Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9]([OH:11])=[O:10])[CH3:2].[N:12]1([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>[OH-].[Na+]>[C:9](=[O:11])=[O:10].[CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:25][CH:24]=1)[CH3:2]
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2)cc1
Product: O=C=O

Procedure:
In a manner similar to that described in Example IA react 5-ethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid and 4-(1H-imidazol-1-yl)benzoic acid, dissolve the crude free base in aqueous sodium hydroxide and reprecipitate with carbon dioxide to produce the title compound.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([O:16]S(C1C=CC=CC=1)(=O)=O)[CH2:5][CH2:6][CH2:7]CCCCCCCC.[Na].[CH2:27](N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O>[C:1]([O:16][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:3])[CH:2]=[CH2:27]
Reactant: C1CO1
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na]
Solvent: O
Product: C=CC(=O)OCCCC

Procedure:
80 g of water, 2 g of a 40.7% by weight aqueous solution of partially sulphated, ethoxylated nonylphenol containing 25 units of ethylene oxide, 3 g of a 20% by weight aqueous solution of sodium dodecylbenzenesulphonate and 60 mg of ethylenediaminetetraacetic acid (EDTA) are mixed in a beaker.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=S)=[CH:38][C:30]=1[O:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:43]([NH:42][C:39]5[CH:40]=[CH:41][C:29]([Cl:28])=[C:30]([O:31][CH2:32][CH:33]6[CH2:37][CH2:36][CH2:35][O:34]6)[CH:38]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Reactant: S=C=Nc1ccc(Cl)c(OCC2CCCO2)c1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCCO5)c4)nc3c2)ccn1

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step E, 162 mg, 0.438 mmol) in CH3CN (20 mL) and DMF (2 mL) was added 2-(2-chloro-5-isothiocyanato-phenoxymethyl)-tetrahydro-furan (112 mg, 0.417 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1 N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound as a yellow solid. MS(MH+)=606.3; Calc'd 605.24 for C32H36ClN5O5.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][OH:34])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OCCN1CCNCC1
Agent: OC1CCNC1
Product: OCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-(2′-hydroxyethyl)piperazine. A yellow solid 137 was obtained (0.034 g, 67%). 1H-NMR (CDCl3, 400 MHz) δ 2.65–3.20 (br m, 4H), 3.24 (br m, 2H), 3.42–3.54 (m, 2H), 4.06 (br m, 2H), 4.05–4.18 (br m, 2H), 4.28–4.34 (m, 4H), 6.88 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.02–7.06 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=5.9 Hz, 1H); MS (APCI) m/z 518 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:14][CH2:13][CH2:12][O:6]1
Reactant: OCCO
Reactant: O=C(CCCCl)c1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: ClCCCC1(c2cccs2)OCCO1
Yield: 97.3 %

Procedure:
Add 4-chloro-1-thiophen-2-yl-butan-1-one (10 g, 53 mmol), ethylene glycol (8.14 g, 131.2 mmol) and p-toluene sulfonic acid (362 mg, 1.6 mmol) to benzene (150 mL) and heat at reflux for 16 h under a water trap. Cool the reaction to RT and wash with 1 N NaOH solution (100 mL) and brine (150 mL). Dry (sodium sulfate) and concentrate to give the title product as a dark oil (12 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([Cl:8])=[O:7].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(OCC)C>C(Cl)Cl>[ClH:8].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=3)[CH2:23][CH2:22]2)=[CH:27][CH:28]=1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(OC)cc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
71.9 g of 3,5-dimethoxybenzoyl chloride dissolved in 700 ml of CH2Cl2 are added at room temperature to a solution of 80.5 g of 1-(p-chlorophenethyl)-piperazine in 1200 ml of CH2Cl2. The rate of addition is so selected that the exothermic reaction remains under control. The whole is then stirred for 15 minutes under reflux and then for a further 1 hour at room temperature. After the addition of 1900 ml of diethyl ether, the whole is stirred for 15 minutes and then the resulting precipitate is filtered off with suction. The precipitate is dissolved in 3.3 litres of boiling ethanol. The colourless precipitate that is obtained after cooling to approximately 20° is filtered off with suction, washed with a little ethanol and dried under a high vacuum for 16 hours at 80°. 1-p-chlorophenethyl-4-(3,5-dimethoxybenzoyl)-piperazine hydrochloride having a melting point of 244°-246° (decomposition) is thus obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg+].[Br-].CO.[BH4-].[Na+]>C1COCC1>[NH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:10][C:11]=1[CH3:17])[CH3:18]
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C#N
Reactant: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C(C)N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butyl-4-cyano-3-methylbenzenesulfonamide (0.4861 g) in THF (19 ml) at 0° C. was treated with MeMgBr (1.4 M in THF, 4.13 ml). The reaction mixture was heated at reflux overnight. After cooling, the reaction was quenched with MeOH and sodium borohydride (3 eq) was added. The mixture was stirred at 0° C. for 1 h, warmed to room temperature and stirred for 4 hours. The reaction mixture was then quenched with H2O, stirred overnight and concentrated to give a yellow solid. The solid was partitioned between EtOAc/H2O and the organic layer was separated, dried (MgSO4) and concentrated to give a yellow oil. The oil was purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.3403 g 4-(1-aminoethyl)-N-tert-butyl-3-methylbenzenesulfonamide as white powder after lyophilization.
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40](Cl)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40]([NH:1][C:2]3([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]3)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)Cl
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)c(F)c3)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.50 g (80.32 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 8.13 g (80.32 mmol) of triethylamine were dissolved in 280 ml of dichloromethane. 21.70 g (73.02 mmol) of (4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)acetyl chloride (Example 4AA), dissolved in 280 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 37.05 g (98% of theory) of the title compound as a beige powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:8]=[C:9]([C:11]([C:14]#N)([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+].[OH2:35]>CCO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[C:14]([OH:35])=[O:33])[CH:8]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C#N)c2)n1CC1CCCCC1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C(=O)O)c2)n1CC1CCCCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of compound 45 (720 mg, 1.58 mmol) and NaOH (5.0 g, 127 mmol) in a mixture of EtOH (15 mL) and H2O (10 mL) was stirred at reflux for 3 d, cooled to rt, concentrated and redissolved in H2O (30 mL) and acidified with 1N HCl solution to pH=6. The formed solid was collected by filtration, washed with EA and dried in vacuum to give the title compound 46 (750 mg, 100%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.63-0.65 (2H, m), 0.90-0.95 (3H, m), 1.22-1.25 (3H, m), 1.30 (9H, s), 1.45 (3H, m), 1.49 (6H, s), 2.43 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.29 (1H, s), 6.92 (2H, s), 7.08 (1H, s), 7.23 (1H, s), 7.34 (1H, s), 12.38 (1H, s). MS Calcd.: 474; MS Found: 475 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:25])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]2)[CH2:11][CH2:10]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>C(#N)C>[CH3:25][C:15]1([N:12]2[CH2:13][CH2:14][CH:9]([N:8]3[C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH:1][C:26]3=[O:27])[CH2:10][CH2:11]2)[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
A solution of ethyl 3-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-3-methyl-pyrrolidine-1-carboxylate (600 mg, 1.70 mmol) in anhydrous acetonitrile (30 mL) was added with 1,1′-carbonyldiimidazole (551.92 mg, 3.40 mmol) and stirred at room temperature for 12 h. The solvent was removed in vacuo; the residue was dissolved in dichloromethane (60 mL), washed with water and brine and dried over anhydrous MgSO4. Concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol) to afford the title compound as a white solid (45 mg). 1H NMR (CD3OD, 400 MHz): δ 4.15 (q, 2H), 3.62-3.51 (m, 2H), 2.41 (m, 2H), 3.22 (m, 1H), 3.19 (brd, 1H), 2.99 (m, 3H), 2.76 (brs, 1H), 2.45 (m, 3H), 2.01-1.82 (m, 6H), 1.74 (brd, 1H), 1.65 (brd, 1H), 1.45 (m, 4H), 1.25 (t, 3H), 1.12 (s, 3H). MS (M+1): 379.18.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C1N=CN([C:31]([N:33]2[CH:37]=[N:36]C=C2)=[O:32])C=1.C[N:39](C=O)C>>[C:37]([NH:33][C:31]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=[O:32])(=[NH:36])[NH2:39]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(CN)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(CNC(=O)NC(=N)N)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (303 mg) was mixed with DMF (5 ml), and CDI (188 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Guanidine hydrochloride (170 mg) and sodium hydride (55% suspended in oil) (77 mg) were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain ethyl 1-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperidine-4-carboxylate (74 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14]Br>CC(C)=O.O>[CH3:11][O:12][CH2:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COCCBr
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
3-Nitrophenol (25 g, 0.18 mol), 2-bromoethyl methyl ether (17 ml, 25 g, 0.18 mol) potassium carbonate (25.0 g, 0.18 mol) in acetone (150 ml) were heated under reflux for 72 h. The suspension was dissolved in water and extracted with ether. The extracts were washed with 2N sodium carbonate, water and saturated brine, dried (K2CO3), and concentrated, to give the title compound (Intermediate 50) as a brown oil (35.12 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([Li])CCC.CCCCCC>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Reactant: C1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 7.32 g. (0.02mole) is dissolved in 100 ml. of dry piperidine. To this solution is added slowly 25 ml. of a 1.6M solution of butyl lithium in hexane (0.04 mole) under anhydrous conditions and then stirred and refluxed for 8 hours under anhydrous conditions. The reaction is cooled and poured into 500 ml. of benzene and extracted 6 times with 100 ml. of water. The benzene is dried over anhydrous MgSO4, filtered, and the benzene removed on a rotary evaporator leaving 1-methyl-4-(10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine as an oil which still has some solvent in it.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH:13]([NH:18]C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=1)=[O:7])[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH:13]([NH2:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(C(N)CC(C)C)no1

Procedure:
A solution of 3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-3-oxo-propionic acid ethyl ester (1.4 g, 3.9 mmol) in 4M HCl in dioxane (5 ml) was stirred at room temperature. After 3 h the mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid. MS [M+1]+ 269.0.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[C:21]([C:22]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:10][N:9]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[C:16]([S:15][CH2:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:13]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: CCCN=C=O
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Yield: 33 %

Procedure:
n-Propyl isocyanate (20 mg, 0.23 mmol) was added to a solution of 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (The free base of Compound No. 3-1, 28 mg, 0.077 mmol) in N,N-dimethylformamide (0.60 mL) at room temperature, and the mixture was stirred for 4 hours at 80° C. Ethyl acetate (10 mL) was added to the reaction mixture, the whole was washed with water (15 mL) and brine (15 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 12 mg of the target compound as a colorless solid(Yield 33%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:19][C@H:18]([NH2:20])[C@H:17]([CH3:21])[CH2:16][C@@H:15]1[NH2:22]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C@H:18]3[CH2:19][C@@H:14]([CH3:13])[C@@H:15]([NH2:22])[CH2:16][C@H:17]3[CH3:21])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1N
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1Nc1ccnc2cc(Cl)ccc12
Temperature: 150 °C

Procedure:
A mixture of 4,7-dichloroquinoline (500 mg, 2.5 mmol) and (1S,2R,4S,5R)-2,5-dimethylcyclohexane-1,4-diamine (750 mg, 5.2 mmol) was heated at 150° C. for 5 hours, cooled to room temperature, and flash chromatographed through silica gel column with dichloromethane and methanol (3:1 ratio by vol) to provide the titled compound. MS(ESI(+)Q1MS m/z 304 (M+H)+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CS([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:20]([CH3:19])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Cc1ccc(Br)cn1
Reaction time: 1 h
Yield: 80 %

Procedure:
Commercially available (5-bromopyridin-2-yl)methanol (2000 mg, 10.6 mmol) in CH2Cl2 (20 mL) is treated with di-isopropylethylamine (2.8 mL, 16 mmol) and methane sulfonylchloride (1.0 mL, 12.8 mmol) stirred for 1 hour and the solvent removed under reduced pressure. The crude solid is dissolved in dimethylformamide (10 mL) and treated with sodium methanesulfinate (4.39 g, 42.5 mmol), 18-crown-6 (580 mg, 2.13 mmol) and the mixture stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine(20 mL), dried over MgSO4, filtered, concentrated, and the crude material purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (2.12 g): m/z (Cl) 251 [M+H].
Reaction SMILES: N[C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cu](C#N)[C:19]#[N:20].N(OCCC(C)C)=O>C(#N)C.C(OCC)(=O)C>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([C:19]#[N:20])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: N#C[Cu]C#N
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.02 mmol) in acetonitrile (50 mL) was added copper cyanide (0.36 g, 4.04 mmol) and isoamyl nitrite (0.54 mL, 4.04 mmol). The reaction mixture was heated to reflux for 1 hour, cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford N-benzyl-2-cyano-4-methylthiazole-5-carboxamide in 29% yield (0.15 g): 1H NMR (300 MHz, CDCl3) δ 7.48-7.18 (m, 5H), 6.87 (br s, 1H), 4.49 (d, J=5.8 Hz, 2H), 2.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1
Reaction time: 18 h
Yield: 43.4 %

Procedure:
To compound 148 (0.27 g, 0.42 mmol) in dichloromethane (75 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with 1M NaOH, brine, dried (anhydrous MgSO4), Filtered, and concentrated. The residue was triturated with ether to afford title compound 149 (0.10 g, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H), 9.23 (s, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.51 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=12.9, 2.3 Hz, 1H), 7.46 (t, J=9.0 Hz, 1H), 7.29-7.26 (m, 1H), 6.65 (d, J=5.5 Hz, 1H), 6.55 (s, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 2.36 (s, 3H). MS (m/z): 549.1 (M+H).