Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH2:15][NH2:16])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:16][CH2:15][C:5]1([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:30]
Reactant: NCC1(CC2CC2)CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(CC2CC2)CCC2(CC1)OCCO2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {[8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}amine (7 g; 31.0 mmol) and n-ethyldiisopropylamine (6.45 ml; 37.2 mmol) in DCM (60 ml) at 0° C. was added 2,4-dichlorobenzoyl chloride (4.781 ml; 34.17 mmol) dropwise and the solution stirred for 4 hours warming to ambient temperature. The reaction was partitioned between DCM (50 ml) and water (20 ml). The aqueous phase was extracted with DCM (20 ml) and the combined organics dried over MgSO4, filtered and evaporated to give a colourless oil which was used in the next step without further purification. (11.5 g) 1H NMR δ (ppm) (CDCl3): 7.67 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=2.0 Hz), 7.32 (1H, dd, J=2.0, 8.4 Hz), 6.25 (1H, s), 3.93 (4H, s), 3.56 (2H, d, J=6.2 Hz), 1.67 (8H, m), 1.33 (2H, d, J=6.7 Hz), 0.75-0.65 (1H, m), 0.51-0.47 (2H, m), 0.05 (2H, q, J=5.0 Hz). MS (m/e)=398
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](Br)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].O1CCN([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)CC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(Br)=NNc1ccc(Cl)cc1
Reactant: C1=C(N2CCOCC2)CCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCCC2
Yield: 54.9 %

Procedure:
A solution of bromo-(4-chlorophenyl)hydrazonoacetic acid ethyl ester (18.24 g, 60 mmol) in toluene (390 ml) and 10.02 g (60 mmol) of morpholinocyclohexene (10.02 g, 60 mmol) was cooled to 0° C. and triethylamine (12.6 ml, 90 mmol) was added. The solution was reacted for 1.5 hours at 0° C. and at ambient temperature for 48 hours. Triethylamine hydrochloride was filtered, the filtrate was washed with 10% hydrochloric acid, dried and evaporated. The crude product was crystallized from methanol to yield pure title compound (10.04 g), m.p. 139°-140° C. (lit 139°-141° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:2]=1.[BH4-].[Na+]>CCO.CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([OH:13])[CH2:8]2)[CH:2]=1
Reactant: O=C1C=C(c2cccnc2)CCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O[C@H]1CCC[C@H](c2cccnc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
A mixture of 3-(3-pyridyl)-2-cyclohexen-1-one (19.1 g, 110 mmol) and 10% Pd/C (1.91 g) in EtOH (300 mL) was stirred under hydrogen atmosphere for 16 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. To a solution of crude product in MeOH (360 ml) was added portionwise NaBH4 (2.08 g. 55.0 mmol) at 3° C., and stirred for 30 min at same temperature. The reaction mixture was poured into ice-water and then extracted with AcOEt. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (NH, Hexane/EtOAc=2/1) to yield trans-3-(3-pyridyl)cyclohexanol (4.19 g, 21%) as colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=C)=[CH:34][CH:33]=1)#[N:31]>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:36][C:35]3[CH:38]=[CH:39][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(C#N)cc1
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=Cc3ccc(C#N)cc3)cccc12)NC(=O)OC(C)(C)C

Procedure:
(2-{7-[2-(4-Cyano-phenyl)-vinyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 4-cyanostyrene as described for the preparation of Amine 23 (93%). FDMS m/e=315.2 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].[Li+].[OH-]>>[F:30][C:27]([F:28])([F:29])[O:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([NH:16][C:14]3[N:13]([CH3:31])[C:12]4[CH:32]=[CH:33][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:8])=[CH:10][C:11]=4[N:15]=3)[S:18][C:19]=2[CH:25]=1
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCC(=O)O)ccc21
Yield: 83.3 %

Procedure:
3-{[2-(6-Trifluoromethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (200 mg) was prepared by following General Procedure E starting from 3-{[2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benz-imidazole-5-carbonyl]-amino}-propionic acid methyl ester (247 mg), and LiOH (1.0 ml, 2.0 N solution in water). LC/MS: m/z 481. 1H NMR (DMSO-d6, 400 MHz): δ 8.51 (t, 1H), 8.10 (br, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.75 (d, 1H), 7.64 (br, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 3.63 (s, 3H), 3.46 (m, 2H), and 2.58 (t, 2H), —COOH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](Cl)[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.ClC1C=C2C(=CC=1)C(=O)CC2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(Cl)cc(Cl)c21
Agent: O=C1CCc2cc(Cl)ccc21
Product: NC1CCc2cc(Cl)ccc21

Procedure:
This compound was prepared using a method analogous to that of 5,7-dichloro-2,3-dihydro-1H-inden-1-amine (A.2.13), 5-chloro-1-indanone replacing 5,7-dichloro-1-indanone.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([F:44])[F:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([F:43])[F:44])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(F)F)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C(F)F)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 19.1 %

Procedure:
Prepared in 19.1% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-(difluoromethyl)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.06 (s, 1H), 7.97-7.65 (m, 1H), 7.57-7.51 (m, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.17 (d, J=4.8 Hz, 2H), 5.83 (br. s., 1H), 4.62 (br. s., 1H), 3.83 (br. s., 1H), 3.57 (d, J=11.7 Hz, 1H), 3.44 (d, J=9.2 Hz, 4H), 2.68 (d, J=10.6 Hz, 1H), 2.53 (br. s., 3H), 1.94-1.58 (m, 9H), 1.53 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.07 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 678.3.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (0.084 g) in tetrahydrofuran (2 ml) were added sodium iodide (0.035 g) and phenylisocyanate (0.038 g). The mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, 1% aqueous Na2S2O3 solution and again with water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.071 g) as a colorless solid. MS: 519.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.110 mol) prepared in the previous step in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared in Preparation 14 and WSC.HCl (32 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (18 mg).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:1]([NH:5][C:6]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use butylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (92% yield). 1H NMR (500 MHz, CDCl3) δ 7.84, 7.74, 7.63, 7.56, 7.36, 7.08, 4.00-4.07, 3.88-3.94, 3.54-3.66, 3.42-3.46, 3.27-3.36, 1.51-1.57, 1.30-1.40, 0.89. MS (ES+) m/z 451 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:20])[CH:7]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:20]=[C:8]1[CH:7]=[C:6]([C:4]([NH:22][NH2:23])=[O:3])[CH:11]=[CH:10][N:9]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: NN
Reactant: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c(=O)c1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
The title compound of example 19.1 (9.5 g, 32 mmol) was stirred in ethanol (100 mL) at 78° C. Hydrazine hydrate (7.8 mL, 159.7 mmol) was added and the reaction mixture was stirred at 78° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was stirred in diethyl ether and filtered to give a yellow solid (8.5 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(C(OC)C(=O)O)c(O)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(O)c1

Procedure:
(RS)-(2-Hydroxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide. Orange amorphous solid. MS 327.3 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCC(CC)c1ccc(C#N)c2nc(Cl)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C#N)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 120 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (250 mg, 0.957 mmol), 2-bromo-4-chlorophenol (595 mg, 2.87 mmol), potassium carbonate (397 mg, 2.87 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120° C. for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (134 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:21]([C:22]([O:24]C)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C1Cc2ccccc2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1Cc2ccccc2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(3,5-Dichlorobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, methyl ester (100 mg, 0.25 mmol) was dissolved in 0.625 mL of MeOH and 0.625 mL of a 0.4 N solution of NaOH in MeOH was added. The resulting mixture was stirred overnight at rt. Volatiles were removed in vacuo and the residue was partitioned between 5% citric acid and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2X). The combined organic extracts were washed with brine, and dried over anhydrous Na2SO4. The residue obtained after filtration and evaporation of volatiles was purified by flash column chromatography on silica gel eluted with mixtures of CH2Cl2 and MeOH to afford N-(3,5 -dichlorobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (85 mg) as a white foam, homogeneous by TLC (9:1 CH2Cl2:MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:13]1[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1.B(Br)(Br)Br.ClCCl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:13]1[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1
Reactant: COc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
10.3 g (28.6 mmol) of 3-(2-chloro-4-methoxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 150 ml of dichloromethane, and 30 ml (90 mmol) of a 3N boron tribromide/dichloromethane solution was dropwise added thereto under cooling in a dry ice-acetone bath. The temperature was raised to room temperature, followed by stirring for 2 hours. Then, the mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with water and a saturated sodium hydrogencarbonate aqueous solution and then dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure to obtain 8.0 g (yield: 80%) of the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][C:17]1=[O:23].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[O:23]=[C:17]1[CH:18]=[C:19]([C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:20][CH2:21][NH:16]1
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: O=C1CCNC(=O)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1C=C(c2c(-c3ccccc3)nn3ccccc23)CCN1
Temperature: 135 °C

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine (0.50 g, 2,4-piperidinedione (0.292 g), concentrated sulfuric acid (1 drop) and acetic acid (0.5 ml) was heated at 135° C. for 13.5 hours. A saturated aqueous solution of sodium hydrogen carbonate (20 ml) was added to the reaction mixture and the mixture was extracted with chloroform (20 ml×2). The combined extract was washed with a saturated aqueous solution of sodium chloride (20 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethyl acetate (9:1) and recrystallized from ethyl acetate to give crystals of 3-(2-oxo-1,2,5,6-tetrahydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[S:2]1[C:6]2[CH2:7][N:8]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(s1)CNCC2
Reactant: O=C(O)CCCCCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCc1ccccc1)N1CCc2ccsc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.272 g (1.548 mmol) of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, 0.33 g (1.7 mmol) of 6-phenylhexanoic acid and 0.86 ml (6.2 mmol) of triethylamine in 30 ml of dichloromethane, 0.28 ml (1.9 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)[CH:14]=[CH:15][CH:16]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]>[Pd]>[NH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH:2]([CH3:1])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1cccc(CCNC(=O)OCc2ccccc2)c1
Agent: [Pd]
Product: CC(CNS(=O)(=O)C(C)C)c1cccc(CCN)c1
Yield: 100.2 %

Procedure:
Scheme Va, step B: N-{2-[3-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]ethyl}(phenylmethoxy)carboxamide (0.84 g, 2 mmol) and 10% palladium on carbon (0.5 g, 60 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, {2-[3-(2-aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, (0.57 g, 100%) as colorless oil. Electron spray M.S. 285 (M*+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H]1CCC[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 75 °C
Yield: 91.3 %

Procedure:
To a suspension of (1S,3R)-3-aminocyclohexanol (5 g, 43.4 mmol; prepared as described in Tetrahedron: Asymmetry 15 (2004) 2051-2056) and sodium bicarbonate (12.03 g, 143 mmol) in ethanol (100 mL) was added (chloromethyl)benzene (15.01 mL, 130 mmol) at room temperature. The reaction mixture was heated at 75° C. overnight. Upon completion of the reaction as indicated by LCMS and TLC the reaction mixture was filtered and the filtrate concentrated. The residue was then dissolved in DCM (250 mL) and washed with aqueous sodium hydroxide solution (1N, 2×100 mL) and brine (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (0%-80% ethyl acetate in hexanes) to yield (1S,3R)-3-(dibenzylamino)cyclohexanol (11.70 g, 91%) as a thick yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.37 (m, 8H), 7.17-7.22 (m, 2H), 4.56 (d, J=4.30 Hz, 1H), 3.57 (s, 4H), 3.16-3.26 (m, 1H), 2.41 (tt, J=3.17, 11.86 Hz, 1H)), 1.99-2.06 (m, 1H), 1.72 (d, J=8.20 Hz, 2H), 1.63-1.69 (m, 1H), 1.18-1.28 (m, 2H), 0.98 (t, 2H); MS (ESI) m/z 296.4 [M+1]+.