g), m. p. 225-227° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=23)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:24](O)(=O)[CH3:25]>>[Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][N:17]([CH2:24][CH3:25])[CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([CH:6]2[CH:11]3[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc2c3c(n4c2c1CCNCC4)CCCC3
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCc2c(Cl)ccc3c2N(CC1)C1CCCCC31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.20 g, 0.73 mmole) in acetic acid (50 mL) was added excess sodium cyanoborohydride (0.23 g, 3.65 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 0.10 g of the title compound. This compound was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 184-187° C. MS (ESI) m/z 305 ([M+H]+).